Science.gov

Sample records for cytokines

  1. Hematopoietic cytokines.

    PubMed

    Metcalf, Donald

    2008-01-15

    The production of hematopoietic cells is under the tight control of a group of hematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating the various responses-survival, proliferation, differentiation commitment, maturation, and functional activation. Individual cytokines can be lineage specific or can regulate cells in multiple lineages, and for some cell types, such as stem cells or megakaryocyte progenitors, the simultaneous action of multiple cytokines is required for proliferative responses. The same cytokines control basal and emergency hematopoietic cell proliferation. Three cytokines, erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, have now been in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. In this little review, discussion will be restricted to those cytokines well established as influencing the production of hematopoietic cells and will exclude newer candidate regulators and those active on lymphoid cells. As requested, this account will describe the cytokines in a historical manner, using a sequential format of discovery, understanding, validation, and puzzlement, a sequence that reflects the evolving views on these cytokines over the past 50 years.

  2. [Cytokines in bone diseases. What is cytokine?].

    PubMed

    Murakami, Yousuke; Kohsaka, Hitoshi

    2010-10-01

    Cytokines have an essential role for cell-cell communication. They can regulate cell proliferation, differentiation, survival, and function. Interaction of cell surface receptor with cytokines is necessary for control of physiological responses. Activation of cytokine receptors transduces specific signal in the receptor-expressing cells, resulting that cytokines can regulate specific cell population. Thus, cytokines contribute directly or indirectly to morphogenesis, host defense and immune response, play critical roles for homeostasis and development.

  3. Cytokines in Drosophila immunity.

    PubMed

    Vanha-Aho, Leena-Maija; Valanne, Susanna; Rämet, Mika

    2016-02-01

    Cytokines are a large and diverse group of small proteins that can affect many biological processes, but most commonly cytokines are known as mediators of the immune response. In the event of an infection, cytokines are produced in response to an immune stimulus, and they function as key regulators of the immune response. Cytokines come in many shapes and sizes, and although they vary greatly in structure, their functions have been well conserved in evolution. The immune signaling pathways that respond to cytokines are remarkably conserved from fly to man. Therefore, Drosophila melanogaster, provides an excellent platform for studying the biology and function of cytokines. In this review, we will describe the cytokines and cytokine-like molecules found in the fly and discuss their roles in host immunity.

  4. Cytokines in sleep regulation.

    PubMed

    Krueger, J M; Takahashi, S; Kapás, L; Bredow, S; Roky, R; Fang, J; Floyd, R; Renegar, K B; Guha-Thakurta, N; Novitsky, S

    1995-01-01

    The central thesis of this essay is that the cytokine network in brain is a key element in the humoral regulation of sleep responses to infection and in the physiological regulation of sleep. We hypothesize that many cytokines, their cellular receptors, soluble receptors, and endogenous antagonists are involved in physiological sleep regulation. The expressions of some cytokines are greatly amplified by microbial challenge. This excess cytokine production during infection induces sleep responses. The excessive sleep and wakefulness that occur at different times during the course of the infectious process results from dynamic changes in various cytokines that occur during the host's response to infectious challenge. Removal of any one somnogenic cytokine inhibits normal sleep, alters the cytokine network by changing the cytokine mix, but does not completely disrupt sleep due to the redundant nature of the cytokine network. The cytokine network operates in a paracrine/autocrine fashion and is responsive to neuronal use. Finally, cytokines elicit their somnogenic actions via endocrine and neurotransmitter systems as well as having direct effects neurons and glia. Evidence in support of these postulates is reviewed in this essay.

  5. Cytokines in psoriasis.

    PubMed

    Baliwag, Jaymie; Barnes, Drew H; Johnston, Andrew

    2015-06-01

    Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The disease is characterized by red, scaly and well-demarcated skin lesions formed by the hyperproliferation of epidermal keratinocytes. This hyperproliferation is driven by cytokines secreted by activated resident immune cells, an infiltrate of T cells, dendritic cells and cells of the innate immune system, as well as the keratinocytes themselves. Psoriasis has a strong hereditary character and has a complex genetic background. Genome-wide association studies have identified polymorphisms within or near a number of genes encoding cytokines, cytokine receptors or elements of their signal transduction pathways, further implicating these cytokines in the psoriasis pathomechanism. A considerable number of inflammatory cytokines have been shown to be elevated in lesional psoriasis skin, and the serum concentrations of a subset of these also correlate with psoriasis disease severity. The combined effects of the cytokines found in psoriasis lesions likely explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularization and skin inflammation. Thus, understanding which cytokines play a pivotal role in the disease process can suggest potential therapeutic targets. A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease. Here we review a number of key cytokines implicated in the pathogenesis of psoriasis.

  6. Insights into cytokine-receptor interactions from cytokine engineering.

    PubMed

    Spangler, Jamie B; Moraga, Ignacio; Mendoza, Juan L; Garcia, K Christopher

    2015-01-01

    Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine-receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4.

  7. Recombinant cytokines from plants.

    PubMed

    Sirko, Agnieszka; Vaněk, Tomas; Góra-Sochacka, Anna; Redkiewicz, Patrycja

    2011-01-01

    Plant-based platforms have been successfully applied for the last two decades for the efficient production of pharmaceutical proteins. The number of commercialized products biomanufactured in plants is, however, rather discouraging. Cytokines are small glycosylated polypeptides used in the treatment of cancer, immune disorders and various other related diseases. Because the clinical use of cytokines is limited by high production costs they are good candidates for plant-made pharmaceuticals. Several research groups explored the possibilities of cost-effective production of animal cytokines in plant systems. This review summarizes recent advances in this field.

  8. Cytokines and Blastocyst Hatching.

    PubMed

    Seshagiri, Polani B; Vani, Venkatappa; Madhulika, Pathak

    2016-03-01

    Blastocyst implantation into the uterine endometrium establishes early pregnancy. This event is regulated by blastocyst- and/or endometrium-derived molecular factors which include hormones, growth factors, cell adhesion molecules, cytokines and proteases. Their coordinated expression and function are critical for a viable pregnancy. A rate-limiting event that immediately precedes implantation is the hatching of blastocyst. Ironically, blastocyst hatching is tacitly linked to peri-implantation events, although it is a distinct developmental phenomenon. The exact molecular network regulating hatching is still unclear. A number of implantation-associated molecular factors are expressed in the pre-implanting blastocyst. Among others, cytokines, expressed by peri-implantation blastocysts, are thought to be important for hatching, making blastocysts implantation competent. Pro-inflammatory (IL-6, LIF, GM-CSF) and anti-inflammatory (IL-11, CSF-1) cytokines improve hatching rates; they modulate proteases (MMPs, tPAs, cathepsins and ISP1). However, functional involvement of cytokines and their specific mediation of hatching-associated proteases are unclear. There is a need to understand mechanistic roles of cytokines and proteases in blastocyst hatching. This review will assess the available knowledge on blastocyst-derived pro-inflammatory and anti-inflammatory cytokines and their role in potentially regulating blastocyst hatching. They have implications in our understanding of early embryonic loss and infertility in mammals, including humans.

  9. Cytokines and autoimmunity.

    PubMed Central

    Cavallo, M G; Pozzilli, P; Thorpe, R

    1994-01-01

    Although the immunopathology of most autoimmune diseases has been well defined, the mechanisms responsible for the breakdown of self-tolerance and which lead to the development of systemic and organ-specific autoaggression are still unclear. Evidence has accumulated which supports a role for a disregulated production of cytokines by leucocytes and possibly other cells in the pathogenesis of some autoimmune diseases. However, due to the complexity and heterogeneity of cytokine effects in the regulation of the immune response, it is difficult to determine whether abnormalities in the patterns of cytokine production are primary or secondary to the pathological process. Confusion is also caused by the fact that the biological activities of cytokines are multiple and often overlapping, and consequently it is difficult to focus on a unique effect of any one cytokine. Characterization of the potential and actual involvement of cytokines is important not only for a better understanding of the pathogenesis of autoimmune conditions, but particularly because of the implications for the development of immunotherapeutic strategies for the prevention and treatment of the diseases. PMID:8149655

  10. Cytokines in rheumatoid arthritis.

    PubMed

    Vervoordeldonk, Margriet J B M; Tak, Paul P

    2002-06-01

    Rheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation that leads to the destruction of cartilage and bone. In the last decade, there was a lot of successful research in the field of cytokine expression and regulation. It has become clear that pro- and anti-inflammatory cytokines, derived predominantely from cells of macrophage lineage, play a major role in the initiation and perpetuation of the chronic inflammatory process in the RA synovial membrane. Monokines are abundant in rheumatoid synovial tissue, whereas low amounts of lymphokines are found. The involvement of pro-inflammatory cytokines, particularly interleukin (IL)-1 and tumor necrosis factor-alpha, in the pathogenesis of RA is well accepted. Recent data provide evidence that the pro-inflammatory cytokine IL-18 plays a crucial role in the development and sustenance of inflammatory joint diseases. There also appears to be a compensatory anti-inflammatory response in RA synovial membrane. It has become clear in the last few years that T cell-derived cytokines expressed preferentially by Th1 cells contribute to joint destruction and inflammation in RA. However, products from Th2 cells may be protective.

  11. [Cytokines and asthma].

    PubMed

    Gani, F; Senna, G; Piglia, P; Grosso, B; Mezzelani, P; Pozzi, E

    1998-10-01

    Asthma is a chronic inflammatory lung disease in which eosinophils are one of the most important involved cells. These cells accumulate in the lung because of cytokines, which are able to regulate cellular responses. The role of cytokines is well known in allergic asthma: IL4, IL5, IL3, GMCSF are the principally cytokine involved. IL4 regulate IgE synthesis while IL5, (and IL3) cause the activation and accumulation of eosinophils. In non allergic asthma, whilst only IL5 seemed to be important recent data, shows that also IL4 plays an important role. Therefore nowadays no relevant difference seems to exist between allergic and non allergic asthma; instead the primer is different: the allergen in allergic asthma and often an unknown factor in the non allergic asthma. Recently other cytokines have been proved to play a role in the pathogenesis of asthma. IL8 is chemotactic not only for neutrophils but also for eosinophils and might cause chronic inflammation in severe asthma. IL13 works like IL4, while RANTES seems to be a more important chemotactic agent than IL5. Finally IL10, which immunoregulates T lymphocyte responses, may reduce asthma inflammation. In conclusion cytokine made us to learn more about the pathogenesis of asthma even if we do not yet know when and how asthma inflammation develops.

  12. Cytokines and anti-cytokines as therapeutics--an update.

    PubMed

    Tayal, Vandana; Kalra, Bhupinder Singh

    2008-01-28

    Cytokines which comprise of a family of proteins--interleukins, lymphokines, monokines, interferons, and chemokines, are important components of the immune system. They act in concert with specific cytokine inhibitors and soluble cytokine receptors to regulate the human immune response. Their physiologic role in inflammation and pathologic role in systemic inflammatory states are now well recognized. An imbalance in cytokine production or cytokine receptor expression and/or dysregulation of a cytokine process contributes to various pathological disorders. Research is progressing rapidly in the area of cytokines and their therapeutic targets, the two major therapeutic modalities being the administration of purified recombinant cytokines and the use of their antagonists in various inflammatory disorders. However, given the large number of cytokines, it is disappointing that only relatively few can be used clinically. In the present article, we have made an attempt to review and present a glimpse of the history as well as up to date information that is pertinent to cytokines and anti-cytokine therapies in the treatment of cancer, autoimmune disorders and various other related diseases.

  13. Coordinate cytokine regulatory sequences

    DOEpatents

    Frazer, Kelly A.; Rubin, Edward M.; Loots, Gabriela G.

    2005-05-10

    The present invention provides CNS sequences that regulate the cytokine gene expression, expression cassettes and vectors comprising or lacking the CNS sequences, host cells and non-human transgenic animals comprising the CNS sequences or lacking the CNS sequences. The present invention also provides methods for identifying compounds that modulate the functions of CNS sequences as well as methods for diagnosing defects in the CNS sequences of patients.

  14. Cytokine therapy for craniosynostosis.

    PubMed

    Mooney, Mark P; Moursi, Amr M; Opperman, Lynne A; Siegel, Michael I

    2004-03-01

    The birth prevalence of craniosynostosis (premature suture fusion) is 300-500 per 1,000,000 live births. Surgical management involves the release of the synostosed suture. In many cases, however, the suturectomy site rapidly reossifies, further restricts the growing brain and alters craniofacial growth. This resynostosis requires additional surgery, which increases patient morbidity and mortality. New findings in bone biology and molecular pathways involved with suture fusion, combined with novel tissue engineering techniques, may allow the design of targeted and complementary therapies to decrease complications inherent in high-risk surgical procedures. This paper selectively reviews recent advances in i) identifying genetic mutations and the aetiopathogenesis of a number of craniosynostotic conditions; ii) cranial suture biology and molecular biochemical pathways involved in suture fusion; and iii) the design, development and application of various vehicles and tissue engineered constructs to deliver cytokines and genes to cranial sutures. Such biologically based therapies may be used as surgical adjuncts to rescue fusing sutures or help manage postoperative resynostosis.

  15. Cytokine receptors and hematopoietic differentiation.

    PubMed

    Robb, L

    2007-10-15

    Colony-stimulating factors and other cytokines signal via their cognate receptors to regulate hematopoiesis. In many developmental systems, inductive signalling determines cell fate and, by analogy with this, it has been postulated that cytokines, signalling via their cognate receptors, may play an instructive role in lineage specification in hematopoiesis. An alternative to this instructive hypothesis is the stochastic or permissive hypothesis. The latter proposes that commitment to a particular hematopoietic lineage is an event that occurs independently of extrinsic signals. It predicts that the role of cytokines is to provide nonspecific survival and proliferation signals. In this review, we look at the role of cytokine receptor signalling in hematopoiesis and consider the evidence for both hypotheses. Data from experiments that genetically manipulate receptor gene expression in vitro or in vivo are reviewed. Experiments in which cytokine receptors were installed in multipotential cells showed that, in some cases, stimulation with the cognate ligand could lead to alterations in lineage output. The creation of genetically manipulated mouse strains demonstrated that cytokine receptors are required for expansion and survival of single lineages but did not reveal a role in lineage commitment. We conclude that hematopoietic differentiation involves mainly stochastic events, but that cytokine receptors also have some instructive role.

  16. Mnk Kinases in Cytokine Signaling and Regulation of Cytokine Responses

    PubMed Central

    Joshi, Sonali; Platanias, Leonidas C.

    2013-01-01

    The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed. PMID:23710261

  17. The Function of Fish Cytokines

    PubMed Central

    Zou, Jun; Secombes, Christopher J.

    2016-01-01

    What is known about the biological activity of fish cytokines is reviewed. Most of the functional studies performed to date have been in teleost fish, and have focused on the induced effects of cytokine recombinant proteins, or have used loss- and gain-of-function experiments in zebrafish. Such studies begin to tell us about the role of these molecules in the regulation of fish immune responses and whether they are similar or divergent to the well-characterised functions of mammalian cytokines. This knowledge will aid our ability to determine and modulate the pathways leading to protective immunity, to improve fish health in aquaculture. PMID:27231948

  18. Cytokines and cytokine-specific therapy in asthma.

    PubMed

    Desai, Dhananjay; Brightling, Christopher

    2012-01-01

    Asthma is increasing in prevalence worldwide. It is characterized by typical symptoms and variable airway obstruction punctuated with episodes of worsening symptoms known as exacerbations. Underlying this clinical expression of disease is airway inflammation and remodeling. Cytokines and their networks are implicated in the innate and adaptive immune responses driving airway inflammation in asthma and are modulated by host-environment interactions. Asthma is a complex heterogeneous disease, and the paradigm of Th2 cytokine-mediated eosinophilic inflammation as a consequence of allergic sensitization has been challenged and probably represents a subgroup of asthma. Indeed, as attention has switched to the importance of severe asthma, which represents the highest burden both to the patient and health care provider, there is an increasing recognition of inflammatory subphenotypes that are likely to be driven by different cytokine networks. Interestingly, these networks may be specific to aspects of clinical expression as well as inflammatory cell profiles and therefore present novel phenotype-specific therapeutic strategies. Here, we review the breadth of cytokines implicated in the pathogenesis of asthma and focus upon the outcomes of early clinical trials conducted using cytokines or cytokine-blocking therapies.

  19. Circadian Rhythm in Cytokines Administration.

    PubMed

    Trufakin, Valery A; Shurlygina, Anna V

    2016-01-01

    In recent times, a number of diseases involving immune system dysfunction have appeared. This increases the importance of research aimed at finding and developing optimized methods for immune system correction. Numerous studies have found a positive effect in using cytokines to treat a variety of diseases, yet the clinical use of cytokines is limited by their toxicity. Research in the field of chronotherapy, aimed at designing schedules of medicine intake using circadian biorhythms of endogenous production of factors, and receptors' expression to the factors on the target cells, as well as chronopharmacodynamics and chronopharmacokinetics of medicines may contribute to the solution of this problem. Advantages of chronotherapy include a greater effectiveness of treatment, reduced dose of required drugs, and minimized adverse effects. This review presents data on the presence of circadian rhythms of spontaneous and induced cytokine production, as well as the expression of cytokine receptors in the healthy body and in a number of diseases. The article reviews various effects of cytokines, used at different times of the day in humans and experimental animals, as well as possible mechanisms underlying the chronodependent effects of cytokines. The article presents the results of chronotherapeutic modes of administering IL-2, interferons, G-CSF, and GM-CSF in treatment of various types of cancer as well as in experimental models of immune suppression and inflammation, which lead to a greater effectiveness of therapy, the possibility of reducing or increasing the dosage, and reduced drug toxicity. Further research in this field will contribute to the effectiveness and safety of cytokine therapy.

  20. Agents to reduce cytokine storm

    PubMed Central

    Gerlach, Herwig

    2016-01-01

    The increasing insight into pathomechanisms of dysregulated host response in several inflammatory diseases led to the implementation of the term “cytokine storm” in the literature more than 20 years ago. Direct toxic effects as well as indirect immunomodulatory mechanisms during cytokine storm have been described and were the basis for the rationale to use several substances and devices in life-threatening infections and hyperinflammatory states. Clinical trials have been performed, most of them in the form of minor, investigator-initiated protocols; major clinical trials focused mostly on sepsis and septic shock. The following review tries to summarize the background, pathophysiology, and results of clinical investigations that had implications for the development of therapeutic strategies and international guidelines for the management of hyperinflammation during syndromes of cytokine storm in adult patients, predominantly in septic shock. PMID:28105327

  1. Agents to reduce cytokine storm.

    PubMed

    Gerlach, Herwig

    2016-01-01

    The increasing insight into pathomechanisms of dysregulated host response in several inflammatory diseases led to the implementation of the term "cytokine storm" in the literature more than 20 years ago. Direct toxic effects as well as indirect immunomodulatory mechanisms during cytokine storm have been described and were the basis for the rationale to use several substances and devices in life-threatening infections and hyperinflammatory states. Clinical trials have been performed, most of them in the form of minor, investigator-initiated protocols; major clinical trials focused mostly on sepsis and septic shock. The following review tries to summarize the background, pathophysiology, and results of clinical investigations that had implications for the development of therapeutic strategies and international guidelines for the management of hyperinflammation during syndromes of cytokine storm in adult patients, predominantly in septic shock.

  2. Depression, cytokines, and pancreatic cancer

    PubMed Central

    Breitbart, William; Rosenfeld, Barry; Tobias, Kristen; Pessin, Hayley; Ku, Geoffrey Y.; Yuan, Jianda; Gibson, Christopher; Wolchok, Jedd

    2014-01-01

    Background To examine the relationships between cytokines, depression, and pancreatic cancer. Method 75 individuals were recruited from two New York City hospitals (a cancer center and a psychiatric hospital) and comprised 4 subgroups: patients with adenocarcinoma of the pancreas who did (n=17) and did not (n=26) have a diagnosis of Major Depressive Episode (MDE), and healthy participants with (n=7) and without (n=25) MDE. All individuals completed a battery of self-report measures. Sera was assayed using Meso Scale Discovery techniques to measure the following pro- and anti-inflammatory cytokines: IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12p70, IFN-gamma, TGF-beta, and TNF-alpha; we also calculated the IL-2/IL-4 ratio. Results Pancreatic cancer patients had significantly higher levels of IL-6 and IL-10, and significantly lower TGF-beta levels than healthy participants. When the sample was divided into those with and without MDE, the groups only differed with regard to serum IL-6 levels. No significant cancer×depression interaction effect was observed. Severity of depressive symptoms was also significantly correlated with IL-6, rs=.28, p=.02, while hopelessness was associated with IFN-alpha, rs=.34, p=.006. Pain, fatigue and sleep disturbance were associated with several of the cytokines assayed including IL-1beta (pain intensity), IL-4 (pain intensity and overall sleep quality), IL-12p70 (pain intensity), TGF-beta (fatigue intensity), but anxiety was not associated with any of the cytokines assayed. Conclusions This study demonstrated an association between depression and IL-6, but not with other cytokines. Moreover, IL-6 was not significantly associated with other measures of psychological distress (anxiety, hopelessness) or with symptom distress (pain, fatigue, sleep quality), although some cytokines assayed were associated with specific symptoms. The implications of these findings for the etiology and treatment of depression in pancreatic cancer

  3. Cytokine crowdsourcing: multicellular production of TH17-associated cytokines.

    PubMed

    Busman-Sahay, Kathleen O; Walrath, Travis; Huber, Samuel; O'Connor, William

    2015-03-01

    In the 2 decades since its discovery, IL-17A has become appreciated for mounting robust, protective responses against bacterial and fungal pathogens. When improperly regulated, however, IL-17A can play a profoundly pathogenic role in perpetuating inflammation and has been linked to a wide variety of debilitating diseases. IL-17A is often present in a composite milieu that includes cytokines produced by TH17 cells (i.e., IL-17F, IL-21, IL-22, and IL-26) or associated with other T cell lineages (e.g., IFN-γ). These combinatorial effects add mechanistic complexity and more importantly, contribute differentially to disease outcome. Whereas TH17 cells are among the best-understood cell types that secrete IL-17A, they are frequently neither the earliest nor dominant producers. Indeed, non-TH17 cell sources of IL-17A can dramatically alter the course and severity of inflammatory episodes. The dissection of the temporal regulation of TH17-associated cytokines and the resulting net signaling outcomes will be critical toward understanding the increasingly intricate role of IL-17A and TH17-associated cytokines in disease, informing our therapeutic decisions. Herein, we discuss important non-TH17 cell sources of IL-17A and other TH17-associated cytokines relevant to inflammatory events in mucosal tissues.

  4. Cytokines in human lung fibrosis.

    PubMed

    Martinet, Y; Menard, O; Vaillant, P; Vignaud, J M; Martinet, N

    1996-01-01

    Fibrosis is a pathological process characterized by the replacement of normal tissue by mesenchymal cells and the extracellular matrix produced by these cells. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in the area of derangement. The same sequence of events occurs in wound healing with normal granulation tissue and scar formation, but, while normal scar formation is very localized and transient, in contrast, in fibrosis, the repair process is exaggerated and usually widespread and can be chronic. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of three human fibrotic lung diseases, two diffuse [idiopathic pulmonary fibrosis (IPF), and the adult respiratory distress syndrome (ARDS)], and one focal (tumor stroma in lung cancer), has shown that several cytokines participate to the local injury and inflammatory reaction [interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha)], while other cytokines are involved in tissue repair and fibrosis [platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)]. A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches.

  5. Formulation and stability of cytokine therapeutics.

    PubMed

    Lipiäinen, Tiina; Peltoniemi, Marikki; Sarkhel, Sanjay; Yrjönen, Teijo; Vuorela, Heikki; Urtti, Arto; Juppo, Anne

    2015-02-01

    Cytokines are messenger proteins that regulate the proliferation and differentiation of cells and control immune responses. Interferons, interleukins, and growth factors have applications in cancer, autoimmune, and viral disease treatment. The cytokines are susceptible to chemical and physical instability. This article reviews the structure and stability issues of clinically used cytokines, as well as formulation strategies for improved stability. Some general aspects for identifying most probable stability concerns, selecting excipients, and developing stable cytokine formulations are presented. The vast group of cytokines offers possibilities for new biopharmaceuticals. The formulation approaches of the current cytokine products could facilitate development of new biopharmaceuticals.

  6. Cytokine determinants of viral tropism.

    PubMed

    McFadden, Grant; Mohamed, Mohamed R; Rahman, Masmudur M; Bartee, Eric

    2009-09-01

    The specificity of a given virus for a cell type, tissue or species - collectively known as viral tropism - is an important factor in determining the outcome of viral infection in any particular host. Owing to the increased prevalence of zoonotic infections and the threat of emerging and re-emerging pathogens, gaining a better understanding of the factors that determine viral tropism has become particularly important. In this Review, we summarize our current understanding of the central role of antiviral and pro-inflammatory cytokines, particularly the interferons and tumour necrosis factor, in dictating viral tropism and how these cytokine pathways can be exploited therapeutically for cancer treatment and to better counter future threats from emerging zoonotic pathogens.

  7. Cytokine Signature in Infective Endocarditis

    PubMed Central

    Araújo, Izabella Rodrigues; Ferrari, Teresa Cristina Abreu; Teixeira-Carvalho, Andréa; Campi-Azevedo, Ana Carolina; Rodrigues, Luan Vieira; Guimarães Júnior, Milton Henriques; Barros, Thais Lins Souza; Gelape, Cláudio Léo; Sousa, Giovane Rodrigo; Nunes, Maria Carmo Pereira

    2015-01-01

    Infective endocarditis (IE) is a severe disease with high mortality rate. Cytokines participate in its pathogenesis and may contribute to early diagnosis improving the outcome. This study aimed to evaluate the cytokine profile in IE. Serum concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-α were measured by cytometric bead array (CBA) at diagnosis in 81 IE patients, and compared with 34 healthy subjects and 30 patients with non-IE infections, matched to the IE patients by age and gender. Mean age of the IE patients was 47±17 years (range, 15–80 years), and 40 (50%) were male. The IE patients had significantly higher serum concentrations of IL-1β, IL-6, IL-8, IL-10 and TNF-α as compared to the healthy individuals. The median levels of IL-1β, TNF-α and IL-12 were higher in the IE than in the non-IE infections group. TNF-α and IL-12 levels were higher in staphylococcal IE than in the non-staphylococcal IE subgroup. There was a higher proportion of both low IL-10 producers and high producers of IL-1β, TNF-α and IL-12 in the staphylococcal IE than in the non-staphylococcal IE subgroup. This study reinforces a relationship between the expression of proinflammatory cytokines, especially IL-1β, IL-12 and TNF-α, and the pathogenesis of IE. A lower production of IL-10 and impairment in cytokine network may reflect the severity of IE and may be useful for risk stratification. PMID:26225421

  8. Cytokine-induced sickness behavior.

    PubMed

    Kelley, Keith W; Bluthé, Rose-Marie; Dantzer, Robert; Zhou, Jian-Hua; Shen, Wen-Hong; Johnson, Rodney W; Broussard, Suzanne R

    2003-02-01

    The behavioral repertoire of humans and animals changes dramatically following infection. Sick individuals have little motivation to eat, are listless, complain of fatigue and malaise, loose interest in social activities and have significant changes in sleep patterns. They display an inability to experience pleasure, have exaggerated responses to pain and fail to concentrate. Proinflammatory cytokines acting in the brain cause sickness behaviors. These nearly universal behavioral changes are a manifestation of a central motivational state that is designed to promote recovery. Exaggerated symptoms of sickness in cancer patients, such as cachexia, can be life-threatening. However, quality of life is often drastically impaired before the cancer becomes totally debilitating. Although basic studies in psychoneuroimmunology have defined proinflammatory cytokines as the central mediators of sickness behavior, a much better understanding of how cytokine and neurotransmitter receptors communicate with each other is needed. Advances that have been made during the past decade should now be extended to clinical studies in an attempt to alleviate sickness symptoms and improve quality of life for cancer patients.

  9. Bioanalytical Chemistry of Cytokines-A Review

    PubMed Central

    Stenken, Julie A.; Poschenrieder, Andreas J.

    2014-01-01

    Cytokines are bioactive proteins produced by many different cells of the immune system. Due to their role in different inflammatory disease states and maintaining homeostasis, there is enormous clinical interest in the quantitation of cytokines. The typical standard methods for quantitation of cytokines are immunoassay-based techniques including enzyme-linked immusorbent assays (ELISA) and bead-based immunoassays read by either standard or modified flow cytometers. A review of recent developments in analytical methods for measurements of cytokine proteins is provided. This review briefly covers cytokine biology and the analysis challenges associated with measurement of these biomarker proteins for understanding both health and disease. New techniques applied to immunoassay-based assays are presented along with the uses of aptamers, electrochemistry, mass spectrometry, optical resonator-based methods. Methods used for elucidating the release of cytokines from single cells as well as in vivo collection methods are described. PMID:25467452

  10. Bioanalytical chemistry of cytokines--a review.

    PubMed

    Stenken, Julie A; Poschenrieder, Andreas J

    2015-01-01

    Cytokines are bioactive proteins produced by many different cells of the immune system. Due to their role in different inflammatory disease states and maintaining homeostasis, there is enormous clinical interest in the quantitation of cytokines. The typical standard methods for quantitation of cytokines are immunoassay-based techniques including enzyme-linked immusorbent assays (ELISA) and bead-based immunoassays read by either standard or modified flow cytometers. A review of recent developments in analytical methods for measurements of cytokine proteins is provided. This review briefly covers cytokine biology and the analysis challenges associated with measurement of these biomarker proteins for understanding both health and disease. New techniques applied to immunoassay-based assays are presented along with the uses of aptamers, electrochemistry, mass spectrometry, optical resonator-based methods. Methods used for elucidating the release of cytokines from single cells as well as in vivo collection methods are described.

  11. Local expression of antiinflammatory cytokines in cancer.

    PubMed Central

    Yamamura, M; Modlin, R L; Ohmen, J D; Moy, R L

    1993-01-01

    To characterize the nature of the local cytokine response to cancer, we chose to investigate cytokine patterns in biopsy specimens of basal cell carcinoma (BCC). We hypothesized that a distinct pattern of local cytokine production may be characteristic of BCC, a neoplasia of epidermis, in comparison to the pattern of seborrheic keratosis (SK), a benign growth of epidermis. We analyzed cytokine mRNAs in BCC versus SK by performing polymerase chain reaction on mRNA derived from biopsy specimens. The mRNAs encoding cytokines for IL-4, IL-5, IL-10, and granulocyte macrophage colony-stimulating factor were strongly expressed in BCC lesions and weakly expressed in SK lesions. Conversely, IL-2, IFN-gamma, and lymphotoxin mRNAs were strongly expressed in SK lesions and weakly expressed in BCC lesions. The response to malignancy, BCC, was typified by cytokines characteristic of murine TH2 cells. This cytokine pattern favors humoral immunity with concomitant immunosuppression of cell-mediated immune responses. In comparison, the response to the benign growth, SK, was typified by cytokines characteristic of murine TH1 cells that favor cell-mediated immune reactions. The findings of a distinct cytokine pattern in skin cancer provide a framework to develop strategies for immunologic intervention. Images PMID:8450029

  12. Cytokines and immune surveillance in humans

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1993-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to further explore the effects of space flight on cytokines and cytokine-directed immunological function.

  13. Treatment of cytokine-induced depression.

    PubMed

    Capuron, Lucile; Hauser, Peter; Hinze-Selch, Dunja; Miller, Andrew H; Neveu, Pierre J

    2002-10-01

    A high proportion of cancer and hepatitis C patients who receive cytokine immunotherapy develop symptoms of depression that are indistinguishable from those found in major depressive disorders. These symptoms are alleviated by anti-depressant treatment. Moreover, preventive treatment with anti-depressants, in particular selective serotonin reuptake inhibitors (SSRIs) attenuates IFN-alpha-associated symptoms of depression, anxiety, and neurotoxicity. The intermediate mechanisms of these effects are still unclear. Studies suggest that the state of depression is associated with an increase in plasma levels of various cytokines and soluble cytokine receptors. Furthermore, anti-depressants have been shown to shift the cytokine network towards a decreased production of pro-inflammatory cytokines and an increased production of anti-inflammatory cytokines. Other studies suggest that anti-depressants can also modify immune reactivity by acting on neural structures involved in neuroimmunomodulation. It is possible that anti-depressants could help to normalize the serotoninergic neurotransmission that is likely disrupted during immunotherapy due to the potent effects of cytokines on the metabolism of the amino acid precursor tryptophan. Further work is needed to optimize strategies for preventing neuropsychiatric side effects of cytokine immunotherapy, to clarify the mechanisms involved in the alleviating effects of anti-depressants on cytokine-induced depression, as well as to assess the possible consequences of anti-depressant therapy on the efficacy of immunotherapy on the disease process.

  14. Current status and challenges of cytokine pharmacology

    PubMed Central

    Zídek, Z; Anzenbacher, P; Kmoníčková, E

    2009-01-01

    The major concern of pharmacology about cytokines has originated from plentiful data showing association between gross changes in their production and pathophysiological processes. Despite the enigmatic role of cytokines in diseases, a number of them have become a subject of cytokine and anti-cytokine immunotherapies. Production of cytokines can be influenced by many endogenous and exogenous stimuli including drugs. Cells of the immune system, such as macrophages and lymphocytes, are richly endowed with receptors for the mediators of physiological functions, such as biogenic amines, adenosine, prostanoids, steroids, etc. Drugs, agonists or antagonists of these receptors can directly or indirectly up- and down-regulate secretion of cytokines and expression of cytokine receptors. Vice versa, cytokines interfere with drug pharmacokinetics and pharmacodynamics through the interactions with cytochrome P450 and multiple drug resistance proteins. The aim of the review is to encourage more intensive studies in these fields of cytokine pharmacology. It also outlines major areas of searching promising candidates for immunotherapeutic interventions. PMID:19371342

  15. Inflammatory cytokines in pulmonary hypertension

    PubMed Central

    2014-01-01

    Pulmonary hypertension is an “umbrella term” used for a spectrum of entities resulting in an elevation of the pulmonary arterial pressure. Clinical symptoms include dyspnea and fatigue which in the absence of adequate therapeutic intervention may lead to progressive right heart failure and death. The pathogenesis of pulmonary hypertension is characterized by three major processes including vasoconstriction, vascular remodeling and microthrombotic events. In addition accumulating evidence point to a cytokine driven inflammatory process as a major contributor to the development of pulmonary hypertension. This review summarizes the latest clinical and experimental developments in inflammation associated with pulmonary hypertension with special focus on Interleukin-6, and its role in vascular remodeling in pulmonary hypertension. PMID:24739042

  16. Evaluating Posttranscriptional Regulation of Cytokine Genes

    PubMed Central

    Rattenbacher, Bernd; Bohjanen, Paul R.

    2014-01-01

    A wide variety of cytokines are necessary for cell–cell communication in multicellular organisms, and cytokine dysregulation has detrimental effects, leading to disease states. Thus, it is a necessity that the expression of cytokines is tightly controlled. Regulation of cytokine gene expression takes place at different levels, including transcriptional and posttranscriptional levels. Ultimately, the steady-state levels of cytokine transcripts are determined by the equilibrium of transcription and degradation of this mRNA. Degradation rates of cytokine mRNAs can be measured in cells by blocking transcription with actinomycin D, harvesting RNA after different time points, and evaluating mRNA levels over time by northern blot. Cis-acting elements that mediate the rapid decay of numerous cytokine transcripts, including AU-rich elements (AREs), are found in the 3′ untranslated region (UTR) of these transcripts. Putative regulatory cis-elements can be cloned into the 3′ UTR of a reporter transcript in order to assess their function in regulating mRNA decay. Cis-elements, such as AREs, regulate cytokine mRNA decay by binding to trans-acting proteins, such as tristetraprolin or HuR. These RNA-binding proteins can be visualized using electromobility shift assays or UV crosslinking assays based on their binding to radioactively labeled RNA sequences. RNA-binding proteins that regulate cytokine mRNA decay can be purified using an RNA affinity method, using their target RNA sequence as the bait. In this chapter, we review the methods for measuring cytokine mRNA decay and methods for characterizing the cis-acting elements and trans-acting factors that regulate cytokine mRNA decay. PMID:22131026

  17. Compartmentalized Cytokine Responses in Hidradenitis Suppurativa

    PubMed Central

    Savva, Athina; Kersten, Brigit; Pistiki, Aikaterini; van de Veerdonk, Frank L.; Netea, Mihai G.; van der Meer, Jos W.; Giamarellos-Bourboulis, Evangelos J.

    2015-01-01

    Background Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS). Methods Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs) were stimulated for cytokine production; this was repeated in 13 severe patients during treatment with etanercept. Cytokines in pus were measured. Results CD14brightCD16dim inflammatory monocytes and patrolling monocytes were increased in Hurley III patients. Cytokine production by stimulated PBMCs was low compared to controls but the cytokine gene copies did not differ, indicating post-translational inhibition. The low production of IL-17 was restored, when cells were incubated with adalimumab. In pus, high concentrations of pro-inflammatory cytokines were detected. Based on the patterns, six different cytokine profiles were discerned, which are potentially relevant for the choice of treatment. Clinical improvement with etanercept was predicted by increased production of IL-1β and IL-17 by PBMCs at week 8. Conclusions Findings indicate compartmentalized cytokine expression in HS; high in pus but suppressed in PBMCs. This is modulated through blockade of TNF. PMID:26091259

  18. Cytokines and Immune Responses in Murine Atherosclerosis.

    PubMed

    Kusters, Pascal J H; Lutgens, Esther

    2015-01-01

    Atherosclerosis is an inflammatory disease of the vessel wall characterized by activation of the innate immune system, with macrophages as the main players, as well as the adaptive immune system, characterized by a Th1-dominant immune response. Cytokines play a major role in the initiation and regulation of inflammation. In recent years, many studies have investigated the role of these molecules in experimental models of atherosclerosis. While some cytokines such as TNF or IFNγ clearly had atherogenic effects, others such as IL-10 were found to be atheroprotective. However, studies investigating the different cytokines in experimental atherosclerosis revealed that the cytokine system is complex with both disease stage-dependent and site-specific effects. In this review, we strive to provide an overview of the main cytokines involved in atherosclerosis and to shed light on their individual role during atherogenesis.

  19. Interactions between Autophagy and Inhibitory Cytokines

    PubMed Central

    Wu, Tian-tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy. PMID:27313501

  20. Inflammatory cytokines in newborn infants.

    PubMed Central

    Sarandakou, A; Giannaki, G; Malamitsi-Puchner, A; Rizos, D; Hourdaki, E; Protonotariou, E; Phocas, I

    1998-01-01

    Serum levels of IL-1beta, IL-6 and TNF-alpha were measured in 48 healthy, termed neonates on the 1st (N1), 5th (N5) and 40th (N40) day after birth, compared with those in maternal serum (MS), umbilical cord (UC) and adult controls. Cytokine values in N1 and N5 were significantly elevated, than those in UC and in controls (P<0.0001). IL-1beta and IL-6 declined significantly from N1 to N40 (P<0.0001), while TNF-alpha increased significantly from N1 to N5 and declined thereafter. MS infinity IL-1beta and IL-6, but not MS infinity TNF-alpha, were significantly higher than those of controls (P<0.0001). IL-1beta values depended on the mode of delivery. In conclusion, the increased concentrations of IL-1beta, IL-6 and TNF-alpha during the perinatal period might suggest their involvement in an inflammation-like process during normal parturition, and reflect also a newborn immune response to the stress of delivery and environmental changes. PMID:9883964

  1. Resistin as an Intrahepatic Cytokine

    PubMed Central

    Bertolani, Cristiana; Sancho-Bru, Pau; Failli, Paola; Bataller, Ramon; Aleffi, Sara; DeFranco, Raffaella; Mazzinghi, Benedetta; Romagnani, Paola; Milani, Stefano; Ginés, Pere; Colmenero, Jordi; Parola, Maurizio; Gelmini, Stefania; Tarquini, Roberto; Laffi, Giacomo; Pinzani, Massimo; Marra, Fabio

    2006-01-01

    Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-κB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-κB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-κB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis. PMID:17148667

  2. Cells and cytokines in pollinosis.

    PubMed

    Carlos, A G; Carlos, M L; Santos, M A; Melo, A

    1998-09-01

    Pollinosis is a spontaneous model of allergic disease self limited in time. In order to evaluate immune response during pollen exposition cellular populations CD2, CD4, CD8, CD19, CD22, CD23, CD28, CD29, CD45RA, CD45RO have been studied before, during and after pollen season by flux cytometry. Simultaneous assays of soluble CD23 and cytokines IL-2, IL-4 and IL-2 soluble receptor have been done by an ELISA method. A decrease of CD23 PBC was observed during pollen season maintained afterwards without significant changes in sol CD23. The level of CD45RO memory cells decreased during pollen season with an opposed pattern for CD45RA naive cells. PBC expressing integrin chain CD29 were also decreased during the peak of pollen season. These results show that allergen exposition triggers a turnover of CD45 PBC, a decrease of low affinity IgE receptor CD23 in PBC and a consumption or binding of cells presenting the CD29 integrin chain. Cellular mechanisms are deeply implied in the immune response to pollens and cellular changes can be used as allergic inflammation markers in pollinosis.

  3. Photonic crystal enhanced cytokine immunoassay.

    PubMed

    Mathias, Patrick C; Ganesh, Nikhil; Cunningham, Brian T

    2009-01-01

    Photonic crystal surfaces are demonstrated as a means for enhancing the detection sensitivity and resolution for assays that use a fluorescent tag to quantify the concentration of an analyte protein molecule in a liquid test sample. Computer modeling of the spatial distribution of resonantly coupled electromagnetic fields on the photonic crystal surface are used to estimate the magnitude of enhancement factor compared to performing the same fluorescent assay on a plain glass surface, and the photonic crystal structure is fabricated and tested to experimentally verify the performance using a sandwich immunoassay for the protein Tumor Necrosis Factor-alpha (TNF-alpha). The demonstrated photonic crystal fabrication method utilizes a nanoreplica molding technique that allows for large-area inexpensive fabrication of the structure in a format that is compatible with confocal microarray laser scanners. The signal-to-noise ratio for fluorescent spots on the photonic crystal is increased by at least five-fold relative to the glass slide, allowing a TNF-alpha concentration of 1.6 pg/ml to be distinguished from noise on a photonic crystal surface. In addition, the minimum quantitative limit of detection on the photonic crystal surface is one-third the limit on the glass slide - a decrease from 18 pg/ml to 6 pg/ml. The increased performance of the immunoassay allows for more accurate quantitation of physiologically relevant concentrations of TNF-alpha in a protein microarray format that can be expanded to multiple cytokines.

  4. Vaccination with cytokines in autoimmune diseases.

    PubMed

    Delavallée, Laure; Assier, Eric; Denys, Anne; Falgarone, Géraldine; Zagury, Jean-François; Muller, Sylvianne; Bessis, Natacha; Boissier, Marie-Christophe

    2008-01-01

    Most autoimmune diseases have an unknown etiology, but all involve cytokines cascade in their development. At the present time, several cytokines have been identified as major targets in various autoimmune diseases, involving the development of monoclonal antibodies (MAbs) against those cytokines. Even if MAbs are indeed efficient, the passive immunotherapies also present some disadvantages and are expensive. To counter this, several strategies have been developed, including active immunotherapy, based on the vaccination principle. The aim of such a strategy is to induce a B cell response and to obtain autoantibodies able to neutralize the interaction of the self-cytokine with its receptor. To that purpose, cytokines (entire or peptide) are either coupled with a protein-carrier or virus-like particle, or modified with foreign Th cell epitopes. DNA vaccination can also be used with cytokine sequences. This review focuses on the different vaccination strategies with cytokines (including Tumor Necrosis Factor (TNF)alpha, Interleukin-1beta (IL-1beta), IL-17) in different autoimmune diseases in preclinical studies; the benefit/risk ratio of such a strategy and the present development of clinical trials in some autoimmune diseases are also discussed.

  5. Side effects of cytokines approved for therapy.

    PubMed

    Baldo, Brian A

    2014-11-01

    Cytokines, currently known to be more than 130 in number, are small MW (<30 kDa) key signaling proteins that modulate cellular activities in immunity, infection, inflammation and malignancy. Key to understanding their function is recognition of their pleiotropism and often overlapping and functional redundancies. Classified here into 9 main families, most of the 20 approved cytokine preparations (18 different cytokines; 3 pegylated), all in recombinant human (rh) form, are grouped in the hematopoietic growth factor, interferon, platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) families. In the hematopoietin family, approved cytokines are aldesleukin (rhIL-2), oprelvekin (rhIL-11), filgrastim and tbo-filgrastim (rhG-CSF), sargramostim (rhGM-CSF), metreleptin (rh-leptin) and the rh-erythropoietins, epoetin and darbepoietin alfa. Anakinra, a recombinant receptor antagonist for IL-1, is in the IL-1 family; recombinant interferons alfa-1, alfa-2, beta-1 and gamma-1 make up the interferon family; palifermin (rhKGF) and becaplermin (rhPDGF) are in the PDGF family; and rhBMP-2 and rhBMP-7 represent the TGFβ family. The main physicochemical features, FDA-approved indications, modes of action and side effects of these approved cytokines are presented. Underlying each adverse events profile is their pleiotropism, potency and capacity to release other cytokines producing cytokine 'cocktails'. Side effects, some serious, occur despite cytokines being endogenous proteins, and this therefore demands caution in attempts to introduce individual members into the clinic. This caution is reflected in the relatively small number of cytokines currently approved by regulatory agencies and by the fact that 14 of the FDA-approved preparations carry warnings, with 10 being black box warnings.

  6. Cytokines in Radiobiological Responses: A Review

    PubMed Central

    Schaue, Dörthe; Kachikwu, Evelyn L.; McBride, William H.

    2013-01-01

    Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). “Self” molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, “driver” cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly

  7. Dynamical Systems, Cytokine Storms, and Blood Filtration

    NASA Astrophysics Data System (ADS)

    Foster, Glenn; Hubler, Alfred

    2008-03-01

    Various infections and non-infectious diseases can trigger immune cells and the proteins (cytokines) the cells use to communicate with each other to be caught in a positive feedback loop; this ``cytokine storm'' is frequently fatal. By examining the network of cytokine-immune cell interactions we will illustrate why anti-mediator drugs have been generally ineffective in stopping this feedback. A more effective approach may be to try and reduce interactions by dampening many signals at once by filtering the cytokines out of the blood directly (think dialysis). We will argue that feedback on an out of control nonlinear dynamical system is easier to understand than its normal healthy state and apply filtration to a toy model of immune response.

  8. Control of Hepatitis B Virus by Cytokines

    PubMed Central

    Xia, Yuchen; Protzer, Ulrike

    2017-01-01

    Hepatitis B virus (HBV) infection remains a major public health problem worldwide with more than 240 million individuals chronically infected. Current treatments can control HBV replication to a large extent, but cannot eliminate HBV infection. Cytokines have been shown to control HBV replication and contribute to HBV cure in different models. Cytokines play an important role in limiting acute HBV infection in patients and mediate a non-cytolytic clearance of the virus. In this review, we summarize the effects of cytokines and cytokine-induced cellular signaling pathways on different steps of the HBV life cycle, and discuss possible strategies that may contribute to the eradication of HBV through innate immune activation. PMID:28117695

  9. Mucosal cytokine network in inflammatory bowel disease

    PubMed Central

    Andoh, Akira; Yagi, Yuhki; Shioya, Makoto; Nishida, Atsushi; Tsujikawa, Tomoyuki; Fujiyama, Yoshihide

    2008-01-01

    Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD) are characterized by ongoing mucosal inflammation in which dysfunction of the host immunologic response against dietary factors and commensal bacteria is involved. The chronic inflammatory process leads to disruption of the epithelial barrier, and the formation of epithelial ulceration. This permits easy access for the luminal microbiota and dietary antigens to cells resident in the lamina propria, and stimulates further pathological immune cell responses. Cytokines are essential mediators of the interactions between activated immune cells and non-immune cells, including epithelial and mesenchymal cells. The clinical efficacy of targeting TNF-α clearly indicates that cytokines are the therapeutic targets in IBD patients. In this manuscript, we focus on the biological activities of recently-reported cytokines [Interleukin (IL)-17 cytokine family, IL-31 and IL-32], which might play a role through interaction with TNF-α in the pathophysiology of IBD. PMID:18777592

  10. Cytokines as potential biomarkers of liver toxicity.

    PubMed

    Lacour, Sandrine; Gautier, Jean-Charles; Pallardy, Marc; Roberts, Ruth

    2005-01-01

    Several important drug classes show pre-clinical hepatotoxicity or, in some cases hepatotoxicity in man in Phase III/IV not predicted by pre-clinical studies. This hepatotoxicity is associated with death of the parenchyma by both necrosis and apoptosis. Recent data have implicated molecular mediators of the immune response such as tumor necrosis factor alpha (TNFalpha), interleukin 1beta(1L-1beta) and interleukin 6 (IL6) in acute and chronic liver damage. These cytokines networks have been implicated in mediating the hepatic response to xenobiotics as diverse as PPAR ligands, acetaminophen and phenobarbitone. Thus, pro-inflammatory cytokines such as TNFalpha, IL1 beta and IL6 are released into the bloodstream both from the liver and from distal sites during hepatic toxic injury. Probably due to differences in the responses of rodent and human hepatocytes to cytokines, some clinical hepatotoxicities are not predicted by rodent models. However, the cytokine changes implicated in this human hepatic cell death could be manifest in rodent models and thus could be detected at the molecular level. Here we review the role of cytokines in different types of drug-induced liver injury and discuss whether these cytokine fingerprints are potential biomarkers of so-called idiosyncratic human liver toxicity.

  11. Temporomandibular joint cytokine profiles in the horse.

    PubMed

    Carmalt, James L; Gordon, John R; Allen, Andrew L

    2006-06-01

    It has been suggested that dental abnormalities lead to temporomandibular joint inflammation and pain that may be mitigated by regular dental care. There is considerable literature on the pathophysiology of equine joint disease including studies on cytokine profiles in diseased appendicular joints. This study examined the effects of age and dental malocclusions summarized as a dental pathology score on equine temporomandibular joint cytokine (IL-1, IL-6, IL-8, TNF alpha and TGF-beta1, -beta2, -beta3) concentrations. TGF-beta3 was not detected in any joint sample. IL-1, IL-6 and TNF alpha were not influenced by age. Foals had significantly lower concentrations of lL-8 and TGF-beta1, and higher levels of TGF-beta2 compared with older horses. Age did not effect cytokine concentration in older horses although there was a trend towards increasing 1L-8 with age. The dental pathology score increased with age in mature horses, however there was no effect of dental pathology score on cytokine concentration. There was no effect of incisor eruption, and presence or number of periodontal lesions on temporomandibular joint cytokine concentration. Our findings indicate that age but not dental pathology affected temporomandibular joint proinflammatory cytokine concentration in this population of horses.

  12. Cytokines as predictive biomarkers of alloreactivity.

    PubMed

    Brunet, M

    2012-09-08

    Clinical use of valid biomarkers enables the prediction of alloreactive response (risk of rejection) and personal susceptibility to immunosuppressive treatment could lead to personalized immunosuppressive therapy. In clinical transplantation, it has been reported that cytokine production and secretion could be modified by immunosuppressive drugs, as well as during the rejection process. Some cytokines such as interferon (IFN)-γ, interleukin (IL)-2, IL-10, and transforming growth factor (TGF)-β have been identified as candidate biomarkers that correlate with graft outcome and personal response to immunosuppressive agents. This review will focus on the current state of knowledge, indicating that monitoring changes in cytokine production could be used to predict the risk of rejection and to guide immunosuppression therapy in transplant recipients. In addition, many questions regarding the characteristics and standardization of the methods used for cytokine monitoring (ELISA; ELISPOT; Flow Cytometry) that need to be addressed before these assays can be clinically applied will be discussed in light of recent studies showing an association between the expression of some cytokines and genetic variants, the impact of immunosuppression, and the incidence of rejection. The clinical implementation of cytokine monitoring should be tested in prospective multicenter clinical trials with standard operating procedures and objective interpretation of the results obtained.

  13. Multiplex cytokine analysis of Werner syndrome

    PubMed Central

    Goto, Makoto; Hayata, Koichiro; Chiba, Junji; Matsuura, Masaaki; Iwaki-Egawa, Sachiko; Watanabe, Yasuhiro

    2015-01-01

    Summary We reported a minor inflammation-driven ageing (inflammageing) assessed by highly sensitive CRP (hsCRP) in normal individuals and patients with Werner syndrome (WS), followed by an ageing associated Th2-biased cytokine change in normal ageing in the previous papers. To further study the association of hsCRP and 26 cytokines/chemokines in 35 WS patients, a multiple cytokine array system was used in the same serum samples as were examined for hsCRP. The serum levels of Th2 cytokines (IL-4, IL-6, IL-10, and GM-CSF), Th1 products (IL-2, TNFα, IL-12, and IFNγ) and monocyte/macrophage products (MCP-1, basic FGF and G-CSF) in WS were significantly elevated compared with normal ageing. Elevated hsCRP level in WS was significantly correlated with IL-6, IL-12 and VEGF levels, if age and sex were taken into account. A pro-inflammatory cytokine/chemokine circuit-stimulated immunological shift to Th2 in WS was similar to normal ageing. These cytokine/chemokine changes may induce a systemic chronic inflammation monitored by hsCRP, though these immunological changes in WS were more complicated than normal ageing, possibly due to the WS-specific chronic inflammation such as skin ulcer, diabetes mellitus and central obesity with visceral fat deposition. Further study may warrant the pathophysiology of Th2 shift and Th2-biased inflammageing in normal ageing and WS. PMID:26668779

  14. A genetic contribution to circulating cytokines and obesity in children

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cytokines are considered to be involved in obesity-related metabolic diseases. Study objectives are to determine the heritability of circulating cytokine levels, to investigate pleiotropy between cytokines and obesity traits, and to present genome scan results for cytokines in 1030 Hispanic children...

  15. Th1 cytokine-based immunotherapy for cancer.

    PubMed

    Xu, Hong-Mei

    2014-10-01

    Cytokine-based immunotherapy is executed by harnessing cytokines to activate the immune system to suppress tumors. Th1-type cytokines including IL-1, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor are potent stimulators of Th1 differentiation and Th1-based antitumor response. Many preclinical studies demonstrated the antitumor effects of Th1 cytokines but their clinical efficacy is limited. Multiple factors influence the efficacy of immunotherapy for tumors. For instance immunosuppressive cells in the tumor microenvironment can produce inhibitory cytokines which suppress antitumor immune response. Most studies on cytokine immunotherapy focused on how to boost Th1 response; many studies combined cytokine-based therapy with other treatments to reverse immunosuppression in tumor microenvironment. In addition, cytokines have pleiotropic functions and some cytokines show paradoxical activities under different settings. Better understanding the physiological and pathological functions of cytokines helps clinicians to design Th1-based cancer therapy in clinical practice.

  16. Antibody-cytokine fusion proteins for treatment of cancer: engineering cytokines for improved efficacy and safety.

    PubMed

    Young, Patricia A; Morrison, Sherie L; Timmerman, John M

    2014-10-01

    The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing interleukin (IL)-2, IL-12, IL-21, tumor necrosis factor (TNF)α, and interferons (IFNs) α, β, and γ have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results.

  17. Induction of inflammatory cytokines by cartilage extracts.

    PubMed

    Merly, Liza; Simjee, Shabana; Smith, Sylvia L

    2007-03-01

    Shark cartilage extracts were examined for induction of cytokines and chemokines in human peripheral blood leukocytes. Primary leukocyte cultures were exposed to a variety of aqueous and organic extracts prepared from several commercial brands of shark cartilage. From all commercial sources of shark cartilage tested the acid extracts induced higher levels of TNFalpha than other extracts. Different commercial brands of shark cartilage varied significantly in cytokine-inducing activity. TNFalpha induction was seen as early as 4 h and IFNgamma at detectable levels for up to four days. Shark cartilage extracts did not induce physiologically significant levels of IL-4. Results suggest that shark cartilage, preferentially, induces Th1 type inflammatory cytokines. When compared to bovine cartilage extract, collagen, and chondroitin sulfate, shark cartilage induced significantly higher levels of TNFalpha. Treatment with digestive proteases (trypsin and chymotrypsin) reduced the cytokine induction response by 80%, suggesting that the active component(s) in cartilage extracts is proteinaceous. The induction of Th1 type cytokine response in leukocytes is a significant finding since shark cartilage, taken as a dietary supplement for a variety of chronic degenerative diseases, would be contraindicated in cases where the underlying pathology of the chronic condition is caused by inflammation.

  18. Cytokines in Neuropathic Pain and Associated Depression.

    PubMed

    Lees, Justin G; Fivelman, Brett; Duffy, Samuel S; Makker, Preet G S; Perera, Chamini J; Moalem-Taylor, Gila

    2015-01-01

    Neuropathic pain occurs as a result of lesion or disease affecting the somatosensory nervous system and is present in a diverse set of peripheral and central pathologies such as nerve trauma, diabetic neuropathy, post-herpetic neuralgia, chemotherapy-induced peripheral neuropathy, spinal cord injury and multiple sclerosis. Debilitating symptoms including allodynia, hyperalgesia and spontaneous pain have a substantial negative impact on patients' quality of life. The currently available therapeutic treatments are generally ineffective and characterised by poor response rates. Accumulating evidence suggests that neuroinflammation and cytokine signalling play a critical role in neuropathic pain. Numerous experimental studies have demonstrated that certain pro-inflammatory cytokines are elevated in neuropathic pain conditions, and administration of these cytokines can elicit pain hypersensitivity in the absence of injury or disease. This phenomenon is also apparent in the 'sickness response', which encompasses a broad inflammatory response to disease and injury and involves a series of physiological and behavioural changes including pain hypersensitivity. Interestingly, the 'sickness response' is also similar in nature to some of the defining characteristics of the depressed state of affective disorder. In this review, we explore links that may relate the co-existence of depression in neuropathic pain patients with the activity of cytokines and discuss the role of several key pro-inflammatory and anti-inflammatory cytokines in neuropathic pain.

  19. Interleukin-1 Family Cytokines in Liver Diseases

    PubMed Central

    Tsutsui, Hiroko; Cai, Xianbin; Hayashi, Shuhei

    2015-01-01

    The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases. PMID:26549942

  20. Cytokine and lipid mediator networks in tuberculosis

    PubMed Central

    Mayer-Barber, Katrin D.; Sher, Alan

    2014-01-01

    Summary A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen control. Cytokines and lipid mediators known as eicosanoids play key roles in regulating this balance and as such represent important targets for immunologic intervention. While the evidence for cytokine/eicosanoid function derives largely from the investigation of murine and zebra fish experimental infection models, clinical studies have confirmed the existence of many of the same pathways in tuberculosis patients. Here we summarize new data that reveal important intersections between the cytokine and eicosanoid networks in the host response to mycobacteria and discuss how targeting this crosstalk can promote resistance to lethal Mycobacterium tuberculosis infection. This approach could lead to new host-directed therapies to be used either as an adjunct for improving the efficacy of standard antibiotic treatment or for the management of drug-resistant infections. PMID:25703565

  1. Treatment of Cancer Pain by Targeting Cytokines.

    PubMed

    Vendrell, I; Macedo, D; Alho, I; Dionísio, M R; Costa, L

    2015-01-01

    Inflammation is one of the most important causes of the majority of cancer symptoms, including pain, fatigue, cachexia, and anorexia. Cancer pain affects 17 million people worldwide and can be caused by different mediators which act in primary efferent neurons directly or indirectly. Cytokines can be aberrantly produced by cancer and immune system cells and are of particular relevance in pain. Currently, there are very few strategies to control the release of cytokines that seems to be related to cancer pain. Nevertheless, in some cases, targeted drugs are available and in use for other diseases. In this paper, we aim to review the importance of cytokines in cancer pain and targeted strategies that can have an impact on controlling this symptom.

  2. The role of cytokines in postmenopausal osteoporosis.

    PubMed

    Brincat, S D; Borg, M; Camilleri, G; Calleja-Agius, J

    2014-08-01

    Postmenopausal osteoporosis is a silent systemic progressive disease characterised by a decrease in bone mass per unit volume. This condition compromises the physical strength of the skeleton and increases the susceptibility to fractures on minor trauma. The imbalance between bone formation and bone resorption is known to be responsible for postmenopausal bone loss. Estrogen deficiency contributes to bone loss by increasing the production of pro-inflammatory cytokines by bone marrow and bone cells. Clinical and molecular evidence indicates that estrogen-regulated cytokines exert regulatory effects on bone turnover implicating their role as being the primary mediators of the accelerated bone loss at menopause. The current perspective on the role and interaction of cytokines such as IL-1, IL-4, IL-6, IL-17, TNF, IFN-γ and TGF-β in bone loss linked with estrogen deficiency is reviewed. Current treatment options and emerging drug therapies in the management of postmenopausal osteoporosis are also evaluated.

  3. [Cytokines in the pathogeny of celiac disease].

    PubMed

    León, Alberto J; Garrote, José A; Arranz, Eduardo

    2005-10-15

    Celiac disease is manifested by an enteropathy caused by intolerance to gluten, a family of proteins found in wheat and other cereals. Following intestinal T-cell activation in predisposed individuals, different inflammatory mechanisms are triggered under the control of the cytokine balance including those with a pro-inflammatory Th1 pattern such as IFNgamma, TNFalpha, IL-15 and IL-18; and regulatory cytokines such as TGFbeta and IL-10. These cytokines, besides increasing the intensity of the activation and the number of immune cells within the intestinal mucosa, regulate the activity of epithelial growth factors and metalloproteinases, a group of molecules involved in the maintenance and turnover of the intestinal mucosa structure; in inflammatory conditions, they also induce the intestinal lesion responsible for malabsorption syndrome.

  4. Treatment of Cancer Pain by Targeting Cytokines

    PubMed Central

    Vendrell, I.; Macedo, D.; Alho, I.; Dionísio, M. R.; Costa, L.

    2015-01-01

    Inflammation is one of the most important causes of the majority of cancer symptoms, including pain, fatigue, cachexia, and anorexia. Cancer pain affects 17 million people worldwide and can be caused by different mediators which act in primary efferent neurons directly or indirectly. Cytokines can be aberrantly produced by cancer and immune system cells and are of particular relevance in pain. Currently, there are very few strategies to control the release of cytokines that seems to be related to cancer pain. Nevertheless, in some cases, targeted drugs are available and in use for other diseases. In this paper, we aim to review the importance of cytokines in cancer pain and targeted strategies that can have an impact on controlling this symptom. PMID:26538839

  5. Proinflammatory Cytokines as Regulators of Vaginal Microbiota.

    PubMed

    Kremleva, E A; Sgibnev, A V

    2016-11-01

    It was shown that IL-1β, IL-8, and IL-6 in concentrations similar to those in the vagina of healthy women stimulated the growth of normal microflora (Lactobacillus spp.) and suppressed the growth and biofilm production by S. aureus and E. coli. On the contrary, these cytokines in higher concentrations typical of vaginal dysbiosis suppressed normal microflora and stimulated the growth of opportunistic microorganisms. TGF-β1 in both doses produced a stimulating effects on study vaginal microsymbionts. It is hypothesized that pro-inflammatory cytokines serve as the molecules of interspecies communication coordinating the interactions of all components of the vaginal symbiotic system.

  6. Future prospects for anti-cytokine treatment

    PubMed Central

    Feldmann, M.; Miotla, J.; Paleolog, E.; Williams, R.; Malfait, A.; Taylor, P.; Brennan, F.; Maini, R.

    2000-01-01

    The era of anti-cytokine treatment in rheumatology has just begun. The first generation therapeutic agents, biological agents that block tumour necrosis factor α such as monoclonal antibodies or receptor Ig fusion proteins are safe and effective, and so this has generated much interest in how to increase the benefit or deliver it more cost effectively. This article provides a personal view of the coming trends in anti-cytokine treatment. Which of these will be realised in the future will be of interest.

 PMID:11053102

  7. Cytokine profile of murine malaria: stage-related production of inflammatory and anti-inflammatory cytokines.

    PubMed

    Bakir, Hanaa Y; Tomiyama, Chikako; Abo, Toru

    2011-06-01

    Balance between inflammatory and anti-inflammatory cytokines may be important in malaria presentation and outcome. To clarify cytokine interactions that produce pathology of malaria and control infection, C57BL/6 mice were infected with 10(4) parasitized RBCs from a non-lethal strain of Plasmodium yoelii. Kinetics was monitored showing the course of parasitemia, and cytokines were determined by RT-PCR from liver and spleen tissues. Inflammatory cytokines such as interferon-γ (IFNγ), interleukin (IL)-12, IL-6, tumor necrosis factor-α (TNFα) and anti-inflammatory cytokines, including IL-4 and IL-10, were investigated as key molecules that interact with immune cells in the activation of the immune responses. The production of IFNγ mRNA was found to be higher on day 7 than on day 21 after infection, and IL-12 and IL-6 showed higher expression in the liver than in the spleen. Though TNFα was highly expressed on day 14 after infection and on day 21 in the liver, such expression was decreased on day 21 in the spleen. Anti-inflammatory cytokines showed high expression in both the liver and spleen. The results suggest that a relative balance between inflammatory and anti-inflammatory cytokines is crucial and that the increase of inflammatory cytokine levels during the acute phase of malaria may reflect an early and effective immune response.The counteraction effect of anti-inflammatory cytokines is thought to play a role in limiting progression from uncomplicated malaria to severe life-threatening complications.

  8. Cytokines and immune surveillance in humans

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1994-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to explore further the effects of space flight on cyotokines and cytokine-directed immunological function. Among the tests carried out are interferon-alpha production, interferon-gamma production, interleukin-1 and -2 production, signal transduction in neutrophils, signal transduction in monocytes, and monocyte phagocytic activity. The experiments will be performed using peripheral blood obtained from human subjects. It is our intent to eventually carry out these experiments using astronauts as subjects to determine the effects of space flight on cytokine production and activity. However, these subjects are not currently available. Until they become available, we will carry out these experiments using subjects maintained in the bed-rest model for microgravity.

  9. Cytokines as biochemical markers for knee osteoarthritis

    PubMed Central

    Mabey, Thomas; Honsawek, Sittisak

    2015-01-01

    Osteoarthritis (OA) is a debilitating degenerative joint disease particularly affecting weightbearing joints within the body, principally the hips and knees. Current radiographic techniques are insufficient to show biochemical changes within joint tissue which can occur many years before symptoms become apparent. The need for better diagnostic and prognostic tools is heightened with the prevalence of OA set to increase in aging and obese populations. As inflammation is increasingly being considered an important part of OAs pathophysiology, cytokines are being assessed as possible candidates for biochemical markers. Cytokines, both pro- and anti-inflammatory, as well as angiogenic and chemotactic, have in recent years been studied for relevant characteristics. Biochemical markers show promise in determination of the severity of disease in addition to monitoring of the efficacy and safety of disease-modifying OA drugs, with the potential to act as diagnostic and prognostic tools. Currently, the diagnostic power of interleukin (IL)-6 and the relationship to disease burden of IL-1β, IL-15, tumor necrosis factor-α, and vascular endothelial growth factor make these the best candidates for assessment. Grouping appropriate cytokine markers together and assessing them collectively alongside other bone and cartilage degradation products will yield a more statistically powerful tool in research and clinical applications, and additionally aid in distinguishing between OA and a number of other diseases in which cytokines are known to have an involvement. Further large scale studies are needed to assess the validity and efficacy of current biomarkers, and to discover other potential biomarker candidates. PMID:25621214

  10. Cytokine therapeutics: lessons from interferon alpha.

    PubMed Central

    Gutterman, J U

    1994-01-01

    Cytokines are soluble proteins that allow for communication between cells and the external environment. Interferon (IFN) alpha, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of growth and differentiation, affecting cellular communication and signal transduction pathways as well as immunological control. This review focuses on the biological and clinical activities of the cytokine. Originally discovered as an antiviral substance, the efficacy of IFN-alpha in malignant, viral, immunological, angiogenic, inflammatory, and fibrotic diseases suggests a spectrum of interrelated pathophysiologies. The principles learned from in vivo studies will be discussed, particularly hairy cell leukemia, chronic myelogenous leukemia, certain angiogenic diseases, and hepatitis. After the surprising discovery of activity in a rare B-cell neoplasm, IFN-alpha emerged as a prototypic tumor suppressor protein that represses the clinical tumorigenic phenotype in some malignancies capable of differentiation. Regulatory agencies throughout the world have approved IFN-alpha for treatment of 13 malignant and viral disorders. The principles established with this cytokine serve as a paradigm for future development of natural proteins for human disease. PMID:8108387

  11. Immunoregulatory properties of the cytokine IL-34.

    PubMed

    Guillonneau, Carole; Bézie, Séverine; Anegon, Ignacio

    2017-03-03

    Interleukin-34 is a cytokine with only partially understood functions, described for the first time in 2008. Although IL-34 shares very little homology with CSF-1 (CSF1, M-CSF), they share a common receptor CSF-1R (CSF-1R) and IL-34 has also two distinct receptors (PTP-ζ) and CD138 (syndecan-1). To make the situation more complex, IL-34 has also been shown as pairing with CSF-1 to form a heterodimer. Until now, studies have demonstrated that this cytokine is released by some tissues that differ to those where CSF-1 is expressed and is involved in the differentiation and survival of macrophages, monocytes, and dendritic cells in response to inflammation. The involvement of IL-34 has been shown in areas as diverse as neuronal protection, autoimmune diseases, infection, cancer, and transplantation. Our recent work has demonstrated a new and possible therapeutic role for IL-34 as a Foxp3(+) Treg-secreted cytokine mediator of transplant tolerance. In this review, we recapitulate most recent findings on IL-34 and its controversial effects on immune responses and address its immunoregulatory properties and the potential of targeting this cytokine in human.

  12. Early cytokine responses during intestinal parasitic infections.

    PubMed Central

    Ishikawa, N; Goyal, P K; Mahida, Y R; Li, K F; Wakelin, D

    1998-01-01

    Infections with gastro-intestinal nematodes elicit immune and inflammatory responses mediated by cytokines released from T-helper type-2 (Th2) cells. In vitro assays of cells from the mesenteric lymph nodes (MLN) of experimentally infected rodents confirm that, after about 1 week, the dominant cytokine responses to mitogens and antigens are those associated with this Th-cell subset. Polarization of the Th response in this way implies an initial local cytokine environment that favours Th2 development. However, experimental infections with Trichinella spiralis and Nippostrongylus brasiliensis show that, within 2 days of worms reaching the intestine, MLN cells (MLNC) respond with a Th1 rather than a Th2 response [i.e. there is an increase in mRNA for the type 1 cytokine interferon-gamma (IFN-gamma), and mitogen-stimulated MLNC release IFN-gamma rather than interleukin-5 (IL-5)]. Antigen stimulation at this time does not elicit IFN-gamma release and the MLNC cannot adoptively transfer immunity. Within a few days the MLNC phenotype changes. There is a Th2 response (IL-5 release) to both mitogen and antigen stimulation and MLNC can adoptively transfer immunity. Early release of IFN-gamma is T-cell dependent, with CD4+ T cells playing the major role. The data are discussed in relation to factors regulating the mucosal response to invasion by parasites. PMID:9616376

  13. Cold weather exercise and airway cytokine expression.

    PubMed

    Davis, Michael S; Malayer, Jerry R; Vandeventer, Lori; Royer, Christopher M; McKenzie, Erica C; Williamson, Katherine K

    2005-06-01

    Athletes who perform repeated exercise while breathing cold air have a high prevalence of asthmalike chronic airway disease, but the mechanism linking such activity to airway inflammation is unknown. We used a novel animal model (exercising horses) to test the hypothesis that exercise-induced chronic airway disease is caused by exposure of intrapulmonary airways to unconditioned air, resulting in the upregulation of cytokine expression. Bronchoalveolar lavage fluid (BALF) was obtained from eight horses 5 h after submaximal exercise while they breathed room temperature or subfreezing air in a random crossover design. BALF total and differential nucleated cell counts were determined, and relative cytokine mRNA expression in BALF nucleated cells was quantified by real-time RT-PCR using primer and probe sequences specific for equine targets. There were no significant changes in total or differential cell concentrations between BALF recovered after warm and cold air exercise, although there was a strong trend toward increased concentrations of airway epithelial cells after cold air exercise (P = 0.0625). T(H)2 cytokines IL-4, IL-5, and IL-10 were preferentially upregulated after cold air exercise 12-, 9-, and 10-fold, respectively, compared with warm air exercise. Other cytokines (IL-2 and IL-6) were upregulated to a lesser extent (6- and 3-fold, respectively) or not at all (IL-1, IL-8, IFN-gamma, and TNF-alpha). These results suggest that cold weather exercise can lead to asthmalike airway disease through the local induction of cytokines typical of the T(H)2 phenotype.

  14. Interactive cytokine regulation of synoviocyte lubricant secretion.

    PubMed

    Blewis, Megan E; Lao, Brian J; Schumacher, Barbara L; Bugbee, William D; Sah, Robert L; Firestein, Gary S

    2010-04-01

    Cytokine regulation of synovial fluid (SF) lubricants, hyaluronan (HA), and proteoglycan 4 (PRG4) is important in health, injury, and disease of synovial joints, and may also provide powerful regulation of lubricant secretion in bioreactors for articulating tissues. This study assessed lubricant secretion rates by human synoviocytes and the molecular weight (MW) of secreted lubricants in response to interleukin (IL)-1beta, IL-17, IL-32, transforming growth factor-beta 1 (TGF-beta1), and tumor necrosis factor-alpha (TNF-alpha), applied individually and in all combinations. Lubricant secretion rates were assessed using ELISA and binding assays, and lubricant MW was assessed using gel electrophoresis and Western blotting. HA secretion rates were increased approximately 40-fold by IL-1beta, and increased synergistically to approximately 80-fold by the combination of IL-1beta + TGF-beta1 or TNF-alpha + IL-17. PRG4 secretion rates were increased approximately 80-fold by TGF-beta1, and this effect was counterbalanced by IL-1beta and TNF-alpha. HA MW was predominantly <1 MDa for controls and individual cytokine stimulation, but was concentrated at >3 MDa after stimulation by IL-1beta + TGF-beta1 + TNF-alpha to resemble the distribution in human SF. PRG4 MW was unaffected by cytokines and similar to that in human SF. These results contribute to an understanding of the relationship between SF cytokine and lubricant content in health, injury, and disease, and provide approaches for using cytokines to modulate lubricant secretion rates and MW to help achieve desired lubricant composition of fluid in bioreactors.

  15. Therapeutic antibodies that target inflammatory cytokines in autoimmune diseases.

    PubMed

    Lai, Yuping; Dong, Chen

    2016-04-01

    Inflammatory cytokines are key regulators of immune responses. Persistent and excessive production of inflammatory cytokines underscores the development of autoimmune diseases. Therefore, neutralizing inflammatory cytokines or antagonizing their receptor function is considered as a useful therapeutic strategy to treat autoimmune diseases. To achieve the success of such a strategy, understanding of the complex actions of these cytokines and cytokine networks is required. In this review we focus on four inflammatory cytokines--tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-23 and IL-17--and dissect how the dysregulation of these cytokines regulates autoimmune diseases. On the basis of pre-clinical and clinical data, we specifically discuss the therapeutic rationale for targeting these cytokines and describe the potential adverse effects.

  16. Drug targets in the cytokine universe for autoimmune disease.

    PubMed

    Liu, Xuebin; Fang, Lei; Guo, Taylor B; Mei, Hongkang; Zhang, Jingwu Z

    2013-03-01

    In autoimmune disease, a network of diverse cytokines is produced in association with disease susceptibility to constitute the 'cytokine milieu' that drives chronic inflammation. It remains elusive how cytokines interact in such a complex network to sustain inflammation in autoimmune disease. This has presented huge challenges for successful drug discovery because it has been difficult to predict how individual cytokine-targeted therapy would work. Here, we combine the principles of Chinese Taoism philosophy and modern bioinformatics tools to dissect multiple layers of arbitrary cytokine interactions into discernible interfaces and connectivity maps to predict movements in the cytokine network. The key principles presented here have important implications in our understanding of cytokine interactions and development of effective cytokine-targeted therapies for autoimmune disorders.

  17. Crustacean hematopoiesis and the astakine cytokines.

    PubMed

    Lin, Xionghui; Söderhäll, Irene

    2011-06-16

    Major contributions to research in hematopoiesis in invertebrate animals have come from studies in the fruit fly, Drosophila melanogaster, and the freshwater crayfish, Pacifastacus leniusculus. These animals lack oxygen-carrying erythrocytes and blood cells of the lymphoid lineage, which participate in adaptive immune defense, thus making them suitable model animals to study the regulation of blood cells of the innate immune system. This review presents an overview of crustacean blood cell formation, the role of these cells in innate immunity, and how their synthesis is regulated by the astakine cytokines. Astakines are among the first invertebrate cytokines shown to be involved in hematopoiesis, and they can stimulate the proliferation, differentiation, and survival of hematopoietic tissue cells. The astakines and their vertebrate homologues, prokineticins, share similar functions in hematopoiesis; thus, studies of astakine-induced hematopoiesis in crustaceans may not only advance our understanding of the regulation of invertebrate hematopoiesis but may also provide new evolutionary perspectives about this process.

  18. Cytokines: The Future of Intranasal Vaccine Adjuvants

    PubMed Central

    Thompson, Afton L.; Staats, Herman F.

    2011-01-01

    Due to its potential as an effective, needle-free route of immunization for use with subunit vaccines, nasal immunization continues to be evaluated as a route of immunization in both research and clinical studies. However, as with other vaccination routes, subunit vaccines often require the addition of adjuvants to induce potent immune responses. Unfortunately, many commonly used experimental vaccine adjuvants, such as cholera toxin and E. coli heat-labile toxin, are too toxic for use in humans. Because new adjuvants are needed, cytokines have been evaluated for their ability to provide effective adjuvant activity when delivered by the nasal route in both animal models and in limited human studies. It is the purpose of this paper to discuss the potential of cytokines as nasal vaccine adjuvants. PMID:21826181

  19. Inflammatory cytokines in atherosclerosis: current therapeutic approaches.

    PubMed

    Tousoulis, Dimitris; Oikonomou, Evangelos; Economou, Evangelos K; Crea, Filippo; Kaski, Juan Carlos

    2016-06-07

    The notion of atherosclerosis as a chronic inflammatory disease has intensified research on the role of cytokines and the way these molecules act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are expressed by all types of cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects, and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leucocytes, and other vascular residing cells. It is now understood that widely used drugs such as statins, aspirin, methotrexate, and colchicine act in an immunomodulatory way that may beneficially affect atherogenesis and/or cardiovascular disease progression. Moreover, advancement in pharmaceutical design has enabled the production of highly specific antibodies against key molecules involved in the perpetuation of the inflammatory cascade, raising hope for advances in the treatment of atherosclerosis. This review describes the actions and effects of these agents, their potential clinical significance, and future prospects.

  20. Cytokine signalling in mammary gland development.

    PubMed

    Watson, Christine J; Oliver, Carrie H; Khaled, Walid T

    2011-03-01

    Mammary gland development occurs in three distinct stages during the lifetime of the female mammal: in embryonic, pubertal and reproductive life. At each of these developmental stages, different signalling molecules induce changes in both the epithelium and the surrounding stroma. However, it is during pregnancy that the most dramatic changes occur, resulting in a massive increase in the number of epithelial cells and in their function. Pregnancy initiates the development of a new epithelial lineage, the alveolar cells, which form the milk-producing lobuloalveolar structures. These cells become redundant at the end of lactation and are removed in an exquisitely controlled process of tissue remodelling coupled with extensive cell death. All of these events require not only steroid hormones but also sequential signalling by cytokines. A recent surprising discovery was that the signalling pathways and cytokines that regulate lineage determination in T helper cells are also involved in mammary gland development during pregnancy.

  1. Suppression of Cytokine Signaling: the SOCS perspective

    PubMed Central

    Linossi, Edmond M.; Babon, Jeffrey J.; Hilton, Douglas J.; Nicholson, Sandra E.

    2013-01-01

    The discovery of the Suppressor Of Cytokine Signaling (SOCS) family of proteins has resulted in a significant body of research dedicated to dissecting their biological functions and the molecular mechanisms by which they achieve potent and specific inhibition of cytokine and growth factor signaling. The Australian contribution to this field has been substantial, with the initial discovery of SOCS1 by Hilton, Starr and colleagues (discovered concurrently by two other groups) and the following work, providing a new perspective on the regulation of JAK/STAT signaling. In this review, we reflect on the critical discoveries that have lead to our current understanding of how SOCS proteins function and discuss what we see as important questions for future research. PMID:23545160

  2. Tumor Vaccination With Cytokine-Loaded Microspheres

    DTIC Science & Technology

    2005-12-01

    indirect effects of IFN-gamma. J Immunol. 2003;170:400–412. 23. Yan J, Vetvicka V, Xia Y, et al. Beta - glucan , a ‘‘specific’’ biologic response...12, GM-CSF, Breast Cancer , Spontaneous tumors 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF... cancer vaccines, cytokines, adjuvants, immunotherapy, tumor models (J Immunother 2006;29:10–20) I t is now well established that numerous immune

  3. Effects of hemorrhage on cytokine gene transcription.

    PubMed

    Shenkar, R; Abraham, E

    1993-08-01

    Injury and blood loss are often followed by infection and the rapid development of organ system dysfunction, frequently involving mucosal sites, such as the lung and intestine. To examine possible mechanisms contributing to these conditions, we used semiquantitative polymerase chain reactions to determine cytokine mRNA expression among cellular populations isolated from mucosal and systemic anatomic sites of mice at predetermined time points following 30% blood volume hemorrhage with resuscitation 1 hr later. Within 1 hr after hemorrhage, significant increases were observed in mRNA levels for IL-1 alpha, IL-1 beta, IL-5, and TGF-beta in intraparenchymal pulmonary mononuclear cells. The levels of TGF-beta transcripts among alveolar macrophages were increased 1 hr following blood loss, and increase in IL-1 alpha transcripts was found starting 2 hr posthemorrhage. Cells from Peyer's patches showed significant increases in mRNA levels for IL-1 beta, IL-2, IL-5, IL-6, IFN-gamma, and TGF-beta during the 4 hr following hemorrhage. Significant increases in mRNA levels for IL-1 beta, TNF-alpha, and TGF-beta were present within 4 hr of blood loss among cells isolated from mesenteric lymph nodes. The expression of mRNA for most cytokines was not significantly altered in splenocytes or peripheral blood mononuclear cells at any time point following hemorrhage. These experiments demonstrate that blood loss, even if resuscitated, produces significant increases in proinflammatory and immunoregulatory cytokine gene transcription as early as 1 hr following hemorrhage. These posthemorrhage alterations in cytokine mRNA expression were particularly prominent at mucosal sites, suggesting a mechanism for the increased incidence of pulmonary and intestinal involvement in organ system failure following severe blood loss and injury.

  4. Cytokine-Induced Modulation of Colorectal Cancer

    PubMed Central

    Mager, Lukas F.; Wasmer, Marie-Hélène; Rau, Tilman T.; Krebs, Philippe

    2016-01-01

    The emergence of novel immunomodulatory cancer therapies over the last decade, above all immune checkpoint blockade, has significantly advanced tumor treatment. For colorectal cancer (CRC), a novel scoring system based on the immune cell infiltration in tumors has greatly improved disease prognostic evaluation and guidance to more specific therapy. These findings underline the relevance of tumor immunology in the future handling and therapeutic approach of malignant disease. Inflammation can either promote or suppress CRC pathogenesis and inflammatory mediators, mainly cytokines, critically determine the pro- or anti-tumorigenic signals within the tumor environment. Here, we review the current knowledge on the cytokines known to be critically involved in CRC development and illustrate their mechanisms of action. We also highlight similarities and differences between CRC patients and murine models of CRC and point out cytokines with an ambivalent role for intestinal cancer. We also identify some of the future challenges in the field that should be addressed for the development of more effective immunomodulatory therapies. PMID:27148488

  5. Cytokines as biomarkers in rheumatoid arthritis.

    PubMed

    Burska, Agata; Boissinot, Marjorie; Ponchel, Frederique

    2014-01-01

    RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge's relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.

  6. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets.

    PubMed

    Furst, Daniel E; Emery, Paul

    2014-09-01

    Biologic therapies that target pathogenic cytokines such as TNF, IL-1β or IL-6 have greatly improved the treatment of RA. Unfortunately, not all RA patients respond to current biologic therapies and responses are not always maintained, suggesting that there are alternative drivers of RA pathogenesis that might serve as promising therapeutic targets. Discovery of the new Th17 subset of Th cells, and their role in autoimmune disease development, has implicated the proinflammatory IL-12 and IL-17 families of cytokines in RA disease pathogenesis. Members of these cytokine families are elevated in the blood and joints of RA patients and have been shown to remain elevated in patients who do not respond to current biologics. In addition, these cytokines have been shown to play roles in joint destruction and erosion. A new subclass of biologics that target the IL-12 and/or IL-17 signalling pathways are under development. Here we review evidence for a role of Th17 cells as well as IL-12 and IL-17 cytokines in RA pathogenesis as the rationale for a subsequent discussion of the ongoing and completed clinical trials of newly emerging biologic therapies directed at IL-12 or IL-17 pathway inhibition.

  7. Molecular transduction mechanisms of cytokine-hormone interactions: role of gp130 cytokines.

    PubMed

    Gerez, Juan; Bonfiglio, José; Sosa, Sebastian; Giacomini, Damiana; Acuña, Matias; Nagashima, Alberto Carbia; Perone, Marcelo J; Silberstein, Susana; Renner, Ulrich; Stalla, Günter K; Arzt, Eduardo

    2007-09-01

    Highly sophisticated mechanisms confer on the immune system the capacity to respond with a certain degree of autonomy. However, the final outcome of an immune response depends on the interaction of the immune system with other systems. The immune and neuroendocrine systems have an intimate cross-communication that makes possible a satisfactory response to environmental changes. Part of this interaction occurs through cytokines and steroid hormones. The last step of this cross-talk is the molecular level. As a model of interaction, this review focuses on the gp130 cytokine family. These cytokines, as well as their receptors, are expressed in pituitary cells. They regulate hormone production as well as growth of pituitary cells. During acute or chronic inflammation or infection, systemic, hypothalamic and hypophyseal gp130 cytokines act on anterior pituitary cells, integrating the neuroendocrine-immune response. Disruptions of these pathways may lead not only to abnormal growth of pituitary cells but also to immune disorders, for which, based on recent findings, targeting these cytokines might be a novel therapeutic approach.

  8. Cytokines: The Good, the Bad, and the Deadly.

    PubMed

    Ramani, Thulasi; Auletta, Carol S; Weinstock, Daniel; Mounho-Zamora, Barbara; Ryan, Patricia C; Salcedo, Theodora W; Bannish, Gregory

    2015-01-01

    Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. An overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities was presented at this symposium. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be "good" when stimulating the immune system to fight a foreign pathogen or attack tumors. Other "good" cytokine effects include reduction of an immune response, for example interferon β reduction of neuron inflammation in patients with multiple sclerosis. They may be "bad" when their expression causes inflammatory diseases, such as the role of tumor necrosis factor α in rheumatoid arthritis or asthma and Crohn's disease. Therapeutic modulation of cytokine expression can help the "good" cytokines to generate or quench the immune system and block the "bad" cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause "ugly" cytokine release which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discussed lessons learned in cytokine toxicology using case studies and suggested future directions.

  9. Insights into Cytokine–Receptor Interactions from Cytokine Engineering

    PubMed Central

    Spangler, Jamie B.; Moraga, Ignacio; Mendoza, Juan L.; Garcia, K. Christopher

    2015-01-01

    Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine–receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4. PMID:25493332

  10. Historical review: Cytokines as therapeutics and targets of therapeutics.

    PubMed

    Vilcek, Jan; Feldmann, Marc

    2004-04-01

    Cytokine research has spawned the introduction of new therapies that have revolutionized the treatment of many important diseases. These therapeutic advances have resulted from two very different strategies. The first therapeutic strategy embodies the administration of purified, recombinant cytokines. The second relies on the administration of therapeutics that inhibit the harmful effects of upregulated, endogenous cytokines. Examples of successful cytokine therapeutics include hematopoietic growth factors (colony stimulating factors) and interferons. Prime examples of cytokine antagonists that have profoundly altered the treatment of some inflammatory disorders are agents that inhibit the effects of tumor necrosis factor (TNF). In this article, we highlight some of the studies that have been responsible for the introduction of cytokine and anti-cytokine therapies, with emphasis on the development of interferons and anti-TNF agents.

  11. Multiple Circulating Cytokines Are Coelevated in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Todd, Ian; John, Michelle; Bolton, Charlotte E.; Harrison, Timothy

    2016-01-01

    Inflammatory biomarkers, including cytokines, are associated with COPD, but the association of particular circulating cytokines with systemic pathology remains equivocal. To investigate this, we developed a protein microarray system to detect multiple cytokines in small volumes of serum. Fourteen cytokines were measured in serum from never-smokers, ex-smokers, current smokers, and COPD patients (GOLD stages 1–3). Certain individual circulating cytokines (particularly TNFα and IL-1β) were significantly elevated in concentration in the serum of particular COPD patients (and some current/ex-smokers without COPD) and may serve as markers of particularly significant systemic inflammation. However, numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD. The coelevation of numerous circulating cytokines in COPD is consistent with the insidious development, chronic nature, and systemic comorbidities of the disease. PMID:27524865

  12. Multiple Circulating Cytokines Are Coelevated in Chronic Obstructive Pulmonary Disease.

    PubMed

    Selvarajah, Senthooran; Todd, Ian; Tighe, Patrick J; John, Michelle; Bolton, Charlotte E; Harrison, Timothy; Fairclough, Lucy C

    2016-01-01

    Inflammatory biomarkers, including cytokines, are associated with COPD, but the association of particular circulating cytokines with systemic pathology remains equivocal. To investigate this, we developed a protein microarray system to detect multiple cytokines in small volumes of serum. Fourteen cytokines were measured in serum from never-smokers, ex-smokers, current smokers, and COPD patients (GOLD stages 1-3). Certain individual circulating cytokines (particularly TNFα and IL-1β) were significantly elevated in concentration in the serum of particular COPD patients (and some current/ex-smokers without COPD) and may serve as markers of particularly significant systemic inflammation. However, numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD. The coelevation of numerous circulating cytokines in COPD is consistent with the insidious development, chronic nature, and systemic comorbidities of the disease.

  13. Cytokines: Names and Numbers You Should Care About.

    PubMed

    Holdsworth, Stephen R; Gan, Poh-Yi

    2015-12-07

    Cytokines play an important role in host defense against microorganisms. They orchestrate innate immunity by inducing protective local inflammation and systemic acute phase responses. Cytokines are important in initiating, amplifying, directing, mediating, and regulating adaptive immunity. Unfortunately, they may also direct tissue damage if excessive responses occur or if they are involved in directing and mediating autoimmunity. Under these circumstances, cytokines are potential therapeutic targets. Over the last 20 years, we have seen the successful development and clinical implementation of biologic strategies that target key cytokines in specific inflammatory diseases with efficacy, specificity, and toxicity profiles challenging conventional drug therapies. These therapies are finding new applications and many new agents show promise. Unfortunately, these new cytokine-based therapies have had little effect on renal disease. This review provides evidence that common renal diseases, including those causing AKI and the autoimmune proliferative and crescentic forms of GN, have cytokine mediation profiles that suggest they would be susceptible to cytokine-targeting therapeutic strategies.

  14. Cytokines, cytokine gene polymorphisms and Helicobacter pylori infection: friend or foe?

    PubMed

    Figueiredo, Camila A; Marques, Cintia Rodrigues; Costa, Ryan dos Santos; da Silva, Hugo Bernardino F; Alcantara-Neves, Neuza M

    2014-05-14

    Helicobacter pylori (H. pylori) is a flagellated, spiral-shaped, microaerophilic Gram-negative bacillus that colonises the gastric mucosa of more than 50% of the human population. Infection is a risk factor for gastritis, ulcer disease and stomach cancer. Immunity against H. pylori is mainly related to Th1/Th17 skewing, and the activation of regulatory T cells is the main strategy used to limit inflammatory responses, which can result in the pathogen persistence and can lead to chronic gastrointestinal diseases, including cancer. Furthermore, host genetic factors that affect cytokines may determine differences in the susceptibility to many diseases. In this review, we present the cytokine profiles and the main cytokine gene polymorphisms associated with resistance/susceptibility to H. pylori and discuss how such polymorphisms may influence infection/disease outcomes.

  15. Solution assembly of cytokine receptor ectodomain complexes

    SciTech Connect

    Wu, Zining; Ciardelli, T.L.; Johnson, K.W.

    1995-09-01

    For the majority of single transmembrane-spanning cell surface receptors, signal transmission across the lipid bilayer barrier involves several discrete components of molecular recognition. The interaction between ligand and the extracellular segment of its cognate receptor (ectodomain) initiates either homomeric or heteromeric association of receptor subunits. Specific recognition among these subunits may then occur between ectodomain regions, within the membrane by interhelical contact or inside the cell between cytoplasmic domains. Any or all of these interactions may contribute to the stability of the signaling complex. It is the characteristics of ligand binding by the ectodomains of these receptors that controls the heteromeric or homomeric nature and the stoichiometry of the complex. Cytokines and their receptors belong to a growing family of macromolecular systems that exhibit these functional features and share many structural similarities as well. Interleukin-2 is a multifunctional cytokine that represents, perhaps, the most complex example to date of ligand recognition among the hematopoietin receptor family. It is the cooperative binding of IL-2 by all three proteins on the surface of activated T-lymphocytes, however, that ultimately results in crosslinking of the {beta}- and {gamma}-subunits and signaling via association of their cytoplasmic domains. Although the high-affinity IL-2R functions as a heterotrimer, heterodimers of the receptor subunits are also physiologically important. The {alpha}/{beta} heterodimer or {open_quotes}pseudo-high affinity{close_quotes} receptor captures IL-2 as a preformed cell surface complex while the {beta}/{gamma} intermediate affinity site exists, in the absence of the {alpha} subunit, on the majority of natural killer cells. We have begun to study stable complexes of cytokine receptor ectodomains of defined composition and that mimic the ligand binding characteristics of the equivalent cell surface receptor sites.

  16. Cytokines and Pancreatic β-Cell Apoptosis.

    PubMed

    Berchtold, L A; Prause, M; Størling, J; Mandrup-Poulsen, T

    The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic β-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of β-cell function and survival and the causes of β-cell failure and destruction in diabetes. Having until then been confined to the use of pathophysiologically irrelevant β-cell toxic chemicals as a model of β-cell death, researchers could now mimic endocrine and paracrine effects of the cytokine response in vitro by titrating concentrations in the low to the high picomolar-femtomolar range and vary exposure time for up to 14-16h to reproduce the acute regulatory effects of systemic inflammation on β-cell secretory responses, with a shift to inhibition at high picomolar concentrations or more than 16h of exposure to illustrate adverse effects of local, chronic islet inflammation. Since then, numerous studies have clarified how these bimodal responses depend on discrete signaling pathways. Most interest has been devoted to the proapoptotic response dependent upon mainly nuclear factor κ B and mitogen-activated protein kinase activation, leading to gene expressional changes, endoplasmic reticulum stress, and triggering of mitochondrial dysfunction. Preclinical studies have shown preventive effects of cytokine antagonism in animal models of diabetes, and clinical trials demonstrating proof of concept are emerging. The full clinical potential of anticytokine therapies has yet to be shown by testing the incremental effects of appropriate dosing, timing, and combinations of treatments. Due to the considerable translational importance of enhancing the precision, specificity, and safety of antiinflammatory treatments of diabetes, we review here the cellular, preclinical, and clinical evidence of which of the death pathways recently proposed in the Nomenclature Committee on Cell Death 2012

  17. Cytokine production capacity in depression and anxiety

    PubMed Central

    Vogelzangs, N; de Jonge, P; Smit, J H; Bahn, S; Penninx, B W

    2016-01-01

    Recent studies have suggested that immune function may be dysregulated in persons with depressive and anxiety disorders. Few studies examined the expression of cytokines in response to ex vivo stimulation of blood by lipopolysaccharide (LPS) to study the innate production capacity of cytokines in depression and anxiety. To investigate this, baseline data from the Netherlands Study of Depression and Anxiety (NESDA) were used, including persons (18–65 years; 66% women) with current (that is, past month; N=591) or remitted (N=354) DSM-IV depressive or anxiety disorders and healthy controls (N=297). Depressive and anxiety symptoms were measured by means of the Inventory of Depressive Symptomatology (IDS) and the Beck Anxiety Inventory (BAI). Using Multi-Analyte Profiling technology, plasma levels of 13 cytokines were assayed after whole blood stimulation by addition of LPS. Basal plasma levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α were also available. A basal and a LPS summary index were created. Results show that LPS-stimulated inflammation was associated with increased odds of current depressive/anxiety disorders (odds ratio (OR)=1.28, P=0.009), as was the case for basal inflammation (OR=1.28, P=0.001). These associations were no longer significant after adjustment for lifestyle and health (OR=1.13, P=0.21; OR=1.07, P=0.45, respectively). After adjustment for lifestyle and health, interleukin-8 was associated with both remitted (OR=1.25, P=0.02) and current (OR=1.28, P=0.005) disorders. In addition, LPS-stimulated inflammation was associated with more severe depressive (β=0.129, P<0.001) and anxiety (β=0.165, P<0.001) symptoms, as was basal inflammation. Unlike basal inflammation, LPS-stimulated inflammation was still associated with (anxiety) symptom severity after adjustment for lifestyle and health (IDS: IL-8, MCP-1, MMP2; BAI: LPS index, IL-6, IL-8, IL-10, IL-18, MCP-1, MMP2, TNF-β). To conclude, lifestyle and health factors may

  18. Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications

    PubMed Central

    Felger, Jennifer C.; Lotrich, Francis E.

    2013-01-01

    Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, e.g. brain derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression’s development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed. PMID:23644052

  19. Temporal trends in the inflammatory cytokine profile of human breastmilk.

    PubMed

    Chollet-Hinton, Lynn S; Stuebe, Alison M; Casbas-Hernandez, Patricia; Chetwynd, Ellen; Troester, Melissa A

    2014-12-01

    A longer lifetime duration of breastfeeding may decrease the risk of breast cancer by reducing breast inflammation and mitigating inflammatory cytokine expression during postlactational involution. However, little is known about how the inflammatory cytokine profile in human breastmilk changes over time. To study temporal trends in breastmilk cytokine expression, we measured 80 human cytokines in the whey fraction of breastmilk samples from 15 mothers at 1, 4, 8, and 12 weeks postpartum. We used mixed models to identify temporal changes in cytokine expression and investigated parity status (multiparous vs. primiparous) as a potential confounder. Nine cytokines (monocyte chemoattractant protein-1, epithelial-derived neutrophil-activating protein-78, hepatocyte growth factor, insulin-like growth factor-binding protein-1, interleukin-16, interleukin-8, macrophage colony-stimulating factor, osteoprotegerin, and tissue inhibitor of metallopeptidase-2) had significantly decreased expression with increasing breastfeeding duration; all nine have known roles in breast involution, inflammation, and cancer and may serve as biomarkers of changing breast microenvironment. No cytokine significantly increased in level over the study period. Total protein concentration significantly decreased over time (p<0.0001), which may mediate the association between length of breastfeeding and inflammatory cytokine expression. Parity status did not confound temporal trends, but levels of several cytokines were significantly higher among multiparous versus primiparous women. Our results suggest that inflammatory cytokine expression during lactation is dynamic, and expressed milk may provide a noninvasive window into the extensive biological changes that occur in the postpartum breast.

  20. A genetic contribution to circulating cytokines and obesity in children.

    PubMed

    Cai, Guowen; Cole, Shelley A; Butte, Nancy F; Smith, C Wayne; Mehta, Nitesh R; Voruganti, V Saroja; Proffitt, J Michael; Comuzzie, Anthony G

    2008-11-01

    Cytokines are considered to be involved in obesity-related metabolic diseases. Study objectives are to determine the heritability of circulating cytokine levels, to investigate pleiotropy between cytokines and obesity traits, and to present genome scan results for cytokines in 1030 Hispanic children enrolled in VIVA LA FAMILIA Study. Cytokine phenotypes included monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), leptin, adiponectin, soluble intercellular adhesion molecule-1 (sICAM-1), transforming growth factor beta 1 (TGF-beta1), C-reactive protein (CRP), regulated upon activation, normal T-cell expressed and secreted (RANTES) and eotaxin. Obesity-related phenotypes included body mass index (BMI), fat mass (FM), truncal FM and fasting serum insulin. Heritabilities ranged from 0.33 to 0.97. Pleiotropy was observed between cytokines and obesity traits. Positive genetic correlations were seen between CRP, leptin, MCP-1 and obesity traits, and negative genetic correlations with adiponectin, ICAM-1 and TGF-beta1. Genome-wide scan of sICAM-1 mapped to chromosome 3 (LOD=3.74) between markers D3S1580 and D3S1601, which flanks the adiponectin gene (ADIPOQ). Suggestive linkage signals were found in other chromosomal regions for other cytokines. In summary, significant heritabilities for circulating cytokines, pleiotropy between cytokines and obesity traits, and linkage for sICAM-1 on chromosome 3q substantiate a genetic contribution to circulating cytokine levels in Hispanic children.

  1. TH1/TH2 cytokines in the central nervous system.

    PubMed

    Sredni-Kenigsbuch, Dvora

    2002-06-01

    For the past 20 years it has become increasingly evident that cytokines play an important role in both the normal development of the brain, acting as neurotrophic factors, and in brain injuries. Although cytokines and their receptors are synthesized and expressed in the brain (normally at low levels), increased cytokine production levels are now associated with various neurological disorders. T lymphocytes are the cells responsible for coordinating the immune response and a major source of cytokines. Different cytokines induce different subsets of T cells or have different effects on proliferation within a particular subset. Recent studies suggest that the immune response is in fact regulated by the balance between Th1 and Th2 cytokines. These two pathways are often mutually exclusive, the one resulting in protection and the other in progression of disease. Various studies describe the function and production of proinflammatory cytokines in the central nervous system (CNS) and their role in health and disease. Inflammation is upregulated following activation of Th1 cells, whereas Th2 cells may play a significant role in downregulating Th1 proinflammatory responses in those instances in which there is overproduction of Th2 cytokines. Although both Th1 and Th2 cytokines may influence CNS functioning, most studies have so far dealt with proinflammatory cytokines, probably because they directly affect CNS cells and are thought to be implicated in CNS pathology. It is of interest that endogenous glucocorticoids also control Th1-Th2 balance, favoring Th2 cell development. This review presents the evidence that cytokines have important functions in the CNS, both during development and as a part of brain pathology. In particular, the author highlighted recent work that supports a major role for the so-called inflammatory cytokines, Th1, and the anti-inflammatory Th2 cytokines.

  2. Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD

    PubMed Central

    Jacob, Noam; Targan, Stephan R

    2016-01-01

    The frequency of fibrosing Crohn’s disease (CD) is significant, with approximately 40% of CD patients with ileal disease developing clinically apparent strictures throughout their lifetime. Although strictures may be subdivided into fibrotic, inflammatory, or mixed forms, despite immunosuppressive therapy in CD patients in the form of steroids or immunomodulators, the frequency of fibrostenosing complications has still remained significant. A vast number of genetic and epigenetic variables are thought to contribute to fibrostenosing disease, including those that affect cytokine biology, and therefore highlight the complexity of disease, but also shed light on targetable pathways. Exclusively targeting fibrosis may be difficult, however, because of the relatively slow evolution of fibrosis in CD, and the potential adverse effects of inhibiting pathways involved in tissue repair and mucosal healing. Acknowledging these caveats, cytokine-targeted therapy has become the mainstay of treatment for many inflammatory conditions and is being evaluated for fibrotic disorders. The question of whether anti-cytokine therapy will prove useful for intestinal fibrosis is, therefore, acutely relevant. This review will highlight some of the current therapeutics targeting cytokines involved in fibrosis. PMID:27536363

  3. Anti-cytokine autoantibodies in autoimmune diseases

    PubMed Central

    Cappellano, Giuseppe; Orilieri, Elisabetta; Woldetsadik, Abiy D; Boggio, Elena; Soluri, Maria F; Comi, Cristoforo; Sblattero, Daniele; Chiocchetti, Annalisa; Dianzani, Umberto

    2012-01-01

    An overview of the current literature is showing that autoantibodies (AutoAbs) against cytokines are produced in several pathological conditions, including autoimmune diseases, but can also be detected in healthy individuals. In autoimmune diseases, these AutoAbs may also be prognostic markers, either negative (such as AutoAbs to IL-8 and IL-1α in rheumatoid arthritis) or positive (such as AutoAbs to IL-6 in systemic sclerosis and those to osteopontin in rheumatoid arthritis). They may have neutralizing activity and influence the course of the physiological and pathological immune responses. High levels of AutoAbs against cytokines may even lead to immunodeficiency, such as those to IL-17 in autoimmune polyendocrine syndrome type I or those to IFN-γ in mycobacterial infections. Their role in human therapy may be exploited not only through passive immunization but also through vaccination, which may improve the costs for long lasting treatments of autoimmune diseases. Detection and quantification of these AutoAbs can be profoundly influenced by the technique used and standardization of these methods is needed to increase the value of their analysis. PMID:23885320

  4. Growth factors and cytokines in wound healing.

    PubMed

    Barrientos, Stephan; Stojadinovic, Olivera; Golinko, Michael S; Brem, Harold; Tomic-Canic, Marjana

    2008-01-01

    Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF-beta) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor necrosis factor-alpha family. Currently, patients are treated by three growth factors: PDGF-BB, bFGF, and GM-CSF. Only PDGF-BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.

  5. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms

    PubMed Central

    Dondeti, Mahmoud Fathy; El-Maadawy, Eman Anwar; Talaat, Roba Mohamed

    2016-01-01

    Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC. PMID:27570418

  6. A primer on cytokines: sources, receptors, effects, and inducers.

    PubMed Central

    Curfs, J H; Meis, J F; Hoogkamp-Korstanje, J A

    1997-01-01

    Protection against pathogens is a prerequisite for survival of most organisms. To cope with this continuous challenge, complex defense mechanisms have evolved. The construction, adaptation, and maintenance of these mechanisms are under control of an extensive network of regulatory proteins called cytokines. A great number of cytokines have been described over the last 2 decades. This review consists of an overview of cytokines that are involved in immune responses and describes some historical and general aspects as well as prospective clinical applications. Major biological effects together with information on cytokine receptors, producers, inducers, and biochemical and molecular characteristics are listed in tables. In addition, some basic information is given on cytokine receptor signal transduction. Finally, the recent discoveries of cytokine receptors functioning as coreceptors in the pathogenesis of human immunodeficiency virus are summarized. PMID:9336671

  7. Inflammatory cytokines in pediatric obstructive sleep apnea

    PubMed Central

    Huang, Yu-Shu; Guilleminault, Christian; Hwang, Fang-Ming; Cheng, Chuan; Lin, Cheng-Hui; Li, Hsueh-Yu; Lee, Li-Ang

    2016-01-01

    Abstract Pediatric obstructive sleep apnea (OSA) is associated with chronic systemic inflammation and with cognitive impairments. This study aimed to investigate the status of proinflammatory cytokines, particularly interleukin 17 (IL-17) and interleukin 23 (IL-23) and cognition in pediatric OSA. Controls and OSA children participated in the study. Exclusion criteria were adenotonsillectomy, heart, neurological and severe psychiatric diseases, craniofacial syndromes, and obesity. Polysomnogram was followed by serum testing for inflammatory markers and neurocognitive tests such as continuous performance task (CPT) and Wisconsin card sorting test, questionnaires, analyses of plasma high-sensitivity C-reactive protein (HS-CRP), tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), IL-17, and IL-23. Seventy-nine, 4 to 12-year-old subjects in 2 groups ended the study: 47 nonobese OSA children (mean age = 7.84 ± 0.56 years, body mass index [BMI] = 16.95 ± 0.47 kg/m2, BMI z-score = 0.15 ± 0.21, and mean apnea–hypopnea index [AHI] = 9.13 ± 1.67 events/h) and 32 healthy control children (mean age = 7.02 ± 0.65 years, with BMI = 16.55 ± 0.58 kg/m2, BMI z-score = −0.12 ± 0.27, and mean AHI = 0.41 ± 0.07 event/h) were enrolled. Serum cytokine analyses showed significantly higher levels of HS-CRP, IL-17, and IL-23 in OSA children (P = 0.002, P = 0.024, and P = 0.047). Regression test showed significant influence of HS-CRP, TNF-α, IL-6, IL-17, and specifically IL-23, with the continuous performance test and Wisconsin card sorting test. OSA children have abnormal levels of IL-17, an interleukin related to T helper 17 cells, a T helper cell involved in development of autoimmunity and inflammation. This high expression level may contribute to the complications of pediatric OSA; we also found a significant influence of inflammatory cytokines, particularly IL-23, on abnormal neurocognitive testing. PMID

  8. Inflammatory Cytokines and White Blood Cell Counts ...

    EPA Pesticide Factsheets

    Epidemiological observations of urban inhalation exposures to diesel exhaust (DE) and ozone (O3) have shown pre-clinical cardiopulmonary responses in humans. Identifying the key biological mechanisms that initiate these health bioindicators is difficult due to variability in environmental exposure in time and from person to person. Previously, environmentally controlled human exposure chambers have been used to study DE and O3 dose-response patterns separately, but investigation of co-exposures has not been performed under controlled conditions. Because a mixture is a more realistic exposure scenario for the general public, in this study we investigate the relationships of urban levels of urban-level DE exposure (300 μg/m3), O3 (0.3 ppm), DE + O3 co-exposure, and innate immune system responses. Fifteen healthy human volunteers were studied for changes in ten inflammatory cytokines (interleukins 1β, 2, 4, 5, 8, 10, 12p70 and 13, IFN-γ, and TNF-α) and counts of three white blood cell types (lymphocytes, monocytes, and neutrophils) following controlled exposures to DE, O3, and DE+O3. The results show subtle cytokines responses to the diesel-only and ozone-only exposures, and that a more complex (possibly synergistic) relationship exists in the combination of these two exposures with suppression of IL-5, IL-12p70, IFN-γ, and TNF-α that persists up to 22-hours for IFN-γ and TNF-α. The white blood cell differential counts showed significant monocyte and lympho

  9. Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

    PubMed

    Alnek, Kristi; Kisand, Kalle; Heilman, Kaire; Peet, Aleksandr; Varik, Karin; Uibo, Raivo

    2015-01-01

    The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th1) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α), Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

  10. Cytokine profiles of seventeen cytokines, growth factors and chemokines in cord blood and its relation to perinatal clinical findings.

    PubMed

    Takahashi, Naoto; Uehara, Ritei; Kobayashi, Mami; Yada, Yukari; Koike, Yasunori; Kawamata, Ryou; Odaka, Jun; Honma, Yoko; Momoi, Mariko Y

    2010-03-01

    Few papers have investigated the cytokine profiles of multiple cytokines in cord blood. We obtained cord blood samples from 224 infants admitted to our neonatal intensive care unit. Cytokine profiles of 17 cytokines were investigated using cytometric bead array technology. We found a wide variety of cytokines of various levels which ranged from 0.59pg/ml (in Interleukin (IL)-4) to 222.0pg/ml (in macrophage inflammatory protein-1beta. Pro-inflammatory cytokines were highly correlated with each other and with granulocyte-colony stimulating factor and IL-8. On the contrary, IL-5, IL-13, and IL-17 did not show any significant correlation with other cytokines. Several maternal factors were strongly related to several cytokines in cord blood. IL-6, IL-8 and monocyte chemotactic protein-1 were closely related to certain neonatal diseases in preterm neonates. Some cytokines may be regulated independently of each other, while others appear to work as a network affecting physiological and pathological conditions in the fetus.

  11. Modulation of Cytokine and Cytokine Receptor/Antagonist by Treatment with Doxycycline and Tetracycline in Patients with Dengue Fever

    PubMed Central

    Castro, J. E. Z.; Vado-Solis, I.; Perez-Osorio, C.; Fredeking, T. M.

    2011-01-01

    Dengue virus infection can lead to dengue fever (DF) or dengue hemorrhagic fever (DHF). Disease severity has been linked to an increase in various cytokine levels. In this study, we evaluated the effectiveness of doxycycline and tetracycline to modulate serum levels of IL-6, IL-1B, and TNF and cytokine receptor/receptor antagonist TNF-R1 and IL-1RA in patients with DF or DHF. Hospitalized patients were randomized to receive standard supportive care or supportive care combined with doxycycline or tetracycline therapy. Serum cytokine and cytokine receptor/antagonist levels were determined at the onset of therapy and after 3 and 7 days. Cytokine and cytokine receptor/antagonist levels were substantially elevated at day 0. IL-6, IL-1β, and TNF remained at or above day 0 levels throughout the study period in untreated patients. Treatment with tetracycline or doxycycline resulted in a significant decline in cytokine levels. Similarly, IL-1RA and TNF-R1 serum concentrations were elevated at baseline and showed a moderate increase among untreated patients. Both drugs resulted in a significant rise in IL-1Ra levels by day 3 in patients. In contrast, treatment did not affect a similar result for TNF-R1. When compared to the control group, however, a significant rise post-treatment was seen upon intragroup analysis. Further analysis demonstrated that doxycycline was significantly more effective at modulating cytokine and cytokine receptor/antagonist levels than tetracycline. PMID:21461372

  12. IL-1β is a key cytokine that induces trypsin upregulation in the influenza virus-cytokine-trypsin cycle.

    PubMed

    Indalao, I L; Sawabuchi, T; Takahashi, E; Kido, H

    2017-01-01

    Severe influenza is characterized by a cytokine storm, and the influenza virus-cytokine-trypsin cycle is one of the important mechanisms of viral multiplication and multiple organ failure. The aim of this study was to define the key cytokine(s) responsible for trypsin upregulation. Mice were infected with influenza virus strain A/Puerto Rico/8/34 (H1N1) or treated individually or with a combination of interleukin-1β, interleukin-6, and tumor necrosis factor α. The levels of these cytokines and trypsin in the lungs were monitored. The neutralizing effects of anti-IL-1β antibodies on cytokine and trypsin expression in human A549 cells and lung inflammation in the infected mice were examined. Infection induced interleukin-1β, interleukin-6, tumor necrosis factor α, and ectopic trypsin in mouse lungs in a dose- and time-dependent manner. Intraperitoneal administration of interleukin-1β combined with other cytokines tended to upregulate trypsin and cytokine expression in the lungs, but the combination without interleukin-1β did not induce trypsin. In contrast, incubation of A549 cells with interleukin-1β alone induced both cytokines and trypsin, and anti-interleukin-1β antibody treatment abrogated these effects. Administration of the antibody in the infected mice reduced lung inflammation area. These findings suggest that IL-1β plays a key role in trypsin upregulation and has a pathological role in multiple organ failure.

  13. Elevated specific peripheral cytokines found in major depressive disorder patients with childhood trauma exposure: a cytokine antibody array analysis.

    PubMed

    Lu, Shaojia; Peng, Hongjun; Wang, Lifeng; Vasish, Seewoobudul; Zhang, Yan; Gao, Weijia; Wu, Weiwei; Liao, Mei; Wang, Mi; Tang, Hao; Li, Wenping; Li, Weihui; Li, Zexuan; Zhou, Jiansong; Zhang, Zhijun; Li, Lingjiang

    2013-10-01

    Taking into consideration the previous evidence of revealing the relationship of early life adversity, major depressive disorder (MDD), and stress-linked immunological changes, we recruited 22 MDD patients with childhood trauma exposures (CTE), 21 MDD patients without CTE, and 22 healthy controls without CTE, and then utilized a novel cytokine antibody array methodology to detect potential biomarkers underlying MDD in 120 peripheral cytokines and to evaluate the effect of CTE on cytokine changes in MDD patients. Although 13 cytokines were identified with highly significant differences in expressions between MDD patients and normal controls, this relationship was significantly attenuated and no longer significant after consideration of the effect of CTE in MDD patients. Depressed individuals with CTE (TD patients) were more likely to have higher peripheral levels of those cytokines. Severity of depression was associated with plasma levels of certain increased cytokines; meanwhile, the increased cytokines led to a proper separation of TD patients from normal controls during clustering analyses. Our research outcomes add great strength to the relationship between depression and cytokine changes and suggest that childhood trauma may play a vital role in the co-appearance of cytokine changes and depression.

  14. Cross-talk among gp130 cytokines in adipocytes.

    PubMed

    Zvonic, Sanjin; Baugh, James E; Arbour-Reily, Patricia; Mynatt, Randall L; Stephens, Jacqueline M

    2005-10-07

    The interleukin-6 (IL-6) family of cytokines is a family of structurally and functionally related proteins, including IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). These proteins are also known as gp130 cytokines because they all share gp130 as a common transducer protein within their functional receptor complexes. Several of these cytokines (LIF, OSM, CNTF, and CT-1) also utilize the LIF receptor (LIFR) as a component of their receptor complex. We have shown that all of these cytokines are capable of activating both the JAK/STAT and p42/44 mitogen-activated protein kinase signaling pathways in 3T3-L1 adipocytes. By performing a variety of preincubation studies and examining the ability of these cytokines to activate STATs, ERKs, and induce transcription of SOCS-3 mRNA, we have also examined the ability of gp130 cytokines to modulate the action of their family members. Our results indicate that a subset of gp130 cytokines, in particular CT-1, LIF, and OSM, has the ability to impair subsequent signaling activity initiated by gp130 cytokines. However, IL-6 and CNTF do not exhibit this cross-talk ability. Moreover, our results indicate that the cross-talk among gp130 cytokines is mediated by the ability of these cytokines to induce ligand-dependent degradation of the LIFR, in a proteasome-independent manner, which coincides with decreased levels of LIFR at the plasma membrane. In summary, our results demonstrate that an inhibitory cross-talk among specific gp130 cytokines in 3T3-L1 adipocytes occurs as a result of specific degradation of LIFR via a lysosome-mediated pathway.

  15. SNP/haplotype associations in cytokine and cytokine receptor genes and immunity to rubella vaccine.

    PubMed

    Dhiman, Neelam; Haralambieva, Iana H; Kennedy, Richard B; Vierkant, Robert A; O'Byrne, Megan M; Ovsyannikova, Inna G; Jacobson, Robert M; Poland, Gregory A

    2010-04-01

    An effective immune response to vaccination is, in part, a complex interaction of alleles of multiple genes regulating cytokine networks. We conducted a genotyping study of Th1/Th2/inflammatory cytokines/cytokine receptors in healthy children (n = 738, 11-19 years) to determine associations between individual single-nucleotide polymorphisms (SNPs)/haplotypes and immune outcomes after two doses of rubella vaccine. SNPs (n = 501) were selected using the ldSelect-approach and genotyped using Illumina GoldenGate and TaqMan assays. Rubella-IgG levels were measured by immunoassay and secreted cytokines by ELISA. Linear regression and post hoc haplotype analyses were used to determine associations between single SNPs/haplotypes and immune outcomes. Increased carriage of minor alleles for the promoter SNPs (rs2844482 and rs2857708) of the TNFA gene were associated with dose-related increases in rubella antibodies. IL-6 secretion was co-directionally associated (p < or = 0.01) with five intronic SNPs in the TNFRSF1B gene in an allele dose-related manner, while five promoter/intronic SNPs in the IL12B gene were associated with variations in IL-6 secretion. TNFA haplotype AAACGGGGC (t-statistic = 3.32) and IL12B promoter haplotype TAG (t-statistic = 2.66) were associated with higher levels of (p < or = 0.01) rubella-IgG and IL-6 secretion, respectively. We identified individual SNPs/haplotypes in TNFA/TNFRSF1B and IL12B genes that appear to modulate immunity to rubella vaccination. Identification of such "genetic fingerprints" may predict the outcome of vaccine response and inform new vaccine strategies.

  16. Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

    PubMed Central

    Rider, Peleg; Carmi, Yaron

    2016-01-01

    Proinflammatory cytokines are potent mediators of numerous biological processes and are tightly regulated in the body. Chronic uncontrolled levels of such cytokines can initiate and derive many pathologies, including incidences of autoimmunity and cancer. Therefore, therapies that regulate the activity of inflammatory cytokines, either by supplementation of anti-inflammatory recombinant cytokines or by neutralizing them by using blocking antibodies, have been extensively used over the past decades. Over the past few years, new innovative biological agents for blocking and regulating cytokine activities have emerged. Here, we review some of the most recent approaches of cytokine targeting, focusing on anti-TNF antibodies or recombinant TNF decoy receptor, recombinant IL-1 receptor antagonist (IL-1Ra) and anti-IL-1 antibodies, anti-IL-6 receptor antibodies, and TH17 targeting antibodies. We discuss their effects as biologic drugs, as evaluated in numerous clinical trials, and highlight their therapeutic potential as well as emphasize their inherent limitations and clinical risks. We suggest that while systemic blocking of proinflammatory cytokines using biological agents can ameliorate disease pathogenesis and progression, it may also abrogate the hosts defense against infections. Moreover, we outline the rational need to develop new therapies, which block inflammatory cytokines only at sites of inflammation, while enabling their function systemically. PMID:28083070

  17. Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies.

    PubMed

    Barrera, David; Díaz, Lorenza; Noyola-Martínez, Nancy; Halhali, Ali

    2015-08-04

    Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant women there is a shift toward a Th2 cytokine profile, which is necessary for an adequate pregnancy outcome. As compared with normal pregnancy, high pro-inflammatory and low anti-inflammatory cytokine levels have been observed in preeclamptic women. Preeclampsia has been associated with low calcitriol levels and vitamin D deficiency is correlated with a higher risk of the development of this disease. It has been demonstrated that placenta is a source as well as the target of calcitriol and cytokines and placental dysfunction has been associated with preeclampsia. Therefore, the present manuscript includes a review about serum calcitriol levels in non-pregnant, pregnant, and preeclamptic women as well as a review on the fetoplacental vitamin D metabolism in healthy and preeclamptic pregnancies. In addition, circulating and fetoplacental inflammatory cytokines in healthy and preeclamptic pregnancies are reviewed. Finally, the effects of calcitriol upon placental pro-inflammatory cytokines are also explored. In conclusion, maternal and placental calcitriol levels are low in preeclampsia which may explain, at least in part, high pro-inflammatory cytokine levels in this disease.

  18. Local and Systemic Cytokine Expression in Patients with Postherpetic Neuralgia

    PubMed Central

    Üçeyler, Nurcan; Valet, Michael; Kafke, Waldemar; Tölle, Thomas R.; Sommer, Claudia

    2014-01-01

    Background Postherpetic neuralgia (PHN) is the painful complication of a varicella zoster virus reactivation. We investigated the systemic and local gene expression of pro- and anti-inflammatory cytokine expression in patients with PHN. Methods Thirteen patients with PHN at the torso (Th4-S1) were recruited. Skin punch biopsies were obtained from the painful and the contralateral painless body area for intraepidermal nerve fiber density (IENFD) and cytokine profiling. Additionally, blood was withdrawn for systemic cytokine expression and compared to blood values of healthy controls. We analyzed the gene expression of selected pro- and anti-inflammatory cytokines (tumor necrosis factor-alpha [TNF] and interleukins [IL]-1β, IL-2, and IL-8). Results IENFD was lower in affected skin compared to unaffected skin (p<0.05), while local gene expression of pro- and anti-inflammatory cytokines did not differ except for two patients who had 7fold higher IL-6 and 10fold higher IL-10 gene expression in the affected skin compared to the contralateral unaffected skin sample. Also, the systemic expression of cytokines in patients with PHN and in healthy controls was similar. Conclusion While the systemic and local expression of the investigated pro- and anti-inflammatory cytokines was not different from controls, this may have been influenced by study limitations like the low number of patients and different disease durations. Furthermore, other cytokines or pain mediators need to be considered. PMID:25127283

  19. Tet2: breaking down barriers to T cell cytokine expression.

    PubMed

    Zhong, Chao; Zhu, Jinfang

    2015-04-21

    It has been unclear whether alteration in DNA methylation at cytokine genes during T helper (Th) cell differentiation is a cause or consequence of gene expression. In this issue of Immunity, Ichiyama et al. (2015) show that oxidation of 5-methylcytosine by the methylcytosine dioxygenase Tet2 regulates cytokine production in Th cells.

  20. Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies

    PubMed Central

    Barrera, David; Díaz, Lorenza; Noyola-Martínez, Nancy; Halhali, Ali

    2015-01-01

    Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant women there is a shift toward a Th2 cytokine profile, which is necessary for an adequate pregnancy outcome. As compared with normal pregnancy, high pro-inflammatory and low anti-inflammatory cytokine levels have been observed in preeclamptic women. Preeclampsia has been associated with low calcitriol levels and vitamin D deficiency is correlated with a higher risk of the development of this disease. It has been demonstrated that placenta is a source as well as the target of calcitriol and cytokines and placental dysfunction has been associated with preeclampsia. Therefore, the present manuscript includes a review about serum calcitriol levels in non-pregnant, pregnant, and preeclamptic women as well as a review on the fetoplacental vitamin D metabolism in healthy and preeclamptic pregnancies. In addition, circulating and fetoplacental inflammatory cytokines in healthy and preeclamptic pregnancies are reviewed. Finally, the effects of calcitriol upon placental pro-inflammatory cytokines are also explored. In conclusion, maternal and placental calcitriol levels are low in preeclampsia which may explain, at least in part, high pro-inflammatory cytokine levels in this disease. PMID:26247971

  1. Cytokine Levels in the Serum of Healthy Subjects

    PubMed Central

    Kleiner, Giulio; Marcuzzi, Annalisa; Zanin, Valentina; Monasta, Lorenzo; Zauli, Giorgio

    2013-01-01

    Growing knowledge about the cytokine network response has led to a better comprehension of mechanisms of pathologies and to the development of new treatments with biological drugs, able to block specific molecules of the immune response. Indeed, when the cytokine production is deregulated, diseases often occur. The understanding of the physiological mechanism of the cytokine network would be useful to better comprehend pathological conditions. Moreover, since the immune system and response change their properties with development, differences in patients' age should be taken into account, both in physiological and in pathological conditions. In this study, we analyzed the profile of 48 cytokines and chemokines in the serum of healthy subjects, comparing adults (≥18 years) with young children and children (1–6 and 7–17 years). We found that a certain number of cytokines were not being produced in healthy subjects; others showed a constant serum level amongst the groups. Certain cytokines exhibited a downward or an upward trend with increasing age. The remaining cytokines were up- or downregulated in the group of the children with respect to the other groups. In conclusion, we drew some kinds of guidelines about the physiological production of cytokines and chemokines, underling the difference caused by aging. PMID:23533306

  2. Cytokine levels in the serum of healthy subjects.

    PubMed

    Kleiner, Giulio; Marcuzzi, Annalisa; Zanin, Valentina; Monasta, Lorenzo; Zauli, Giorgio

    2013-01-01

    Growing knowledge about the cytokine network response has led to a better comprehension of mechanisms of pathologies and to the development of new treatments with biological drugs, able to block specific molecules of the immune response. Indeed, when the cytokine production is deregulated, diseases often occur. The understanding of the physiological mechanism of the cytokine network would be useful to better comprehend pathological conditions. Moreover, since the immune system and response change their properties with development, differences in patients' age should be taken into account, both in physiological and in pathological conditions. In this study, we analyzed the profile of 48 cytokines and chemokines in the serum of healthy subjects, comparing adults (≥18 years) with young children and children (1-6 and 7-17 years). We found that a certain number of cytokines were not being produced in healthy subjects; others showed a constant serum level amongst the groups. Certain cytokines exhibited a downward or an upward trend with increasing age. The remaining cytokines were up- or downregulated in the group of the children with respect to the other groups. In conclusion, we drew some kinds of guidelines about the physiological production of cytokines and chemokines, underling the difference caused by aging.

  3. The cytokines cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF) and ciliary neurotrophic factor (CNTF) differ in their receptor specificities.

    PubMed

    Tormo, Aurélie Jeanne; Letellier, Marie-Claude; Lissilaa, Rami; Batraville, Laurie-Anne; Sharma, Mukut; Ferlin, Walter; Elson, Greg; Crabé, Sandrine; Gauchat, Jean-François

    2012-12-01

    Ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC) are two cytokines with neurotrophic and immunomodulatory activities. CNTF is a cytoplasmic factor believed to be released upon cellular damage, while CLC requires interaction with a soluble cytokine receptor, cytokine-like factor 1 (CLF), to be efficiently secreted. Both cytokines activate a receptor complex comprising the cytokine binding CNTF receptor α (CNTFRα) and two signaling chains namely, leukemia inhibitory factor receptor β (LIFRβ) and gp130. Human CNTF can recruit and activate an alternative receptor in which CNTFRα is substituted by IL-6Rα. As both CNTF and CLC have immune-regulatory activities in mice, we compared their ability to recruit mouse receptors comprising both gp130 and LIFRβ signaling chains and either IL-6Rα or IL-11Rα which, unlike CNTFRα, are expressed by immune cells. Our results indicate that 1) mouse CNTF, like its human homologue, can activate cells expressing gp130/LIFRβ with either CNTFRα or IL-6Rα and, 2) CLC/CLF is more restricted in its specificity in that it activates only the tripartite CNTFR. Several gp130 signaling cytokines influence T helper cell differentiation. We therefore investigated the effect of CNTF on CD4 T cell cytokine production. We observed that CNTF increased the number of IFN-γ producing CD4 T cells. As IFN-γ is considered a mediator of the therapeutic effect of IFN-β in multiple sclerosis, induction of IFN-γ by CNTF may contribute to the beneficial immunomodulatory effect of CNTF in mouse multiple sclerosis models. Together, our results indicate that CNTF activates the same tripartite receptors in mouse and human cells and further validate rodent models for pre-clinical investigation of CNTF and CNTF derivatives. Furthermore, CNTF and CLC/CLF differ in their receptor specificities. The receptor α chain involved in the immunomodulatory effects of CLC/CLF remains to be identified.

  4. Cytokines in Bipolar Disorder: Paving the Way for Neuroprogression

    PubMed Central

    Barbosa, Izabela Guimarães; Bauer, Moisés Evandro; Machado-Vieira, Rodrigo; Teixeira, Antonio Lucio

    2014-01-01

    Bipolar disorder (BD) is a severe, chronic, and recurrent psychiatric illness. It has been associated with high prevalence of medical comorbidities and cognitive impairment. Its neurobiology is not completely understood, but recent evidence has shown a wide range of immune changes. Cytokines are proteins involved in the regulation and the orchestration of the immune response. We performed a review on the involvement of cytokines in BD. We also discuss the cytokines involvement in the neuroprogression of BD. It has been demonstrated that increased expression of cytokines in the central nervous system in postmortem studies is in line with the elevated circulating levels of proinflammatory cytokines in BD patients. The proinflammatory profile and the immune imbalance in BD might be regarded as potential targets to the development of new therapeutic strategies. PMID:25313338

  5. [Cytokine imbalance in critically ill patients: SIRS and CARS].

    PubMed

    Murata, A; Kikuchi, M; Mishima, S; Sakaki, S; Goto, H; Matsuoka, T; Tanaka, H; Yukioka, T; Shimazaki, S

    1999-07-01

    It remains difficult to treat severely ill patients, especially those who have sepsis and subsequent multiple organ dysfunction syndrome. We propose the hypothesis that the pathophysiology in the sequential sepsis and multiple organ dysfunction syndrome may be strongly related to the imbalance between inflammatory cytokines and antiinflammatory cytokines induced for the host defense to active neutrophils and endothelial cells. Thus we attempted to develop cytokine modulation therapy to normalize the cytokine balance in the host defense system. In this review, we elucidate the relationship between cytokine imbalance and SIRS/CARS in patients with severe burn injury. Furthermore, we examine the possible usage of G-CSF to amplify neutrophil function, and clarify the reasons why various innovative therapies against sepsis have failed.

  6. The role of cytokines in immune changes induced by spaceflight

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Miller, E. S.

    1993-01-01

    It has become apparent that spaceflight alters many immune responses. Among the regulatory components of the immune response that have been shown to be affected by spaceflight is the cytokine network. Spaceflight, as well as model systems of spaceflight, have been shown to affect the production and action of various cytokines including interferons, interleukins, colony stimulating factors, and tumor necrosis factors. These changes have been shown not to involve a general shutdown of the cytokine network but, rather, to involve selective alterations of specific cytokine functions by spaceflight. The full breadth of changes in cytokines induced by spaceflight, as well as mechanisms, duration, adaptation, reversibility, and significance to resistance to infection and neoplastic diseases, remains to be established.

  7. The inflammatory cytokines: molecular biomarkers for major depressive disorder?

    PubMed

    Martin, Charlotte; Tansey, Katherine E; Schalkwyk, Leonard C; Powell, Timothy R

    2015-01-01

    Cytokines are pleotropic cell signaling proteins that, in addition to their role as inflammatory mediators, also affect neurotransmitter systems, brain functionality and mood. Here we explore the potential utility of cytokine biomarkers for major depressive disorder. Specifically, we explore how genetic, transcriptomic and proteomic information relating to the cytokines might act as biomarkers, aiding clinical diagnosis and treatment selection processes. We advise future studies to investigate whether cytokine biomarkers might differentiate major depressive disorder patients from other patient groups with overlapping clinical characteristics. Furthermore, we invite future pharmacogenetic studies to investigate whether early antidepressant-induced changes to cytokine mRNA or protein levels precede behavioral changes and act as longer-term predictors of clinical antidepressant response.

  8. Kitasato Symposium 2009: New Prospects for Cytokine Inhibition

    PubMed Central

    2009-01-01

    The Kitasato Symposium 2009: New Prospects for Cytokine Inhibition was held in Berlin, Germany from 7 to 9 May 2009. The key aims of this meeting were to bring together a group of front-line researchers and rheumatologists to evaluate the use of cytokine blockade and to examine the role of certain cytokines in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. A keynote lecture delivered by Professor Jean-Michel Dayer provided an up-to-date overview of the interactions occurring between the immune system and acute phase proteins. Other speakers discussed the role of cytokines in rheumatoid arthritis, including their role in joint destruction, as well as their regulatory role upon T cells and B cells. The involvement of cytokines in other autoimmune diseases was also addressed. PMID:20067593

  9. Interleukin-6: a cytokine to forget.

    PubMed

    Balschun, D; Wetzel, W; Del Rey, A; Pitossi, F; Schneider, H; Zuschratter, W; Besedovsky, H O

    2004-11-01

    It is known that proinflammatory cytokines such as interleukin-6 (IL-6) are expressed in the central nervous system (CNS) during disease conditions and affect several brain functions including memory and learning. In contrast to these effects observed during pathological conditions, here we describe a physiological function of IL-6 in the "healthy" brain in synaptic plasticity and memory consolidation. During long-term potentiation (LTP) in vitro and in freely moving rats, IL-6 gene expression in the hippocampus was substantially increased. This increase was long lasting, specific to potentiation, and was prevented by inhibition of N-methyl-D-aspartate receptors with (+/-)-2-amino-5-phosphonopentanoic acid (AP-5). Blockade of endogenous IL-6 by application of a neutralizing anti-IL-6 antibody 90 min after tetanus caused a remarkable prolongation of LTP. Consistently, blockade of endogenous IL-6, 90 min after hippocampus-dependent spatial alternation learning resulted in a significant improvement of long-term memory. In view of the suggested role of LTP in memory formation, these data implicate IL-6 in the mechanisms controlling the kinetics and amount of information storage.

  10. The cytokine TWEAK modulates renal tubulointerstitial inflammation.

    PubMed

    Sanz, Ana Belen; Justo, Pilar; Sanchez-Niño, Maria Dolores; Blanco-Colio, Luis Miguel; Winkles, Jeffrey A; Kreztler, Matthias; Jakubowski, Aniela; Blanco, Julia; Egido, Jesús; Ruiz-Ortega, Marta; Ortiz, Alberto

    2008-04-01

    TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of cytokines. In addition to binding and activating the fibroblast growth factor-inducible 14 receptor, TWEAK may regulate apoptosis, proliferation, and inflammation; however, the role of this system in kidney injury is unknown. In vitro, it was found that TWEAK induced the sustained activation of NF-kappaB in a murine tubular epithelial cell line (MCT). NF-kappaB activation was associated with degradation of IkappaB-alpha; translocation of RelA to the nucleus; and increased mRNA and protein expression of monocyte chemoattractant protein-1, RANTES, and IL-6. Similarly, in vivo, the systemic administration of TWEAK induced renal NF-kappaB activation, chemokine and IL-6 expression, and interstitial inflammation in mice. Parthenolide, which prevents IkappaB-alpha degradation, inhibited TWEAK-induced NF-kappaB activation and prevented the aforementioned changes in vitro and in vivo. After folic acid-induced acute kidney injury, fibroblast growth factor-inducible 14 expression increased in mouse tubular epithelium. Neutralization of TWEAK decreased the expression of chemokines in tubular cells and reduced interstitial inflammation. In conclusion, TWEAK has NF-kappaB-dependent proinflammatory effects on tubular epithelial cells in vitro and in vivo. Moreover, blockade of TWEAK reduces tubular chemokine expression and macrophage infiltration, suggesting that TWEAK modulates acute kidney injury by regulating the inflammatory response.

  11. Chronic fatigue syndrome and circulating cytokines: A systematic review.

    PubMed

    Blundell, S; Ray, K K; Buckland, M; White, P D

    2015-11-01

    There has been much interest in the role of the immune system in the pathophysiology of chronic fatigue syndrome (CFS), as CFS may develop following an infection and cytokines are known to induce acute sickness behaviour, with similar symptoms to CFS. Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a search was conducted on PubMed, Web of Science, Embase and PsycINFO, for CFS related-terms in combination with cytokine-related terms. Cases had to meet established criteria for CFS and be compared with healthy controls. Papers retrieved were assessed for both inclusionary criteria and quality. 38 papers met the inclusionary criteria. The quality of the studies varied. 77 serum or plasma cytokines were measured without immune stimulation. Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-β) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies, although insufficient data were available for some cytokines. Following physical exercise there were no differences in circulating cytokine levels between cases and controls and exercise made no difference to already elevated TGF-β concentrations. The finding of elevated TGF-β concentration, at biologically relevant levels, needs further exploration, but circulating cytokines do not seem to explain the core characteristic of post-exertional fatigue.

  12. Divergent T-Cell Cytokine Patterns in Inflammatory Arthritis

    NASA Astrophysics Data System (ADS)

    Simon, A. K.; Seipelt, E.; Sieper, J.

    1994-08-01

    A major immunoregulatory mechanism in inflammatory infections and allergic diseases is the control of the balance of cytokines secreted by Th1/Th2 subsets of T helper (Th) cells. This might also be true in autoimmune diseases; a Th2 pattern that prevents an effective immune response in infections with intracellular bacteria may favor immunosuppression in autoimmune diseases. The pattern of cytokine expression was compared in the synovial tissue from patients with a typical autoimmune disease, rheumatoid arthritis, and with a disorder with similar synovial pathology but driven by persisting exogenous antigen, reactive arthritis. We screened 12 rheumatoid and 9 reactive arthritis synovial tissues by PCR and in situ hybridization for their expression of T-cell cytokines. The cytokine pattern differs significantly between the two diseases; rheumatoid arthritis samples express a Th1-like pattern whereas in reactive arthritis interferon γ expression is accompanied by that of interleukin 4. Studying the expression of cytokines by in situ hybridization confirmed the results found by PCR; they also show an extremely low frequency of cytokine-transcribing cells. In a double-staining experiment, it was demonstrated that interleukin 4 is made by CD4 cells. These experiments favor the possibility of therapeutic intervention in inflammatory rheumatic diseases by means of inhibitory cytokines.

  13. The IL-2 cytokine family in cancer immunotherapy.

    PubMed

    Sim, Geok Choo; Radvanyi, Laszlo

    2014-08-01

    The use of cytokines from the IL-2 family (also called the common γ chain cytokine family) such as interleukin (IL)-2, IL-7, IL-15, and IL-21 to activate the immune system of cancer patients is one of the most important areas of current cancer immunotherapy research. The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions. The initial clinical success observed in some IL-2-treated patients encouraged further efforts focused on developing and improving the application of other IL-2 family cytokines (IL-4, IL-7, IL-9, IL-15, and IL-21) that have unique biological effects playing important roles in the development, proliferation, and function of specific subsets of lymphocytes at different stages of differentiation with some overlapping effects with IL-2. IL-7, IL-15, and IL-21, as well as mutant forms or variants of IL-2, are now also being actively pursued in the clinic with some measured early successes. In this review, we summarize the current knowledge on the biology of the IL-2 cytokine family focusing on IL-2, IL-15 and IL-21. We discuss the similarities and differences between the signaling pathways mediated by these cytokines and their immunomodulatory effects on different subsets of immune cells. Current clinical application of IL-2, IL-15 and IL-21 either as single agents or in combination with other biological agents and the limitation and potential drawbacks of these cytokines for cancer immunotherapy are also described. Lastly, we discuss the future direction of research on these cytokines, such as the development of new cytokine mutants and variants for improving cytokine-based immunotherapy through differential binding to specific receptor subunits.

  14. Fc-based cytokines : prospects for engineering superior therapeutics.

    PubMed

    Jazayeri, Jalal A; Carroll, Graeme J

    2008-01-01

    The application of Fc (fragment crystallizable)-based cytokines (the fusion of the constant region of IgG to a cytokine of interest) as biotherapeutic agents to modulate inflammatory and immune responses has become increasingly popular in recent years. This is because in their monomeric form, cytokines are relatively small molecules with short serum half-lives, which necessitates frequent administration and thus limits their clinical utility. To rectify the problem, attempts have been made to improve the stability of these agents in vivo. This has been achieved through diverse strategies such as modification with polyethylene glycol (PEGylation) or by ligating the cytokine to protein moieties such as the constant heavy chain of IgG, known as the Fc fragment. The construction of Fc chimeric proteins has been shown to improve pharmacokinetics. However, since there is an inverse relationship between the size of molecules and the rate at which they diffuse through mucus, Fc fusion constructs potentially have a lower rate of diffusion. Consequently, a compromise is reached whereby Fc constructs are engineered to incorporate ligated cytokines in a monomeric form (one molecule of cytokine fused to a single Fc dimer) rather than in a dimeric form (two molecules of cytokine fused to a single Fc dimer). A recent and novel approach to improve stability in serum is a procedure that involves sheathing cytokines in protective protein covers called latency peptides. The enclosed cytokine is protected from degradation and allowed to act where needed when the outer peptide cover is removed. For some applications, a reduced serum half-life is desirable; for example, where there is a need to reduce IgG levels in antibody-mediated diseases. To achieve this goal, a strategy called AbDeg, which involves enhanced Ig degradation, has been devised. This article provides an overview of the design and construction of Fc-based cytokines, in both dimeric and monomeric forms. Several examples

  15. Effects of exchange transfusion on cytokine profiles in necrotizing enterocolitis.

    PubMed

    Sugiura, Tokio; Kouwaki, Masanori; Goto, Kenji; Endo, Takeshi; Ito, Koichi; Koyama, Norihisa; Togari, Hajime

    2012-12-01

    To study the effect of exchange transfusion on cytokine profiles in a patient with necrotizing enterocolitis, the levels of 12 cytokines and serum calprotectin were measured among exchange transfusion. A male extremely low birth weight infant was in non-compensated shock and diagnosed stage 3 necrotizing enterocolitis. Exchange transfusion was performed for critical condition, refractory hypotension and disseminated intravascular coagulation. After exchange transfusion, the patient's blood pressure increased and stabilized. Then an enterostomy was performed and revealed necrosis of the ascending colon. Of the cytokines examined, interleukin-8 and serum calprotectin were high before exchange transfusion and decreased after exchange transfusion.

  16. Common Gamma Chain Cytokines in Combinatorial Immune Strategies against Cancer

    PubMed Central

    Pulliam, Stephanie R.; Uzhachenko, Roman V.; Adunyah, Samuel E.; Shanker, Anil

    2015-01-01

    Common γ chain (γC) cytokines, namely IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 are important for the proliferation, differentiation, and survival of lymphocytes that display antitumor activity, thus stimulating considerable interest for the use of cytokines in cancer immunotherapy. In this review, we will focus on the γC cytokines that demonstrate the greatest potential for immunotherapy, IL-2, IL-7, IL-15, and IL-21. We will briefly cover their biological function, potential applications in cancer therapy, and update on their use in combinatorial immune strategies for eradicating tumors and hematopoietic malignancies. PMID:26597610

  17. Atopic dermatitis and cytokines: the immunoregulatory and therapeutic implications of cytokines in atopic dermatitis--part II: negative regulation and cytokine therapy in atopic dermatitis.

    PubMed

    Noh, Geunwoong; Lee, Jaeho

    2012-09-01

    Atopic dermatitis is an immunologic disease that results in allergic inflammations of the skin. Cytokines are involved in the negative regulation of immunopathogenesis of atopic dermatitis. Negative immune regulation is also achieved by immune cells in addition to cytokines which are subsequently regulated by a counter-regulatory mechanism. Allergen tolerance is an important aspect of the treatment of atopic dermatitis. Recently, the IL-27, IL-21, and IL-10 cytokines were found to be important components of the counter regulatory mechanism that terminates immune response, and protects the host from excessive immune responses. IL-10 and TGF-β are well-known to be involved in the immune tolerance. IL-10 and IFN-γ are promising cytokines with respect to the prevention of allergen sensitization and the induction of allergen-specific tolerance. In particular, IFN-γ has unique tolerogenic effects with respect to pre-sensitized allergens, especially in atopic dermatitis. In this review, the role of cytokines in the immune tolerance and relevant patents are reviewed, and therapeutic strategies are presented based on the immunologic architecture of AD.

  18. Pro-angiogenic cytokines as cardiovascular therapeutics: assessing the potential.

    PubMed

    Atluri, Pavan; Woo, Y Joseph

    2008-01-01

    Coronary artery and peripheral vascular disease are global health concerns with limited therapies. Currently available medical and surgical therapies for these disease processes are highly effective for only a fraction of patients. Extensive effort has been devoted to finding molecular therapies to enhance perfusion and function of ischemic myocardial and peripheral skeletal muscle. Angiogenic cytokines (fibroblast growth factor [FGF], vascular endothelial growth factor [VEGF], hepatocyte growth factor [HGF], placental growth factor, stromal cell-derived factor-1alpha) have shown theoretical and experimental promise in upregulating endogenous endothelial progenitor cell-mediated angiogenesis. Preliminary clinical trials have suggested improvements in myocardial and peripheral perfusion following therapy with FGF, VEGF, and HGF. Further studies on the efficacy of cytokine-mediated angiogenesis are required before widespread clinical application is possible. Investigation into adjunctive cytokine therapies for myocardial and peripheral muscle ischemia is warranted. Based on experimental evidence, appropriate angiogenic cytokine therapy should provide benefits in both perfusion and hemodynamic function.

  19. High efficiency cell-specific targeting of cytokine activity

    NASA Astrophysics Data System (ADS)

    Garcin, Geneviève; Paul, Franciane; Staufenbiel, Markus; Bordat, Yann; van der Heyden, José; Wilmes, Stephan; Cartron, Guillaume; Apparailly, Florence; de Koker, Stefaan; Piehler, Jacob; Tavernier, Jan; Uzé, Gilles

    2014-01-01

    Systemic toxicity currently prevents exploiting the huge potential of many cytokines for medical applications. Here we present a novel strategy to engineer immunocytokines with very high targeting efficacies. The method lies in the use of mutants of toxic cytokines that markedly reduce their receptor-binding affinities, and that are thus rendered essentially inactive. Upon fusion to nanobodies specifically binding to marker proteins, activity of these cytokines is selectively restored for cell populations expressing this marker. This ‘activity-by-targeting’ concept was validated for type I interferons and leptin. In the case of interferon, activity can be directed to target cells in vitro and to selected cell populations in mice, with up to 1,000-fold increased specific activity. This targeting strategy holds promise to revitalize the clinical potential of many cytokines.

  20. In Vivo Cytokine-Associated Responses to Biomaterials

    PubMed Central

    Schutte, RJ; Xie, L; Klitzman, B; Reichert, WM

    2008-01-01

    Cytokines, chemokines, and growth factors were analyzed periodically over eight weeks from the wound exudate fluid surrounding biomaterials implanted subcutaneously within stainless steel mesh cages. TNF-α, MCP-1, MIP-1α, IL-2, IL-6, IL-1β, VEGF, IL-4, and IL-10 were measured from exudate samples collected from cages containing specimens of polyethylene (PE), polyurethane (PU), or organo-tin polyvinyl chloride (ot-PVC). Empty cages served as negative controls, and lipopolysaccharide (LPS) served as a positive control. Cytokine, chemokine, and growth factor concentrations decreased from the time of implantation to eight weeks post-implantation, and there was an overall increase in cytokine, chemokine, and growth factor production for material-containing cages compared to empty cages. However, cytokine production was only modestly affected by the different surface chemistries of the three implanted polymeric materials. PMID:18849070

  1. In vivo cytokine-associated responses to biomaterials.

    PubMed

    Schutte, Robert J; Xie, Lola; Klitzman, Bruce; Reichert, William M

    2009-01-01

    Cytokines, chemokines, and growth factors were analyzed periodically over eight weeks from the wound exudate fluid surrounding biomaterials implanted subcutaneously within stainless steel mesh cages. TNF-alpha, MCP-1, MIP-1alpha, IL-2, IL-6, IL-1beta, VEGF, IL-4, and IL-10 were measured from exudate samples collected from cages containing specimens of polyethylene (PE), polyurethane (PU), or organotin polyvinyl chloride (ot-PVC). Empty cages served as negative controls, and lipopolysaccharide (LPS) served as a positive control. Cytokine, chemokine, and growth factor concentrations decreased from the time of implantation to eight weeks post-implantation, and there was an overall increase in cytokine, chemokine, and growth factor production for material-containing cages compared to empty cages. However, cytokine production was only modestly affected by the different surface chemistries of the three implanted polymeric materials.

  2. The Enigmatic Cytokine Oncostatin M and Roles in Disease

    PubMed Central

    Richards, Carl D.

    2013-01-01

    Oncostatin M is a secreted cytokine involved in homeostasis and in diseases involving chronic inflammation. It is a member of the gp130 family of cytokines that have pleiotropic functions in differentiation, cell proliferation, and hematopoetic, immunologic, and inflammatory networks. However, Oncostatin M also has activities novel to mediators of this cytokine family and others and may have fundamental roles in mechanisms of inflammation in pathology. Studies have explored Oncostatin M functions in cancer, bone metabolism, liver regeneration, and conditions with chronic inflammation including rheumatoid arthritis, lung and skin inflammatory disease, atherosclerosis, and cardiovascular disease. This paper will review Oncostatin M biology in a historical fashion and focus on its unique activities, in vitro and in vivo, that differentiate it from other cytokines and inspire further study or consideration in therapeutic approaches. PMID:24381786

  3. The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder.

    PubMed

    Masi, Anne; Glozier, Nicholas; Dale, Russell; Guastella, Adam J

    2017-04-01

    Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental condition characterized by variable impairments in communication and social interaction as well as restricted interests and repetitive behaviors. Heterogeneity of presentation is a hallmark. Investigations of immune system problems in ASD, including aberrations in cytokine profiles and signaling, have been increasing in recent times and are the subject of ongoing interest. With the aim of establishing whether cytokines have utility as potential biomarkers that may define a subgroup of ASD, or function as an objective measure of response to treatment, this review summarizes the role of the immune system, discusses the relationship between the immune system, the brain, and behavior, and presents previously-identified immune system abnormalities in ASD, specifically addressing the role of cytokines in these aberrations. The roles and identification of biomarkers are also addressed, particularly with respect to cytokine profiles in ASD.

  4. Trial Watch—Immunostimulation with cytokines in cancer therapy

    PubMed Central

    Vacchelli, Erika; Aranda, Fernando; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-01-01

    ABSTRACT During the past decade, great efforts have been dedicated to the development of clinically relevant interventions that would trigger potent (and hence potentially curative) anticancer immune responses. Indeed, developing neoplasms normally establish local and systemic immunosuppressive networks that inhibit tumor-targeting immune effector cells, be them natural or elicited by (immuno)therapy. One possible approach to boost anticancer immunity consists in the (generally systemic) administration of recombinant immunostimulatory cytokines. In a limited number of oncological indications, immunostimulatory cytokines mediate clinical activity as standalone immunotherapeutic interventions. Most often, however, immunostimulatory cytokines are employed as immunological adjuvants, i.e., to unleash the immunogenic potential of other immunotherapeutic agents, like tumor-targeting vaccines and checkpoint blockers. Here, we discuss recent preclinical and clinical advances in the use of some cytokines as immunostimulatory agents in oncological indications. PMID:27057468

  5. AMBIENT PARTICULATE MATTER DECREASED IN HUMAN ALVEOLAR MACHROPHAGE CYTOKINE RELEASE

    EPA Science Inventory

    Human exposure to ambient airborne particulate matter (PM) is associated with cardiopulmonary mortality and morbidity, including increased hospitalizations for lung infection. Normal lung immune responses to bacterial infection include alveolar macrophage cytokine production and...

  6. [Interleukins network in rheumatoid arthritis pathophysiology: beyond proinflammatory cytokines].

    PubMed

    Sánchez-Ramón, Silvia; López-Longo, Francisco Javier; Carreño, Luis

    2011-03-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovitis and progressive destruction of the joint cartilage and underlying bone, together with diverse extra-articular manifestations. Cytokines act as soluble effector mediators of the inflammatory process. Therapeutic neutralization with monoclonal antibodies against the pro-inflammatory cytokines TNF-alpha and interleukin 1 (IL-1) has shown a clear efficacy on inflammation and clinical manifestations of RA, although a percentage of patients do not respond. This review covers new relevant cytokines in the RA physiopathology and potential biomarkers of inflammation. The current challenge is to develop biomarkers that enable an earlier diagnosis, as well as prognostic markers and new therapeutic candidates. Combined administration of several of these cytokines could eventually address a personalized treatment approach for each patient.

  7. The role of Th17 cytokines in primary mucosal immunity

    PubMed Central

    Kolls, Jay K.; Khader, Shabaana A.

    2010-01-01

    The T helper type 17 (Th17) lineage of CD4+ T-cells produce several effector molecules including IL-17A, IL-17F, IL-21, and IL-22. In addition to CD4+, αβ T-cells, these cytokines can be produced by natural killer and γδ T-cells. These effector cytokines can be produced rapidly upon infection at mucosal sites and evidence to date strongly implicates that this arm of the immune system plays a critical role in mucosal immunity to many extracellular pathogens. Moreover these cytokines can also coordinate adaptive immunity to some intracellular pathogens. In this review, we will highlight recent progress in our understanding of these cytokines, and mechanisms of their effector function in the mucosa. PMID:21095154

  8. Peripheral blood neutrophil cytokine hyper-reactivity in chronic periodontitis.

    PubMed

    Ling, Martin R; Chapple, Iain L C; Matthews, John B

    2015-10-01

    Pro-inflammatory cytokine release (IL-8, IL-6, TNF-α, IL-1β) by peripheral blood neutrophils, isolated from periodontitis patients (before/after therapy) and matched controls, was determined after 18 h culture in the presence/absence of Escherichia coli LPS, opsonised Staphylococcus aureus, heat-killed Fusobacterium nucleatum and Porphyromonas gingivalis. All cultures demonstrated differences in the amounts of each cytokine detected (P < 0.0001), with a clear release pattern (IL-8 > IL-6 > TNF-α = IL-1β). Median cytokine release from unstimulated patient neutrophils was consistently, but non-significantly, higher than from control cells. Stimulated cytokine release from untreated patient neutrophils was also consistently higher than from control cells. This hyper-reactivity was significant for all tested cytokines when data for all stimuli were combined (P < 0.016). In terms of individual stimuli, significant hyper-reactivity was detected with LPS (IL-8), F. nucleatum (IL-8, TNF-α), opsonised S. aureus (IL-8, TNF-α, IL-1β) and P. gingivalis (IL-8, IL-1β). Cytokine production by patient neutrophils did not reduce following successful non-surgical periodontal therapy and, except for responses to F. nucleatum, the cytokine hyper-reactivity detected pre-therapy was retained. These data demonstrate that chronic periodontitis is characterised by neutrophils that constitutively exhibit cytokine hyper-reactivity, the effects of which could modulate local and systemic inflammatory-immune responses and influence the risk and severity of periodontitis-associated systemic inflammatory diseases.

  9. Dysregulation of in vitro cytokine production by monocytes during sepsis.

    PubMed Central

    Munoz, C; Carlet, J; Fitting, C; Misset, B; Blériot, J P; Cavaillon, J M

    1991-01-01

    The production by monocytes of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) in intensive care unit (ICU) patients with sepsis syndrome (n = 23) or noninfectious shock (n = 6) is reported. Plasma cytokines, cell-associated cytokines within freshly isolated monocytes and LPS-induced in vitro cytokine production were assessed at admission and at regular intervals during ICU stay. TNF alpha and IL-6 were the most frequently detected circulating cytokines. Despite the fact that IL-1 alpha is the main cytokine found within monocytes upon in vitro activation of cells from healthy individuals, it was very rarely detected within freshly isolated monocytes from septic patients, and levels of cell-associated IL-1 beta were lower than those of TNF alpha. Cell-associated IL-1 beta and TNF alpha were not correlated with corresponding levels in plasma. Upon LPS stimulation, we observed a profound decrease of in vitro IL-1 alpha production by monocytes in all patients, and of IL-1 beta, IL-6, and TNF alpha in septic patients. This reduced LPS-induced production of cytokines was most pronounced in patients with gram-negative infections. Finally, monocytes from survival patients, but not from nonsurvival ones recovered their capacity to produce normal amounts of cytokines upon LPS stimulation. In conclusion, our data indicate an in vivo activation of circulating monocytes during sepsis as well as in noninfectious shock and suggest that complex regulatory mechanisms can downregulate the production of cytokines by monocytes during severe infections. Images PMID:1939659

  10. Multisite comparison of high-sensitivity multiplex cytokine assays.

    PubMed

    Breen, Elizabeth Crabb; Reynolds, Sandra M; Cox, Christopher; Jacobson, Lisa P; Magpantay, Larry; Mulder, Candice B; Dibben, Oliver; Margolick, Joseph B; Bream, Jay H; Sambrano, Elise; Martínez-Maza, Otoniel; Sinclair, Elizabeth; Borrow, Persephone; Landay, Alan L; Rinaldo, Charles R; Norris, Philip J

    2011-08-01

    The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1β was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important.

  11. Cytokine and nitric oxide production following severe envenomation.

    PubMed

    Petricevich, Vera L

    2004-09-01

    Venom is a complex mixture of many substances such as toxins, enzymes, growth factor activators, and inhibitors are particularly responsible for the deleterious effects of cells. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Envenomation by bees, scorpions, snakes, spiders and wasps involves the activation of the inflammatory response with the release and activation of pro-inflammatory cytokines and other mediators, such as nitric oxide. Recently, a battery of cytokines produced by activated T cells or macrophages have been added to in envenomations. Cytokines are important for the interactions between cells in the immune and inflammatory responses. Although the pathophysiology of envenomation is not fully understood, venom and immune responses are known to trigger the release of cytokines and nitric oxide. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and, as well as a host of physiologic events such as activation of vasodilation, hypotension and increased nitric oxide production. Accumulating evidence indicates that these cytokines play important roles in mediating cell recruitment and activation necessary for inflammation and the repair of tissue damage. A better understanding of the involvement of the inflammatory system in different envenoming syndromes may have future therapeutic benefits.

  12. Increased production of inflammatory cytokines in mild cognitive impairment.

    PubMed

    Magaki, Shino; Mueller, Claudius; Dickson, Cindy; Kirsch, Wolff

    2007-03-01

    Recent studies indicate that chronic inflammation plays a pathogenic role in both the central nervous system (CNS) and periphery in Alzheimer's disease (AD). We have screened for cytokines differentially produced by peripheral blood mononuclear cells (PBMCs) isolated from subjects with mild cognitive impairment (MCI) and mild AD subjects who had progressed from MCI using a commercially available cytokine array. Following determination of expressed cytokines, we quantified levels of the proinflammatory cytokines TNF-alpha, IL-6, and IL-8, and the anti-inflammatory cytokine IL-10 using flow cytometry. We have found a significant increase in the levels of IL-6, IL-8, and IL-10 produced by PBMCs stimulated for 24 h with phytohemagglutinin (PHA) in MCI subjects compared to healthy elderly controls. However, in PBMCs stimulated for 48 h with lipopolysaccharide (LPS), lower TNF-alpha/IL-10, IL-6/IL-10, and IL-8/IL-10 ratios were seen in MCI subjects. There were no differences in plasma levels of IL-8 between aged controls, MCI, and mild AD, and the levels of circulating IL-6 and IL-10 were below detection limits. Our data indicate that changes in cytokine production by PBMCs may be detected early in MCI, and an alteration of the immune response may precede clinical AD.

  13. Cytokines as biomarkers in depressive disorder: current standing and prospects.

    PubMed

    Lichtblau, Nicole; Schmidt, Frank M; Schumann, Robert; Kirkby, Kenneth C; Himmerich, Hubertus

    2013-10-01

    The frequently observed co-occurrence of depressive disorders and inflammatory diseases suggests a close connection between the nervous and the immune systems. Increased pro-inflammatory and type 1 cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, appear to be an important link. Cytokines are synthesized by immune cells in the blood and peripheral tissues and by glial cells in the central nervous system (CNS). Evidence suggests that the blood-brain barrier (BBB) is permeable to cytokines and immune cells, and that afferent nerves, e.g. the vagus nerve, mediate the communication between peripheral inflammatory processes and CNS. Cytokines such as IL-1ß, TNF-α and IFN-γ seem to contribute to the pathophysiology of depression by activating monoamine reuptake, stimulating the hypothalamic-pituitary-adrenocortical (HPA) axis and decreasing production of serotonin due to increased activity of indolamine-2,3-dioxygenase (IDO). However, critical appraisal of these hypotheses is required, because cytokine elevation is not specific to depression. Moreover, several effective antidepressants such as amitriptyline and mirtazapine have been shown to increase cytokine production. When applying immunomodulatory therapies, these drugs may increase the risk of specific side effects such as infections or interact with antidepressant drugs on important functions of the body such as the coagulation system.

  14. Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.

    PubMed

    Neitzke, Daniel J; Bowers, Jacob S; Andrijauskaite, Kristina; O'Connell, Nathaniel S; Garrett-Mayer, Elizabeth; Wrangle, John; Li, Zihai; Paulos, Chrystal M; Cole, David J; Rubinstein, Mark P

    2017-03-09

    Adoptive cellular therapy (ACT) with the Th17 subset of CD4(+) T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets, including conventionally activated CD8(+) T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

  15. Plasma cytokine expression in adolescent chronic fatigue syndrome.

    PubMed

    Wyller, Vegard Bruun; Sørensen, Øystein; Sulheim, Dag; Fagermoen, Even; Ueland, Thor; Mollnes, Tom Eirik

    2015-05-01

    Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescents. The pathophysiology is poorly understood, but low-grade systemic inflammation has been suggested as an important component. This study compared circulating levels of individual cytokines and parameters of cytokine networks in a large set of adolescent CFS patients and healthy controls, and explored associations between cytokines and symptoms in the CFS group. CFS patients (12-18years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring three months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Thus, the case definition was broader than the Fukuda-criteria of CFS. Healthy controls having comparable distribution of gender and age were recruited from local schools. Twenty-seven plasma cytokines, including interleukins, chemokines and growth factors were assayed using multiplex technology. The results were subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and patients were subgrouped according to the Fukuda-criteria. A total of 120 CFS patients and 68 healthy controls were included. CFS patients had higher scores for fatigue (p<0.001) and inflammatory symptoms (p<0.001) than healthy controls. All cytokine levels and cytokine network parameters were similar, and none of the differences were statistically different across the two groups, also when adjusting for adherence to the Fukuda criteria of CFS. Within the CFS group, there were no associations between aggregate cytokine network parameters and symptom scores. Adolescent CFS patients are burdened by symptoms that might suggest low-grade systemic inflammation, but plasma levels of individual cytokines as well as cytokine network measures were not different from healthy controls, and

  16. Continuous infusion of proinflammatory cytokines into the brain to study brain cytokine induced local and systemic immune effects.

    PubMed

    Schöning, B; Elepfandt, P; Lanksch, W R; Volk, H D; Woiciechowsky, C

    1999-07-01

    Proinflammatory cytokines are produced in the brain after various kinds of insult (ischemia, trauma, infection). In this process interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha are most important. These cytokines are key mediators of inflammation. Furthermore, these cytokines can act as neurotransmitters and develop direct effects on the central nervous system (CNS) including fever, sleep and stimulation of the neuroendocrine as well as sympathetic nervous system. Moreover, IL-1beta and TNF-alpha may also be involved in brain repair and regenerating processes. However, most of the data about the role of cytokines in the brain have been obtained from either in vitro studies or bolus injections into the brain parenchyma or cerebroventricular system. On the other hand, it is known that cytokines are released continuously into the brain after a cerebral insult over a period of 24 to 48 h. In order to further complete the knowledge about the interactions between neural and immune cells to overcome the primary insult and initiate repair and regeneration in the CNS, a new animal model of local inflammation reaction was established using chronic intracerebral infusion of rat recombinant cytokines.

  17. [Cytokines in bone diseases. Anti-cytokine therapies for bone and joint diseases].

    PubMed

    Tanaka, Yoshiya

    2010-10-01

    The efficacy of biologics targeting inflammatory cytokines such as TNF and IL-6 for bone and joint diseases has been emerging. Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis and bone damage. By the use of TNF-inhibitors, clinical remission, structural remission and functional remission have become possible during the treatment of RA. Especially, the progress of joint and bone destruction is completely suppressed by TNF-inhibitors in the vast majority of RA patients. On the other hand, anti-RANKL antibody inhibits joint destruction as well as systemic osteoporosis, though no effects on synovitis of RA. Thus, differential efficacy of different therapies in bone destruction and osteoporosis would warrant further study to clarify the mechanisms of bone and joints diseases.

  18. Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimer's Disease.

    PubMed

    Nagae, Tomone; Araki, Kiho; Shimoda, Yuki; Sue, Lucia I; Beach, Thomas G; Konishi, Yoshihiro

    2016-08-01

    Inflammatory mechanisms are implicated in the pathology of Alzheimer's disease (AD). However, it is unclear whether inflammatory alterations are a cause or consequence of neurodegeneration leading to dementia. Clarifying this issue would provide valuable insight into the early diagnosis and therapeutic management of AD. To address this, we compared the mRNA expression profiles of cytokines in the brains of AD patients with "non-demented individuals with AD pathology" and non-demented healthy control (ND) individuals. "Non-demented individuals with AD pathology" are referred to as high pathology control (HPC) individuals that are considered an intermediate subset between AD and ND. HPC represents a transition between normal aging and early stage of AD, and therefore, is useful for determining whether neuroinflammation is a cause or consequence of AD pathology. We observed that immunological conditions that produce cytokines in the HPC brain were more representative of ND than AD. To validate these result, we investigated the expression of inflammatory mediators at the protein level in postmortem brain tissues. We examined the protein expression of tumor necrosis factor (TNF)α and its receptors (TNFRs) in the brains of AD, HPC, and ND individuals. We found differences in soluble TNFα and TNFRs expression between AD and ND groups and between AD and HPC groups. Expression in the temporal cortex was lower in the AD brains than HPC and ND. Our findings indicate that alterations in immunological conditions involving TNFR-mediated signaling are not the primary events initiating AD pathology, such as amyloid plaques and tangle formation. These may be early events occurring along with synaptic and neuronal changes or later events caused by these changes. In this review, we emphasize that elucidating the temporal expression of TNFα signaling molecules during AD is important to understand the selective tuning of these pathways required to develop effective therapeutic

  19. Plasma Cytokine Levels in Astronauts Before and after Spaceflight

    NASA Technical Reports Server (NTRS)

    Mehta, Satish K.; Aggarwal, Barat B.; Feiveson, Alan H.; Hammond, Dinne K.; Castro, Victoria A.; Stowe, Raymond; Pierson Duane L.

    2008-01-01

    Space flight is a unique experience and results in adverse effects on human physiology. Changes have been reported in various physiological systems, including musculoskeletal, neurovestibular, cardiovascular, endocrine, immunity and increased latent viral reactivation as well as others. The potential mechanisms behind these changes are not fully understood. Various cytokines such as IL-1, IL-6, TNF and chemokines have been linked to several of these changes, like muscle loss, bone loss, fatigue, sleep deprivation and viral reactivation. Eighteen astronauts (15 M and 3 F) from 8 spaceflights and 10 healthy age-matched adults (6 M, 4 F) were included in the present study. A panel of 21 plasma cytokines was analyzed with the Luminex 100 to measure the cytokines in these subjects 10 days before the flight (L-10), 2-3 hour after landing (R+0), 3 days after landing (R+3), and at their annual medical exam (AME). IL-10, IL-1, IFN-alpha, MCP-1 and IP-10 increased significantly at L-10 as compared with AME levels. IL-6 and IFN-alpha showed significant increases at R + 0 (P less than .05) over their baseline levels (AME). Cytokine levels at R+3 were not significantly different from R+0. IL-10 and IL-6 have been reported to increase in during viral reactivation. These data show that there was a shift from TH1 to TH2 cytokines L-10 and R+0. We also studied viral reactivation in 10 of the 18 subjects included in the present study before, during, and after space flight. Increased salivary varicella zoster virus (VZV) shedding in these subjects was found either during or after the mission. VZV shedding correlated with the increased levels of cytokines especially IL-10 and IL-6. Overall, our data suggests that cytokines may play an important role in regulating adverse changes in astronauts, and further studies are needed to fully understand the mechanism.

  20. Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone

    PubMed Central

    1996-01-01

    An overproduction of proinflammatory cytokines by activated macrophages/monocytes mediates the injurious sequelae of inflammation, septic shock, tissue injury, and cachexia. We recently synthesized a tetravalent guanylhydrazone compound (CNI-1493) that inhibits cytokine- inducible arginine transport and nitric oxide (NO) production in macrophages, and protects mice against lethal endotoxemia and carrageenan-induced inflammation. During these investigations we noticed that CNI-1493 effectively prevented lipopolysaccharide (LPS)- induced NO production, even when added in concentrations 10-fold less than required to competitively inhibit L-arginine uptake, suggesting that the suppressive effects of this guanylhydrazone compound might extend to other LPS-induced responses. Here, we report that CNI-1493 suppressed the LPS-stimulated production of proinflammatory cytokines (tumor necrosis factor [TNF], interleukins 1beta and 6, macrophage inflammatory proteins 1alpha and 1beta) from human peripheral blood mononuclear cells. Cytokine suppression was specific, in that CNI-1493 did not inhibit either the constitutive synthesis of transforming growth factor beta or the upregulation of major histocompatibility complex class II by interferon gamma (IFN-gamma). In contrast to the macrophage suppressive actions of dexamethasone, which are overridden in the presence of IFN-gamma, CNI-1493 retained its suppressive effects even in the presence of IFN-gamma. The mechanism of cytokine- suppressive action by CNI-1493 was independent of extracellular L- arginine content and NO production and is not restricted to induction by LPS. As a selective inhibitor of macrophage activation that prevents TNF production, this tetravalent guanylhydrazone could be useful in the development of cytokine-suppressive agents for the treatment of diseases mediated by overproduction of cytokines. PMID:8642296

  1. Delayed cytokine expression in rat brain following experimental contusion.

    PubMed

    Holmin, S; Schalling, M; Höjeberg, B; Nordqvist, A C; Skeftruna, A K; Mathiesen, T

    1997-03-01

    Proinflammatory cytokines mediate brain injury in experimental studies. This study was undertaken to analyze the production of proinflammatory cytokines in experimental contusion. A brain contusion causing delayed edema was mimicked experimentally in rats using a weight-drop model. Intracerebral expression of the cytokines interleukin (IL)-1 beta, tumor necrosis factor-alpha (TNF alpha), IL-6, and interferon-gamma (IFN gamma) was studied by in situ hybridization and immunohistochemistry. The animals were killed at 6 hours or 1, 2, 4, 6, 8, or 16 days postinjury. In the injured area, no messenger (m)RNA expression was seen during the first 2 days after the trauma. On Days 4 to 6 posttrauma, however, strong IL-1 beta, TNF alpha, and IL-6 mRNA expression was detected in mononuclear cells surrounding the contusion. Expression of IFN gamma was not detected. Immunohistochemical double labeling confirmed the in situ hybridization results and demonstrated that mononuclear phagocytes and astrocytes produced IL-1 beta and that mainly astrocytes produced TNF alpha. The findings showed, somewhat unexpectedly, a late peak of intracerebral cytokine production in the injured area and in the contralateral corpus callosum, allowing for both local and global effects on the brain. An unexpected difference in the cellular sources of TNF alpha and IL-1 beta was detected. The cytokine pattern differs from that seen in other central nervous system inflammatory diseases and trauma models, suggesting that the intracerebral immune response is not a uniform event. The dominance of late cytokine production indicates that many cytokine effects are late events in an experimental contusion: Different pathogenic mechanisms may thus be operative at different times after brain injury.

  2. The influence of traditional herbal formulas on cytokine activity.

    PubMed

    Burns, J J; Zhao, Lijun; Taylor, Ethan Will; Spelman, Kevin

    2010-11-28

    Many of the botanical "immunomodulators", a class of herbal medicines widely recognized in traditional medical systems such as Chinese Medicine (TCM) and Ayurvedic Medicine, alter immune function and may offer clinically relevant therapeutics or leads to therapeutics. Many of these traditional remedies are prepared from combinations of medicinal plants which may influence numerous molecular pathways. These effects may differ from the sum of effects from the individual plants and therefore, research demonstrating the effects of the formula is crucial for insights into the effects of traditional remedies. In this review we surveyed the primary literature for research that focused on combinations of medicinal plants and effects on cytokine activity. The results demonstrate that many extracts of herb mixtures have effects on at least one cytokine. The most commonly studies cytokines were IL-4, IL-6, IL-10, TNF and IFN-γ. The majority of the formulas researched derived from TCM. The following formulas had activity on at least three cytokines; Chizukit N, CKBM, Daeganghwal-tang, Food Allergy Formula, Gamcho-Sasim-Tang, Hachimi-jio-gan, Herbkines, Hochuekki, Immune System Formula, Jeo-Dang-Tang, Juzen-taiho-to, Kakkon-to, Kan jang, Mao-Bushi-Saishin-to, MSSM-002, Ninjin-youei-to, PG201, Protec, Qing-huo-bai-du-yin, Qingfu Guanjieshu, Sambucol Active Defense, Seng-fu-tang, Shin-Xiao-Xiang, Tien Hsien, Thuja formula, Unkei-to, Vigconic, Wheeze-relief-formula, Xia-Bai-San, Yangyuk-Sanhwa-Tang, Yi-fey Ruenn-hou, and Yuldahansotang. Of the western based combinations, formulas with Echinacea spp. were common and showed multiple activities. Numerous formulas demonstrated activity on both gene and protein expression. The research demonstrates that the reviewed botanical formulas modulate cytokine activity, although the bulk of the research is in vitro. Therapeutic success using these formulas may be partially due to their effects on cytokines. Further study of phytotherapy on

  3. Serum Cytokine Profiles in Children with Crohn's Disease

    PubMed Central

    Vasilyeva, Ekaterina; Abdulkhakov, Sayar; Cherepnev, Georgi; Mayanskaya, Irina; Valeeva, Alina; Abdulkhakov, Rustam; Safina, Dilyara

    2016-01-01

    Crohn's disease (CD) is a chronic inflammatory bowel disease that can be diagnosed at any age. There are two major patient groups based on diagnosis of this disease, before or after the age of 20 (juvenile/adolescent or adult), with disease progression in adults usually milder than in juvenile CD patients. Immune mechanisms have been suggested to play an important role in CD pathogenesis, with cytokines governing the development of the immune response. Upregulation of inflammatory cytokines in serum of juvenile and adult CD patients has been documented; still little is known about age-dependent differences in serum cytokine profiles of CD patients. We applied multiplex technology to analyze serum levels of 12 cytokines in juveniles and adults. We show that during the acute stage of the disease all CD patients have high serum levels of CXCL10, which remains upregulated during remission. Increased serum levels of TNF-α and IL-6 during the acute stage was characteristic of juvenile CD patients, whereas adult CD patients had upregulated levels of GM-CSF and IFN-γ. Taken together, these results demonstrate age-dependent differences in cytokine profiles, which may affect the pathogenesis of CD in patients at different ages of disease onset. PMID:28070144

  4. Integration of Cytokine Biology and Lipid Metabolism in Stroke**

    PubMed Central

    Adibhatla, Rao Muralikrishna; Dempsey, R.; Hatcher, J. F.

    2007-01-01

    Cytokines regulate the innate and adaptive immune responses and are pleiotropic, redundant and multifunctional. Expression of most cytokines, including TNF-α and IL-1α/ß, is very low in normal brain. Metabolism of lipids is of particular interest due to their high concentration in the brain. Inflammatory response after stroke suggests that cytokines (TNF-α, IL-1 α/ß, IL-6), affect the phospholipid metabolism and subsequent production of eicosanoids, ceramide, and ROS that may potentiate brain injury. Phosphatidylcholine and sphingomyelin are source for lipid messengers. Sphingomyelin synthase serves as a bridge between metabolism of glycerolipids and sphingolipids. TNF-α and IL-1 α/ß can induce phospholipases (A2, C, and D) and sphingomyelinases, and concomitantly proteolyse phosphatidylcholine and sphingomyelin synthesizing enzymes. Together, these alterations contribute to loss of phosphatidylcholine and sphingomyelin after stroke that can be attenuated by inhibiting TNF-α or IL-1 α/ß signaling. Inflammatory responses are instrumental in the formation and destabilization of atherosclerotic plaques. Secretory PLA2 IIA is found in human atherosclerotic lesions and is implicated in initiation, progression and maturation of atherosclerosis, a risk factor for stroke. Lipoprotein-PLA2, part of apolipoprotein B-100 of LDL, plays a role in vascular inflammation and coronary endothelial dysfunction. Cytokine antagonism attenuated secretory PLA2 IIA actions, suggesting cytokine-lipid integration studies will lead to new concepts contributing to bench-to-bedside transition for stroke therapy. PMID:17981627

  5. Plasma inflammatory cytokines correlate to the ovarian hyperstimulation syndrome.

    PubMed

    Abramov, Y; Schenker, J G; Lewin, A; Friedler, S; Nisman, B; Barak, V

    1996-07-01

    The objective of this study was to follow the kinetics of four inflammatory cytokines in the plasma and ascitic fluid of seven patients who developed severe ovarian hyperstimulation syndrome (OHSS) after induction of ovulation for in-vitro fertilization. Blood samples were obtained from these patients at three different times: upon hospitalization; when significant clinical improvement was evident; and after complete resolution. Samples were analysed for interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor alpha (TNF-alpha). Ascitic fluid was obtained by therapeutic paracentesis from all study patients during the active phase and analysed for these cytokines. Two control groups were available: the first included 15 women undergoing controlled ovarian stimulation for in-vitro fertilization without developing OHSS, while the second consisted of 25 healthy women not undergoing ovulation induction or any other medical treatment. High concentrations of IL-1, IL-6 and TNF-alpha were detected in all individuals upon admission for severe OHSS. Concentrations dropped significantly along with clinical improvement, reaching normal values after complete resolution. A statistically significant correlation was found between plasma cytokine concentrations and certain biological characteristics of the syndrome such as leukocytosis, increased haematocrit, and elevated plasma 17-beta-oestradiol concentrations. Ascitic fluid obtained from the study patients contained high IL-6 and IL-8 concentrations, while other cytokines were unaltered. These results suggest close association between inflammatory cytokines and the pathophysiology of the ovarian hyperstimulation syndrome.

  6. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims.

    PubMed

    Pandey, Ghanshyam N; Rizavi, Hooriyah S; Ren, Xinguo; Fareed, Jawed; Hoppensteadt, Debra A; Roberts, Rosalinda C; Conley, Robert R; Dwivedi, Yogesh

    2012-01-01

    Teenage suicide is a major public health concern, but its neurobiology is not well understood. Proinflammatory cytokines play an important role in stress and in the pathophysiology of depression-two major risk factors for suicide. Cytokines are increased in the serum of patients with depression and suicidal behavior; however, it is not clear if similar abnormality in cytokines occurs in brains of suicide victims. We therefore measured the gene and protein expression levels of proinflammatory cytokines interleukin (IL)-1β, IL-6, and tissue necrosis factor (TNF)-α in the prefrontal cortex (PFC) of 24 teenage suicide victims and 24 matched normal control subjects. Our results show that the mRNA and protein expression levels of IL-1β, IL-6, and TNF-α were significantly increased in Brodmann area 10 (BA-10) of suicide victims compared with normal control subjects. These results suggest an important role for IL-1β, IL-6, and TNF-α in the pathophysiology of suicidal behavior and that proinflammatory cytokines may be an appropriate target for developing therapeutic agents.

  7. Integrative biology approach identifies cytokine targeting strategies for psoriasis.

    PubMed

    Perera, Gayathri K; Ainali, Chrysanthi; Semenova, Ekaterina; Hundhausen, Christian; Barinaga, Guillermo; Kassen, Deepika; Williams, Andrew E; Mirza, Muddassar M; Balazs, Mercedesz; Wang, Xiaoting; Rodriguez, Robert Sanchez; Alendar, Andrej; Barker, Jonathan; Tsoka, Sophia; Ouyang, Wenjun; Nestle, Frank O

    2014-02-12

    Cytokines are critical checkpoints of inflammation. The treatment of human autoimmune disease has been revolutionized by targeting inflammatory cytokines as key drivers of disease pathogenesis. Despite this, there exist numerous pitfalls when translating preclinical data into the clinic. We developed an integrative biology approach combining human disease transcriptome data sets with clinically relevant in vivo models in an attempt to bridge this translational gap. We chose interleukin-22 (IL-22) as a model cytokine because of its potentially important proinflammatory role in epithelial tissues. Injection of IL-22 into normal human skin grafts produced marked inflammatory skin changes resembling human psoriasis. Injection of anti-IL-22 monoclonal antibody in a human xenotransplant model of psoriasis, developed specifically to test potential therapeutic candidates, efficiently blocked skin inflammation. Bioinformatic analysis integrating both the IL-22 and anti-IL-22 cytokine transcriptomes and mapping them onto a psoriasis disease gene coexpression network identified key cytokine-dependent hub genes. Using knockout mice and small-molecule blockade, we show that one of these hub genes, the so far unexplored serine/threonine kinase PIM1, is a critical checkpoint for human skin inflammation and potential future therapeutic target in psoriasis. Using in silico integration of human data sets and biological models, we were able to identify a new target in the treatment of psoriasis.

  8. Discrimination, Racial Identity, and Cytokine Levels Among African American Adolescents

    PubMed Central

    Brody, Gene H.; Yu, Tianyi; Miller, Gregory E.; Chen, Edith

    2015-01-01

    Purpose Low-grade inflammation, measured by circulating levels of cytokines, is a pathogenic mechanism for several chronic diseases of aging. Identifying factors related to inflammation among African American youths may yield insights into mechanisms underlying racial disparities in health. The purpose of the study was to determine whether (a) reported racial discrimination from ages 17 to 19 forecast heightened cytokine levels at age 22, and (b) this association is lower for youths with positive racial identities. Methods A longitudinal research design was used with a community sample of 160 African Americans who were 17 at the beginning of the study. Discrimination and racial identity were measured with questionnaires, and blood was drawn to measure basal cytokine levels. Ordinary least squares regression analyses were used to examine the hypotheses. Results After controlling for socioeconomic risk, life stress, depressive symptoms, and body mass index, racial discrimination (β = .307, p < .01), racial identity (β = −.179, p < .05), and their interaction (β = −.180, p < .05) forecast cytokine levels. Youths exposed to high levels of racial discrimination evinced elevated cytokine levels 3 years later. This association was not significant for young adults with positive racial identities. Conclusions High levels of interpersonal racial discrimination and the development of a positive racial identity operate jointly to determine low-grade inflammation levels that have been found to forecast chronic diseases of aging, such as coronary disease and stroke. PMID:25907649

  9. Relationships among prenatal depression, plasma cortisol, and inflammatory cytokines.

    PubMed

    Shelton, Melissa M; Schminkey, Donna L; Groer, Maureen W

    2015-05-01

    A secondary pilot study was carried out as part of a larger parent study of thyroid function in pregnancy and postpartum. All women in the parent study (N = 631) had blood samples, demographic data, and measures of perceived stress and dysphoric moods collected between 16 and 26 weeks' gestation. The current study was completed with a subset of 105 pregnant women to examine the relationships among perceived stress, depression, plasma cortisol, and cytokines during the second trimester of pregnancy. Stress was measured using Cohen's Perceived Stress Scale and dysphoric moods using the Profile of Mood States Depression/Dejection Scale. Cytokines were measured by a 12-plex analysis on a Luminex-200, and cortisol was measured by enzyme-linked immunosorbent assay on stored plasma samples. Stress and depression scores were highly correlated, and depressive symptoms were inversely correlated with 3 of the 12 cytokines: interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-7. Cortisol was inversely correlated with proinflammatory cytokines (IL-1β and TNF-α) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). These data support the new conceptualizations of normal pregnancy as an inflammatory state that is carefully regulated, as both excessive and inadequate inflammation are potentially hazardous to the health of the pregnancy and fetus.

  10. Genomic identification of chemokines and cytokines in opossum.

    PubMed

    Wong, Emily S W; Papenfuss, Anthony T; Belov, Katherine

    2011-03-01

    The cytokine repertoire of marsupials is largely unknown. The sequencing of the opossum genome has expedited the identification of many immune genes. However, many genes have not been identified using automated annotation pipelines because of high levels of sequence divergence. To fill gaps in our knowledge of the cytokine gene complement in marsupials, we searched the genome assembly of the gray short-tailed opossum for chemokine, interleukin, colony-stimulating factor, tumor necrosis factor, and transforming growth factor genes. In particular, we focused on genes that were not previously identified through Ensembl's automatic annotations. We report that the vast majority of cytokines are conserved, with direct orthologs between therian species. The major exceptions are chemokine genes, which show lineage-specific duplication/loss. Thirty-six chemokines were identified in opossum, including a lineage-specific expansion of macrophage inflammatory protein family genes. Divergent cytokines IL7, IL9, IL31, IL33, and CSF2 were identified. This is the first time IL31 and IL33 have been described outside of eutherian species. The high levels of similarities between the cytokine gene repertoires of therians suggest that the marsupial immune response is highly similar to eutherians.

  11. Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways

    PubMed Central

    Zhao, Michael; Song, Lan; Yu, Tao; Liu, Yu; Liu, Jeffrey C.; McCurdy, Sean; Ma, Anqi; Wither, Joan; Jin, Jian; Zacksenhaus, Eldad; Wrana, Jeffrey L.; Bremner, Rod

    2015-01-01

    Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator induced in many cancers. It is thought to drive tumorigenesis by repressing division, stemness, and/or developmental regulators. Cancers evade immune detection, and diverse immune regulators are perturbed in different tumors. It is unclear how such cell-specific effects are coordinated. Here, we show a profound and cancer-selective role for PRC2 in repressing multiple cytokine pathways. We find that PRC2 represses hundreds of IFNγ stimulated genes (ISGs), cytokines and cytokine receptors. This target repertoire is significantly broadened in cancer vs non-cancer cells, and is distinct in different cancer types. PRC2 is therefore a higher order regulator of the immune program in cancer cells. Inhibiting PRC2 with either RNAi or EZH2 inhibitors activates cytokine/cytokine receptor promoters marked with bivalent H3K27me3/H3K4me3 chromatin, and augments responsiveness to diverse immune signals. PRC2 inhibition rescues immune gene induction even in the absence of SWI/SNF, a tumor suppressor defective in ~20% of human cancers. This novel PRC2 function in tumor cells could profoundly impact the mechanism of action and efficacy of EZH2 inhibitors in cancer treatment. PMID:26030458

  12. The Association of Cytokines with Severe Dengue in Children

    PubMed Central

    Mangione, Julia N.A.; Huy, Nguyen Tien; Lan, Nguyen Thi Phuong; Mbanefo, Evaristus Chibunna; Ha, Tran Thi Ngoc; Bao, Lam Quoc; Nga, Cao Thi Phi; Tuong, Vo Van; Dat, Tran Van; Thuy, Tran Thi; Tuan, Ha Manh; Huong, Vu Thi Que; Hirayama, Kenji

    2014-01-01

    Background: Dengue virus infection is a major public health problem. A hypothesis put forward for severe dengue is the cytokine storm, a sudden increase in cytokines that induces vascular permeability. Previous studies and our recent meta-analysis showed that IL-6, IL-8, IFNγ, TNFα, VEGF-A and VCAM-1 are associated with dengue shock syndrome. Therefore, in this study we aim to validate the association of these cytokines with severe dengue. Methods & Findings: In a hospital based-case control study in Vietnam, children with dengue fever, other febrile illness and healthy controls were recruited. Dengue virus infection was confirmed by several diagnostic tests. Multiplex immunoassay using Luminex technology was used to measure cytokines simultaneously. A positive association with dengue shock syndrome was found for VCAM-1, whereas a negative association was found for IFNγ. Furthermore, multivariate logistic analysis also showed that VCAM-1 and IFNγ were independently correlated with dengue shock syndrome. Conclusion: IFNγ and VCAM-1 were associated with dengue shock syndrome, although their role in the severe dengue pathogenesis remains unclear. Additional studies are required to shed further light on the function of these cytokines in severe dengue. PMID:25589878

  13. Regulation of cytokine gene transcription in the immune system.

    PubMed

    Holloway, A F; Rao, S; Shannon, M F

    2002-01-01

    The controlled expression of cytokine genes is an essential component of an immune response. The specific types of cytokines as well as the time and place of their production is important in generating an appropriate immune response to an infectious agent. Aberrant expression is associated with pathological conditions of the immune system such as autoimmunity, atopy and chronic inflammation. Cytokine gene transcription is generally induced in a cell-specific manner. Over the last 15 years, a large amount of information has been generated describing the transcriptional controls that are exerted on cytokine genes. Recently, efforts have been directed at understanding how these genes are transcribed in a chromatin context. This review will discuss the mechanisms by which cytokine genes become available for transcription in a cell-restricted manner as well as the mechanisms by which these genes sense their environment and activate high level transcription in a transient manner. Particular attention will be paid to the role of chromatin in allowing transcription factor access to appropriate genes.

  14. Angiogenesis meets immunology: cytokine gene therapy of cancer.

    PubMed

    Minuzzo, Sonia; Moserle, Lidia; Indraccolo, Stefano; Amadori, Alberto

    2007-02-01

    Delivery of cytokine genes at the tumor site in pre-clinical models has been shown to recruit host inflammatory cells followed by inhibition of tumor growth. This local effect is often accompanied by systemic protection mediated by the immune system, mainly by CD8(+) T and NK cells. On this basis, cytokine gene-transduced tumor cells have widely been used as vaccines in clinical trials, which have shown good safety profiles and some local responses but substantial lack of systemic efficacy. Are these findings the end of the story? Possibly not, if major improvements will be attained in the coming years. These should be directed at the level of gene selection and delivery, in order to identify the optimal cytokine and achieve efficient and durable cytokine expression, and at the level of improving immune stimulation, i.e. by co-administration of co-stimulatory molecules including B7 and CD40, or boosting the expression of tumor antigens or MHC class I molecules. Interestingly, some of the cytokines which have shown encouraging anti-tumor activity, including IFNs, IL-4, IL-12 and TNF-alpha, are endowed with anti-angiogenic or vasculotoxic effects, which may significantly contribute to local tumor control. Therapeutic exploitation of this property may result in the design of novel approaches which, by maximizing immune-stimulating and anti-angiogenic effects, could possibly lead to starvation of established tumors in patients.

  15. The Effect of Inflammatory Cytokines in Alcoholic Liver Disease

    PubMed Central

    Kawaratani, Hideto; Tsujimoto, Tatsuhiro; Douhara, Akitoshi; Takaya, Hiroaki; Moriya, Kei; Namisaki, Tadashi; Noguchi, Ryuichi; Yoshiji, Hitoshi; Fujimoto, Masao; Fukui, Hiroshi

    2013-01-01

    Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-α and IFN-γ, induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro- and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation. PMID:24385684

  16. Relationships Among Prenatal Depression, Plasma Cortisol, and Inflammatory Cytokines

    PubMed Central

    Shelton, Melissa M.; Schminkey, Donna L.; Groer, Maureen W.

    2014-01-01

    A secondary pilot study was carried out as part of a larger parent study of thyroid function in pregnancy and postpartum. All women in the parent study (N = 631) had blood samples, demographic data, and measures of perceived stress and dysphoric moods collected between 16 and 26 weeks’ gestation. The current study was completed with a subset of 105 pregnant women to examine the relationships among perceived stress, depression, plasma cortisol and cytokines during the second trimester of pregnancy. Stress was measured using Cohen’s Perceived Stress Scale and dysphoric moods using the Profile of Mood States depression/dejection scale. Cytokines were measured by a 12-plex analysis on a Luminex-200 and cortisol was measured by ELISA on stored plasma samples. Stress and depression scores were highly correlated, and depressive symptoms were inversely correlated with 3 of the 12 cytokines: interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-7. Cortisol was inversely correlated with pro-inflammatory cytokines (IL-1β, and TNF-α) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, IL-13). These data support the new conceptualizations of normal pregnancy as an inflammatory state that is carefully regulated, as both excessive and inadequate inflammation are potentially hazardous to the health of the pregnancy and fetus. PMID:25230746

  17. Instruction of hematopoietic lineage choice by cytokine signaling

    SciTech Connect

    Endele, Max; Etzrodt, Martin; Schroeder, Timm

    2014-12-10

    Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

  18. Human Invasive Muscular Sarcocystosis Induces Th2 Cytokine Polarization and Biphasic Cytokine Changes, Based on an Investigation among Travelers Returning from Tioman Island, Malaysia.

    PubMed

    Tappe, Dennis; Slesak, Günther; Pérez-Girón, José Vicente; Schäfer, Johannes; Langeheinecke, Andreas; Just-Nübling, Gudrun; Muñoz-Fontela, César; Püllmann, Kerstin

    2015-06-01

    Sarcocystis nesbitti is a parasite responsible for a biphasic eosinophilic febrile myositis syndrome in two recent outbreaks in Malaysia. We demonstrate Th2 cytokine polarization in infected travelers, an overall cytokine production decrease in the early phase of the disease suggestive of initial immunosuppression, and elevated levels of proinflammatory and chemotactic cytokines in the later myositic phase.

  19. MicroRNA-Regulated Proinflammatory Cytokines in Sarcopenia

    PubMed Central

    Fan, Jingjing; Kou, Xianjuan; Yang, Yi; Chen, Ning

    2016-01-01

    Sarcopenia has been defined as the aging-related disease with the declined mass, strength, and function of skeletal muscle, which is the major cause of frailty and falls in elders. The activation of inflammatory signal pathways due to diseases and aging is suggested to reveal the critical impact on sarcopenia. Several proinflammatory cytokines, especially interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), play crucial roles in modulation of inflammatory signaling pathway during the aging-related loss of skeletal muscle. MicroRNAs (miRNAs) have emerged as the important regulators for the mass and functional maintenance of skeletal muscle through regulating gene expression of proinflammatory cytokines. In this paper, we have systematically discussed regulatory mechanisms of miRNAs for the expression and secretion of inflammatory cytokines during sarcopenia, which will provide some novel targets and therapeutic strategies for controlling aging-related atrophy of skeletal muscle and corresponding chronic inflammatory diseases. PMID:27382188

  20. Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

    NASA Astrophysics Data System (ADS)

    Mitchell, Michael J.; Webster, Jamie; Chung, Amanda; Guimarães, Pedro P. G.; Khan, Omar F.; Langer, Robert

    2017-03-01

    Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces.

  1. Cytokines for monitoring anti-tuberculous therapy: A systematic review.

    PubMed

    Clifford, Vanessa; Zufferey, Christel; Street, Alan; Denholm, Justin; Tebruegge, Marc; Curtis, Nigel

    2015-05-01

    The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon-gamma based assays means that they are unlikely to be useful for monitoring therapy. Several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than interferon-gamma for monitoring anti-tuberculous therapy. A systematic review of these studies was performed to identify the most promising candidate biomarkers. TNF-α, IL-2, IL-6, IL-10 and IL-12 were the most extensively investigated cytokines. There was significant heterogeneity between studies in relation to study design and laboratory methodology, complicating direct comparisons. There was marked variation between studies in the observed changes during treatment for many of the biomarkers. Further longitudinal studies in sufficiently large patient cohorts with rigorous methodology are needed to determine the true potential of individual cytokine biomarkers, or combinations, for monitoring TB treatment.

  2. Cytokines and chemokines in neuromyelitis optica: pathogenetic and therapeutic implications.

    PubMed

    Uzawa, Akiyuki; Mori, Masahiro; Masahiro, Mori; Kuwabara, Satoshi

    2014-01-01

    Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO-specific autoantibody to the aquaporin-4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17- and Th2-related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin-6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines.

  3. Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

    PubMed Central

    Mitchell, Michael J.; Webster, Jamie; Chung, Amanda; Guimarães, Pedro P. G.; Khan, Omar F.; Langer, Robert

    2017-01-01

    Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces. PMID:28317839

  4. The Role of Cytokines in Breast Cancer Development and Progression

    PubMed Central

    Esquivel-Velázquez, Marcela; Ostoa-Saloma, Pedro; Palacios-Arreola, Margarita Isabel; Nava-Castro, Karen E.; Castro, Julieta Ivonne

    2015-01-01

    Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer-related disorders. PMID:25068787

  5. ROCKing cytokine secretion balance in human T cells.

    PubMed

    Zanin-Zhorov, Alexandra; Waksal, Samuel D

    2015-04-01

    Balanced regulation of cytokine secretion in T cells is critical for maintenance of immune homeostasis and prevention of autoimmunity. The Rho-associated kinase (ROCK) 2 signaling pathway was previously shown to be involved in controlling of cellular movement and shape. However, recent work from our group and others has demonstrated a new and important role of ROCK2 in regulating cytokine secretion in T cells. We found that ROCK2 promotes pro-inflammatory cytokines such as IL-17 and IL-21, whereas IL-2 and IL-10 secretion are negatively regulated by ROCK2 under Th17-skewing activation. Also, in disease, but not in steady state conditions, ROCK2 contributes to regulation of IFN-γ secretion in T cells from rheumatoid arthritis patients. Thus, ROCK2 signaling is a key pathway in modulation of T-cell mediated immune responses underscoring the therapeutic potential of targeted inhibition of ROCK2 in autoimmunity.

  6. Structural basis of receptor sharing by interleukin 17 cytokines

    SciTech Connect

    Ely, Lauren K.; Fischer, Suzanne; Garcia, K. Christopher; Stanford-MED

    2010-02-19

    Interleukin 17 (IL-17)-producing helper T cells (T{sub H}-17 cells), together with their effector cytokines, including members of the IL-17 family, are emerging as key mediators of chronic inflammatory and autoimmune disorders. Here we present the crystal structure of a complex of IL-17 receptor A (IL-17RA) bound to IL-17F in a 1:2 stoichiometry. The mechanism of complex formation was unique for cytokines and involved the engagement of IL-17 by two fibronectin-type domains of IL-17RA in a groove between the IL-17 homodimer interface. Binding of the first receptor to the IL-17 cytokines modulated the affinity and specificity of the second receptor-binding event, thereby promoting heterodimeric versus homodimeric complex formation. IL-17RA used a common recognition strategy to bind to several members of the IL-17 family, which allows it to potentially act as a shared receptor in multiple different signaling complexes.

  7. Regulation of Human Helper T Cell Subset Differentiation by Cytokines

    PubMed Central

    Schmitt, Nathalie; Ueno, Hideki

    2015-01-01

    Since the discovery of Th1 and Th2 cells in the late 80’s, the family of effector CD4+ helper T (Th) cell subsets has expanded. The differentiation of naïve CD4+ T cells is largely determined when they interact with dendritic cells in lymphoid organs, and cytokines play a major role in the regulation of Th differentiation in the early stages. Recent studies show that the developmental mechanism of certain Th subsets is not fully shared between mice and humans. Here we will review recent discoveries on the roles of cytokines in the regulation of Th differentiation in humans, and discuss the differences between mice and humans in the developmental mechanisms of several Th subsets, including Th17 cells and T follicular helper (Tfh) cells. We propose that the differentiation of human Th subsets is largely regulated by the three cytokines, IL-12, IL-23, and TGF-β. PMID:25879814

  8. Cytokine knockouts in reproduction: the use of gene ablation to dissect roles of cytokines in reproductive biology.

    PubMed

    Ingman, Wendy V; Jones, Rebecca L

    2008-01-01

    Cytokines play many diverse and important roles in reproductive biology, and dissecting the complex interactions between these proteins and the different reproductive organs is a difficult task. One approach is to use gene ablation, or 'knockout', to analyse the effect of deletion of a single cytokine on mouse reproductive function. This review summarizes the essential roles of cytokines in reproductive biology that have been revealed by gene knockout studies, including development and regulation of the hypothalamo-pituitary-gondal axis, ovarian folliculogenesis, implantation and immune system modulation during pregnancy. However, successful utilization of this approach must consider the caveats associated with gene ablation studies, e.g. embryonic lethality, systemic effects of cytokine ablation on local reproductive processes and the limited exposure to pathogens in mice housed in laboratory conditions. New sophisticated technology that temporally or spatially regulates gene ablation can overcome some of these limitations. Discoveries on the roles of cytokines in reproductive function uncovered by gene ablation studies can now be applied to improve in vitro fertilization for infertile couples and in the development of contraceptive therapies.

  9. Serum cytokines and anxiety in adolescent depression patients: Gender effect.

    PubMed

    Pallavi, Pooja; Sagar, Rajesh; Mehta, Manju; Sharma, Subhadra; Subramanium, Arulselvi; Shamshi, Farah; Sengupta, Utpal; Pandey, Ravindra M; Mukhopadhyay, Asok K

    2015-09-30

    The present study compares the serum cytokine levels between adolescent depression patients and healthy controls and assesses correlation between depression, anxiety scores and serum levels of eight cytokines. Study also checked the variation in serum levels with medication status (medication free/naïve vs. patients on medication). Following clinical and psychometric assessment of 77 adolescent (aged 13-18 years) depression patients (49 males and 28 females; 56 medication free/naïve) and 54 healthy controls (25 males, 29 females), eight cytokines (IL-1β, IL-2, IL-6, IL-10, TNF-α, IFN-γ, TGF-β1 and IL-17A {denoted IL-17 throughout}) were measured in serum using ELISA. Depressed adolescents had significantly high levels of IL-2 (p<0.001) and IL-6 (p=0.03) as compared to controls. The female population skewed the result of one cytokine (IL-6) in patients. Anxiety scores showed positive correlation (only in female patients) with IL-1β, IL-10 and negative correlation with TGF-β1 and IL-17. The gender effect in relationship between anxiety and cytokines was not straightforward. On comparing study groups on the medication/naïve status, IL-2 and TGF-β1 showed significant difference between the groups (p<0.001, p=0.007 higher in medicated). Depression in adolescents was associated with elevation of proinflammatory serum cytokines with a gender bias for females. Anxiety scores correlated negatively with TGF-β1 and IL-17.

  10. Cytokines in the blood and semen of infertile patients

    PubMed Central

    Havrylyuk, Anna; Chopyak, Valentyna; Boyko, Yaryna; Kril, Iryna

    2015-01-01

    Cytokines have been important mediators of the immunity and can be involved in numerous processes in the male genital tract including acting as immunomodulatory elements within the male gonad. The aims of this study were: 1) to detect pro- and anti-inflammatory cytokine levels in the control group and subgroups of infertile men; and 2) to set up the practical recommendations concerning determination of cytokine levels for the male infertility diagnosis. Observations were performed in a group of 82 men: healthy controls (n = 27) and infertile patients (n = 55). The male infertility group was further subdivided into patients with: varicocele (n = 22), idiopathic infertility (n = 13) and partners of couples with recurrent spontaneous abortion (RSA; n = 20). Semen analysis was determined following WHO criteria. The cytokine interleukin 1β (IL-1β), IL-6, IL-10, IL-18; tumor necrosis factor α (TNF-α), interferon g (IFN-g) and transforming growth factor β1 (TGF-β1) contents in serum and seminal plasma were determined by quantitative ELISA. An interesting marker of male infertility appears to be TGF-β1 (blood) significantly elevated in idiopathically infertile males and in the RSA group. Besides elevated TGF-β1 in a group of idiopathic infertility significantly elevated IL-10, IL-18, IFN-g (blood) and statistically decreased IL-1β while increased IFN-g were revealed in seminal plasma compared to healthy controls. We may postulate novel cytokine micropatterns for patients with different background of infertility. Therefore, circulating cytokines: IL-1β, IL-10, IL-18, TGF-β1, IFN-g and IL-1β, IFN-g and TGF-β1 in seminal plasma should be extended in evaluation of specific types of male infertility. PMID:26648778

  11. Analysis of inflammatory cytokines in human blood, breath ...

    EPA Pesticide Factsheets

    A change in the expression of cytokines in human biological media indicates an inflammatory response to external stressors and reflects an early step along the adverse outcome pathway (AOP) for various health endpoints. To characterize and interpret this inflammatory response, methodology was developed for measuring a suite of 10 different cytokines in human blood, exhaled breath condensate (EBC), and urine using an electrochemiluminescent multiplex Th1/Th2 cytokine immunoassay platform. Measurement distributions and correlations for eight interleukins (IL) (1β, 2, 4, 5, 8, 10, 12p70 and 13), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were evaluated using 90 blood plasma, 77 EBC, and 400 urine samples collected from nominally healthy adults subjects in North Carolina in 2008-2012. The in vivo results show that there is sufficient sensitivity for characterizing all 10 cytokines at levels of 0.05-0.10 ρg/ml with a dynamic range up to 100 ng/ml across all three of these biological media. The measured in vivo results also show that the duplicate analysis of blood, EBC and urine samples have average estimated fold ranges of 2.21, 3.49, and 2.50, respectively, which are similar to the mean estimated fold range (2.88) for the lowest concentration (0.610ρg/ml) from a series of spiked control samples; the cytokine method can be used for all three biological media. Nine out of the 10 cytokines measured in EBC were highly correlated within one a

  12. Tributyltin exposure alters cytokine levels in mouse serum.

    PubMed

    Lawrence, Shanieek; Pellom, Samuel T; Shanker, Anil; Whalen, Margaret M

    2016-11-01

    Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, keratinocyte chemoattractant (KC), macrophage inflammatory protein 1β (MIP), MIP2 and regulated on activation normal T-cell-expressed and secreted (RANTES) was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40 and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in the serum of mice exposed to TBT for less than 24 h. Levels of IL1β, IL-12 βp40, IL-5 and IL-15 were also modulated in mouse serum, depending on the specific experiment and exposure level. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines.

  13. EFFECT OF CYTOKINE AND PHARMACOGENOMIC GENETIC POLYMORPHISMS IN TRANSPLANTATION

    PubMed Central

    Girnita, Diana M; Burckart, Gilbert; Zeevi, Adriana

    2008-01-01

    Purpose of review Recent investigations related to the polymorphism of genes that affect drug therapy and the polymorphisms of cytokines and growth factors that control immune responses have been associated with outcomes following solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). This review will provide a current update on the most recent findings and discuss the challenges for developing individualized therapeutic strategies based on clinical and genetic profiles. Recent Findings Single nucleotide polymorphisms (SNPs) of cytokine genes have been shown to have an impact in vitro or in vivo protein secretion, dividing the individuals into High, Low or Intermediate producers for a given molecule. Many studies have been performed to determine the contribution of single cytokine gene SNPs on SOT or HSCT outcomes and the reported results are still controversial. However, analysis of a combination of several cytokines and/or cytokine receptor polymorphisms adjusted for known clinical risk factors and ethnicity have resulted in significant clinical correlations. Furthermore, associations with gene polymorphisms that affect immunosuppressive drug therapy in solid organ transplantation have also been extensively studied. There is a continuous flow of new information regarding functional SNPs that may affect the immune response to the allograft or to drug therapy and their impact on clinical outcomes have yet to be validated in large cohorts SOT or HSCT Summary Consolidating the information that we have on pharmacogenetics and on cytokine genetics to produce patient-oriented individualized drug regimens is an important challenge in transplantation medicine. Using a multi-variant approach based on genetic profile and other relevant clinical factors a score system may be developed to predict the severity of rejection, infection or other complications associated with transplantation. The ultimate goal of these studies is to improve patient

  14. [Behavior-immunity relationship: the role of cytokines].

    PubMed

    Espinosa, E; Bermúdez-Rattoni, F

    2001-01-01

    There are several phenomena in which the immune and the central nervous systems regulate each other. However, their mechanisms are poorly understood. Since cytokines have a central role in the regulation of the immune response, this review describes their participation in two forms of neuro-immune communication, immunomodulation by psychological stress and behavioral conditioning of immune response. The role of cytokines in the endocrine and behavioral effects of acute phase, where cytokines have an effect in functions of the central nervous system, is also reviewed. The effects of psychological stress are described as both immunosuppressing and immunoenhancing. Among them, a relevant immunosuppressing one is the reduction of IL-1, IL-2, and IFN-gamma levels. In contrast, some of the pro-inflammatory effects of stress are mediated by an increase in the levels of IL-6, IL-1, and TNF mediated by the neurotransmitter Substance P. A possible role for IL-1 and IFN-beta as possible messengers in immune regulation by behavioral conditioning is proposed. Pro-inflammatory cytokines in turn can activate the hypothalamus-pituitary-adrenal axis and induce sickness behavior during the acute phase response, during which the parasympathetic nervous system serves as pathway for their detection by the central nervous system. An account is given about recent findings on the regulation of cytokine expression by neurotransmitters from the sympathetic nervous system (epinephrine and norepinephrine), a key piece in all these mechanisms of brain-immune communication. Possible mechanisms and pathways of communication between the brain and the immune system, as well as the possible participation of other cytokines are discussed.

  15. Cytokine Profiles at Birth Predict Malaria Severity during Infancy

    PubMed Central

    Prevots, D. Rebecca; Morrison, Robert; Harrington, Whitney; Gwamaka, Moses; Kurtis, Jonathan D.; Fried, Michal; Duffy, Patrick E.

    2013-01-01

    Background Severe malaria risk varies between individuals, and most of this variation remains unexplained. Here, we examined the hypothesis that cytokine profiles at birth reflect inter-individual differences that persist and influence malaria parasite density and disease severity throughout early childhood. Methods and Findings Cytokine levels (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-6 and IL-10) were measured at birth (cord blood; N=783) and during subsequent routine follow-up visits (peripheral blood) for children enrolled between 2002 and 2006 into a birth cohort in Muheza, Tanzania. Children underwent blood smear and clinical assessments every 2-4 weeks, and at the time of any illness. Cord blood levels of all cytokines were positively correlated with each other (Spearman’s rank correlation). Cord levels of IL-1β and TNF-α (but not other cytokines) correlated with levels of the same cytokine measured at routine visits during early life (P < 0.05). Higher cord levels of IL-1β but not TNF-α were associated with lower parasite densities during infancy (P=0.003; Generalized Estimating Equation (GEE) method), with an average ~40% reduction versus children with low cord IL-1β levels, and with decreased risk of severe malaria during follow-up (Cox regression): adjusted hazard ratio (95% CI) 0.60 (0.39-0.92), P = 0.02. Conclusion IL-1β levels at birth are related to future IL-1β levels as well as the risk of severe malaria in early life. The effect on severe malaria risk may be due in part to the effect of inflammatory cytokines to control parasite density. PMID:24130857

  16. Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review

    PubMed Central

    Yako, Yandiswa Yolanda; Kruger, Deirdré; Smith, Martin; Brand, Martin

    2016-01-01

    Objectives A systematic review of the role of cytokines in clinical medicine as diagnostic, prognostic, or predictive biomarkers in pancreatic ductal adenocarcinoma was undertaken. Materials and Methods A systematic review was conducted according to the 2009 PRISMA guidelines. PubMed database was searched for all original articles on the topic of interest published until June 2015, and this was supplemented with references cited in relevant articles. Studies were evaluated for risk of bias using the Quality in Prognosis Studies tools. Results Forty one cytokines were investigated with relation to pancreatic ductal adenocarcinoma (PDAC) in 65 studies, ten of which were analyzed by more than three studies. Six cytokines (interleukin[IL]-1β, -6, -8, -10, vascular endothelial growth factor, and transforming growth factor) were consistently reported to be increased in PDAC by more than four studies; irrespective of sample type; method of measurement; or statistical analysis model used. When evaluated as part of distinct panels that included CA19-9, IL-1β, -6 and -8 improved the performance of CA19-9 alone in differentiating PDAC from healthy controls. For example, a panel comprising IL-1β, IL-8, and CA 19–9 had a sensitivity of 94.1% vs 85.9%, specificity of 100% vs 96.3%, and area under the curve of 0.984 vs 0.925. The above-mentioned cytokines were associated with the severity of PDAC. IL-2, -6, -10, VEGF, and TGF levels were reported to be altered after patients received therapy or surgery. However, studies did not show any evidence of their ability to predict treatment response. Conclusion Our review demonstrates that there is insufficient evidence to support the role of individual cytokines as diagnostic, predictive or prognostic biomarkers for PDAC. However, emerging evidence indicates that a panel of cytokines may be a better tool for discriminating PDAC from other non-malignant pancreatic diseases or healthy individuals. PMID:27170998

  17. The effect of proinflammatory cytokines in Cognitive Behavioral Therapy.

    PubMed

    Moreira, Fernanda Pedrotti; Cardoso, Taiane de Azevedo; Mondin, Thaíse Campos; Souza, Luciano Dias de Mattos; Silva, Ricardo; Jansen, Karen; Oses, Jean Pierre; Wiener, Carolina David

    2015-08-15

    Major depressive disorder (MDD) is a debilitating disorder and its pathophysiology is associated with deregulation of the immune system. We investigated the changes in circulating levels of proinflammatory cytokines (specifically IL-6 and TNF-α) measured by the ELISA kit in two psychotherapeutic interventions for MDD: Narrative Cognitive Therapy (NCT) and Cognitive Behavioral Therapy (CBT). This is a randomized clinical trial including 97 individuals (18 to 29years-old) with MDD. In CBT there was a significant difference in serum levels of IL-6 and TNF-α, therefore indicating that CBT was more effective than NCT on serum levels proinflammatory cytokines.

  18. Exploiting cytokines in adoptive T-cell therapy of cancer.

    PubMed

    Petrozziello, Elisabetta; Sturmheit, Tabea; Mondino, Anna

    2015-01-01

    Adoptive immunotherapy with tumor-reactive autologous T cells, either expanded from tumor specimens or genetically engineered to express tumor-reactive T-cell receptors and chimeric antigen receptors, is holding promising results in clinical trials. Several critical issues have been identified and results underline the possibility to exploit cytokines to further ameliorate the efficacy of current treatment protocols, also encompassing adoptive T-cell therapy. Here we review latest developments on the use of cytokines to better direct the nature of the T-cell infusion product, T-cell function and persistence in vivo, as well as to modulate the tumor microenvironment.

  19. The Role of Cytokines and Chemokines in Filovirus Infection

    PubMed Central

    Bixler, Sandra L.; Goff, Arthur J.

    2015-01-01

    Ebola- and marburgviruses are highly pathogenic filoviruses and causative agents of viral hemorrhagic fever. Filovirus disease is characterized by a dysregulated immune response, severe organ damage, and coagulation abnormalities. This includes modulation of cytokines, signaling mediators that regulate various components of the immune system as well as other biological processes. Here we examine the role of cytokines in filovirus infection, with an emphasis on understanding how these molecules affect development of the antiviral immune response and influence pathology. These proteins may present targets for immune modulation by therapeutic agents and vaccines in an effort to boost the natural immune response to infection and/or reduce immunopathology. PMID:26512687

  20. Cytokine mRNA expression in postischemic/reperfused myocardium.

    PubMed Central

    Herskowitz, A.; Choi, S.; Ansari, A. A.; Wesselingh, S.

    1995-01-01

    While the role of cytokines in mediating injury during hind limb skeletal muscle ischemia followed by reperfusion has recently been described, the role of cytokines in myocardial infarction and ischemia/reperfusion have remained relatively unexplored. We hypothesize that cytokines play an important role in the regulation of postischemic myocardial inflammation. This study reports the temporal sequence of proinflammatory cytokine gene expression in postischemic/reperfused myocardium and localizes interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha)-protein by immunostaining. Rats were subjected to either permanent left anterior descending (LAD) occlusion or to 35 minutes of LAD occlusion followed by reperfusion and sacrificed up to 7 days later. Rat-specific oligonucleotide probes were used to semiquantitatively assess the relative expression of mRNA for TNF-alpha, IL-1 beta, IL-2, IL-6, interferon-gamma (IFN-gamma), and transforming growth factor-beta 1 (TGF-beta 1) utilizing the reverse transcriptase-polymerase chain reaction amplification technique. Increased cardiac mRNA levels for all cytokines except IL-6 and IFN-gamma were measurable within 15 to 30 minutes of LAD occlusion and increased levels were generally sustained for 3 hours. During early reperfusion, mRNA levels for IL-6 and TGF-beta 1 were significantly reduced compared with permanent LAD occlusion. In both groups, cytokine mRNA levels all returned to baseline levels at 24 hours, while IL-1 beta, TNF-alpha, and TGF-beta 1 mRNA levels again rose significantly at 7 days only in animals with permanent LAD occlusion. Immunostaining for IL-1 beta and TNF-alpha protein revealed two patterns of reactivity: 1) microvascular staining for both IL-1 beta and TNF-alpha protein only in postischemic reperfused myocardium in early post-reperfusion time points; and 2) staining of infiltrating macrophages in healing infarct zones which was most prominent at 7 days after permanent LAD occlusion

  1. Tear cytokine response to multipurpose solutions for contact lenses

    PubMed Central

    Kalsow, Carolyn M; Reindel, William T; Merchea, Mohinder M; Bateman, Kirk M; Barr, Joseph T

    2013-01-01

    Purpose An increased risk of corneal infiltrative events has been noted with the use of certain contact lenses and multipurpose solutions (MPS). This study was designed to evaluate tear cytokine assay as a sensitive, objective, and quantitative measure of the ocular surface response to contact lens/MPS and to consider the assay’s clinical relevance in the context of other measures of ocular surface response. Methods Two MPS, ReNu® Fresh™ (RNF) and Opti-Free® RepleniSH (OFR), were used with daily wear silicone hydrogel contact lenses in a randomized, prospective crossover study involving 26 subjects. Clinical data collection (conjunctival hyperemia, ocular surface sensitivity, solution induced corneal staining (SICS) test score, and subjective responses) and tear cytokine assays were conducted masked. Responses were tracked as change from baseline throughout the experimental schedule. Results Similar response patterns for several inflammatory cytokines were seen throughout both phases: subjects who received OFR in Phase I had mean tear concentrations that were generally higher than those of the RNF Phase I group. OFR Phase I subjects had significant (P < 0.01) increases over baseline at day 1 and/or following washout for 13 cytokines (cc chemokine ligands [CCL] 3, CCL5, CCL11, granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon [INF]-γ, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-13, IL-15, IL-17, tumor necrosis factor [TNF]-α). These changes were not observed in RNF Phase I subjects, even though SICS test scores increased. Phase I OFR subjects also had increased dryness, while RNF Phase I subjects had decreased bulbar hyperemia. No changes were detected with respect to limbal hyperemia or surface sensitivity thresholds. Conclusion The tear cytokine assay can detect and differentiate contact lens/MPS induced increases in inflammatory cytokines. Changes in cytokine levels were consistent with measurement of hyperemia and dryness but not with

  2. The cytokines (IFN-gamma, IL-2, IL-4, IL-10, IL-17) and Treg cytokine (TGF-beta1) levels in adults with immune thrombocytopenia.

    PubMed

    Ma, Liangliang; Liang, Yan; Fang, Meiyun; Guan, Yanchun; Si, Yang; Jiang, Feng; Wang, Fangting

    2014-09-01

    Previous studies have indicated that autoimmune diseases might be caused by an imbalance of T helper cells (Th), cytokines, and regulatory T cells (Treg) cytokines. We measured the plasma concentrations of Th1-associated cytokines (IFN-gamma, IL-2), Th2 -associated cytokines (IL-4, IL-10), Th17-associated cytokine (IL-17) and Treg -associated cytokine (TGF-beta1) in adult patients with immune thrombocytopenia (ITP) and evaluated their clinical relevance. Plasma IFN-gamma, IL-2, IL-4, IL-10, IL-17 and TGF-beta1 concentrations of 52 ITP patients and 30 age- and sex-matched healthy controls were measured by enzyme-linked immunosorbent assay method (ELISA). Concentration of Th2 cytokines (IL-4 and IL-10) were significantly higher in ITP patients compared to controls (P < 0.05). However, concentrations of Th1 cytokines (IFN-gamma, IL-2), Th17 cytokine (IL-17) and Treg cytokine (TGF-beta1) were lower in ITP patients (P < 0.05). Concentration of IL-17 was significantly higher in chronic ITP patients compared to severe ITP patients (P < 0.05), and no significant difference of cytokine concentration among the other subgroups in ITP patients was found. Among the ITP patients, concentration of IFN-gamma correlated positively and significantly with PAIgG (r = 0.48, P = 0.02). A significant correlation was neither found between other cytokine levels and platelet count, nor between cytokine levels and megakaryocytes number, nor between cytokines levels and PAIgG or GPIIb/IIIa and/or GPIb/IX autoantibodies. The present study demonstrates that an imbalance of Th and Treg cytokines may mediate the pathogenesis of ITP.

  3. Plasma cytokine concentration and the cytokine producing ability of whole blood cell cultures from healthy females with pharmacologically induced hyperprolactinemia.

    PubMed

    Rovenský, J; Lackovic, V; Veselková, Z; Horváthová, M; Koska, J; Blazícková, S; Vigas, M

    1999-01-01

    We investigated the in vitro effect of domperidone-induced hyperprolactinemia on plasma cytokine concentration and blood leukocyte cytokine production in healthy female volunteers. No changes were found in the plasma concentration of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-10, IL-6 and IL-13 during hyperprolactinemia when compared with control values. Using unseparated blood leukocytes, we found that the spontaneous production of IL-6 (4-8 h) and transforming growth factor (TGF)-beta 1 (2-4 h) was significantly decreased and that the in vitro stimulated production of IFN-gamma (2-8 h) and TNF (4 h) was significantly increased compared with control. Our data concerning the increased IFN-gamma and TNF producing capacity of unseparated leukocytes during pharmacologically induced hyperprolactinemia strongly support the possibility that the lymphocyte production of these cytokines can be rapidly amplified by prolactin via a priming mechanism.

  4. Biology of recently discovered cytokines: Interleukin-17 – a unique inflammatory cytokine with roles in bone biology and arthritis

    PubMed Central

    Gaffen, Sarah L

    2004-01-01

    IL-17 and its receptor are founding members of an emerging family of cytokines and receptors with many unique characteristics. IL-17 is produced primarily by T cells, particularly those of the memory compartment. In contrast, IL-17 receptor is ubiquitously expressed, making nearly all cells potential targets of IL-17. Although it has only limited homology to other cytokines, IL-17 exhibits proinflammatory properties similar to those of tumor necrosis factor-α, particularly with respect to induction of other inflammatory effectors. In addition, IL-17 synergizes potently with other cytokines, placing it in the center of the inflammatory network. Strikingly, IL-17 has been associated with several bone pathologies, most notably rheumatoid arthritis. PMID:15535837

  5. Validation of a commercial canine assay kit to measure pinniped cytokines.

    PubMed

    Levin, Milton; Romano, Tracy; Matassa, Keith; De Guise, Sylvain

    2014-07-15

    The present study was conducted to assess and validate the cross-reactivity of commercially available multiplex human and canine cytokine kits coupled with the Bio-Plex 200 platform to measure cytokines in three pinniped species, harbor seals (Phoca vitulina), gray seals (Halichoerus grypus), and harp seals (Pagophilus groenlandicus). Cytokines are important small proteins that help direct a proper immune response to pathogens. The human cytokine kit allowed the detection of cytokines in the supernatant of mitogen-stimulated human peripheral blood mononuclear cells, but not in the three pinniped species studied, with the exception of TNFα and GM-CSF. In contrast, the canine cytokine kit appeared to cross-react with the majority of cytokines in the three pinniped species tested, including the pro-inflammatory cytokine TNFα, the Th1 cytokine INFγ, and the Th2 cytokine IL-10, an anti-inflammatory cytokine. In addition, the pro-inflammatory cytokines IL-6 and IL-8 were also measured in all pinniped species. Overall, the Bio-Plex 200 platform and the canine multiplex cytokine kit allowed the successful measurement of potentially clinically important pinniped cytokines. This additional tool may provide veterinarians with additional information to detect sub-clinical signs of inflammation or evidence for immune response, which may not be revealed during regular medical evaluation, e.g. physical examination, hematology, and serum chemistry.

  6. PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines.

    PubMed

    Yanagi, Teruki; Shi, Ranxin; Aza-Blanc, Pedro; Reed, John C; Matsuzawa, Shu-ichi

    2015-01-01

    While PCTAIRE1/PCTK1/Cdk16 is overexpressed in malignant cells and is crucial in tumorigenesis, its function in apoptosis remains unclear. Here we investigated the role of PCTAIRE1 in apoptosis, especially in the extrinsic cell death pathway. Gene-knockdown of PCTAIRE1 sensitized prostate cancer PPC1 and Du145 cells, and breast cancer MDA-MB-468 cells to TNF-family cytokines, including TNF-related apoptosis-inducing ligand (TRAIL). Meanwhile, PCTAIRE1-knockdown did not sensitize non-malignant cells, including diploid fibroblasts IMR-90 and the immortalized prostate epithelial cell line 267B1. PCTAIRE1-knockdown did not up-regulate death receptor expression on the cell surface or affect caspase-8, FADD and FLIP expression levels. PCTAIRE1-knockdown did promote caspase-8 cleavage and RIPK1 degradation, while RIPK1 mRNA knockdown sensitized PPC1 cells to TNF-family cytokines. Furthermore, the kinase inhibitor SNS-032, which inhibits PCTAIRE1 kinase activity, sensitized PPC1 cells to TRAIL-induced apoptosis. Together these results suggest that PCTAIRE1 contributes to the resistance of cancer cell lines to apoptosis induced by TNF-family cytokines, which implies that PCTAIRE1 inhibitors could have synergistic effects with TNF-family cytokines for cytodestruction of cancer cells.

  7. Human malarial disease: a consequence of inflammatory cytokine release

    PubMed Central

    Clark, Ian A; Budd, Alison C; Alleva, Lisa M; Cowden, William B

    2006-01-01

    Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease. PMID:17029647

  8. Cytokine and hormonal changes after cholecystectomy. Effect of ibuprofen pretreatment.

    PubMed Central

    Chambrier, C; Chassard, D; Bienvenu, J; Saudin, F; Paturel, B; Garrigue, C; Barbier, Y; Boulétreau, P

    1996-01-01

    OBJECTIVE: Surgical stress induces hormonal and cytokine responses proportional to the extent of the injury. Therefore, the authors assessed the effect of ibuprofen pretreatment on metabolic and hormonal changes after surgery. SUMMARY BACKGROUND DATA: Postoperative administration of cyclo-oxygenase inhibitor reduces cytokine production and nitrogen losses. METHODS: The authors studied the plasma hormones and metabolic and cytokines changes after perioperative ibuprofen administration in 22 patients undergoing cholecystectomy under inhalational anesthesia. Suppositories containing ibuprofen (500 mg) or placebo were administered 12 and 2 hours before surgery, and every 8 hours until the third postoperative day. Blood samples were collected 24 and 2 hours before surgery and 2, 4, 6, 24, 48, and 72 hours after surgery for glucose, C-reactive protein, leukocytes, adrenocorticotropic hormone (ACTH), cortisol, tumor necrosis factor, and interleukin-1 and interleukin-6 determinations. RESULTS: In both groups, plasma cortisol levels remained elevated for 3 days, whereas plasma ACTH levels returned to the basal level at day 1. The ACTH (p < 0.01), cortisol (p < 0.01), and glucose changes (p < 0.001) were smaller in the ibuprofen group and their duration was shorter. The interleukin-6 levels increased gradually after skin incision until the sixth hour and were significantly lower (p < 0.05) in the ibuprofen group. CONCLUSION: Ibuprofen pretreatment in perioperative course is able to reduce the endocrine response and cytokine release. Therefore, ibuprofen may be useful in decreasing the stress response in severely surgical patients. PMID:8757381

  9. TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin

    PubMed Central

    Yabe-Wada, Toshiki; Matsuba, Shintaro; Takeda, Kazuya; Sato, Tetsuya; Suyama, Mikita; Ohkawa, Yasuyuki; Takai, Toshiyuki; Shi, Haifeng; Philpott, Caroline C.; Nakamura, Akira

    2016-01-01

    Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN-α, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-α secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-α in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3′ UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals. PMID:27220277

  10. Interaction of BDNF with cytokines in chronic schizophrenia.

    PubMed

    Zhang, Xiang Yang; Tan, Yun-Long; Chen, Da-Chun; Tan, Shu-Ping; Yang, Fu-De; Wu, Hanjing Emily; Zunta-Soares, Giovana B; Huang, Xu-Feng; Kosten, Thomas R; Soares, Jair C

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.

  11. Adenosine modulates LPS-induced cytokine production in porcine monocytes.

    PubMed

    Ondrackova, Petra; Kovaru, Hana; Kovaru, Frantisek; Leva, Lenka; Faldyna, Martin

    2013-03-01

    Adenosine plays an important role during inflammation, particularly through modulation of monocyte function. The objective of the present study was to evaluate the effect of synthetic adenosine analogs on cytokine production by porcine monocytes. The LPS-stimulated cytokine production was measured by flow cytometry and quantitative real-time PCR. Adenosine receptor expression was measured by quantitative real-time PCR. The present study demonstrates that adenosine analog N-ethylcarboxyamidoadenosine (NECA) down-regulates TNF-α production and up-regulates IL-8 production by LPS-stimulated porcine monocytes. The effect was more pronounced in CD163(-) subset of monocytes compared to the CD163(+) subset. Although both monocyte subsets express mRNA for A1, A2A, A2B and A3 adenosine receptors, the treatment of monocytes with various adenosine receptor agonists and antagonists proved that the effect of adenosine is mediated preferentially via A2A adenosine receptor. Moreover, the study suggests that the effect of NECA on porcine monocytes alters the levels of the cytokines which could play a role in the differentiation of naive T cells into Th17 cells. The results suggest that adenosine plays an important role in modulation of cytokine production by porcine monocytes.

  12. Proinflammatory cytokines in injured rat brain following perinatal asphyxia.

    PubMed

    Maślińska, Danuta; Laure-Kamionowska, Milena; Kaliszek, Agnieszka; Makarewicz, Dorota

    2002-01-01

    In contrast to astrogliosis, which is common to injuries of the adult CNS, in the developing brain this process is minimal. Reasons postulated for this include the relative immaturity of the immune system and the consequent insufficient production of cytokines to evoke astrogliosis. To explore this hypothesis, the study was undertaken to detect the presence of some proinflammatory cytokines in the injured rat brain following perinatal asphyxia (ischaemia/hypoxia). The localisation of TNF-alpha, IL-15, IL-17 and IL-17 receptors was visualised by means of immunohistochemistry. In numerous neurones of the rat brain, the IL-17 appeared to be constitutively expressed. In the early period of inflammation the IL-15 was produced mainly by the blood cells penetrating the injured brain but later it was synthesised also by reactive astrocytes surrounding brain cysts and forming dense astrogliosis around necrotic brain regions. The direct effect on astrogliosis of other estimated cytokines seems to be negligible. All the results lead to the conclusion that from all cytokines identified in the injured immature rat brain the IL-15 plays the most important role during inflammatory response and participates in the gliosis of reactive astrocytes.

  13. Dual-color ELISPOT assay for analyzing cytokine balance.

    PubMed

    Okamoto, Yoshihiro; Nishida, Mikio

    2005-01-01

    A dual-color enzyme-linked immunospot (ELISPOT) assay enabled us to analyze three kinds of cytokine-secreting cells simultaneously. T helper (Th) cells can be subdivided into at least two distinct functional subsets based on their cytokine secretion profiles. The first type of clones (Th1) produces interleukin (IL)-2 and interferon (IFN)-gamma but not IL-4 or IL-5. The second type of clones (Th2) produces IL-4 and IL-5 but not IL-2 or IFN-gamma. Furthermore, the presence of the third type (Th0) cell, which is a precursor of Th1 or Th2 cells, has been demonstrated to produce both Th1- and Th2-type cytokines. The dual-color ELISPOT assay is developed to differentiate these three subtypes of Th cells in an identical well. In the system, the red spots corresponding to IL-2-secreting cells (Th1) were developed with horseradish peroxidase and amino-ethyl-carbazole/H2O2. The light blue spots corresponding to IL-4-secreting cells (Th2) were developed with alkaline phosphatase and Vector blue (chromogenic substrate for alkaline phosphatase). The mixed colored (indigo) spots corresponding to both kinds of cytokine-secreting cells (Th0 cells) were developed with both chromogenic substrates. With this system, we could detect the IL-2- and/or IL-4-secreting cells simultaneously in a murine spleen cell or human peripheral mononuclear cell preparation.

  14. Cytokine release assays: current practices and future directions.

    PubMed

    Finco, D; Grimaldi, C; Fort, M; Walker, M; Kiessling, A; Wolf, B; Salcedo, T; Faggioni, R; Schneider, A; Ibraghimov, A; Scesney, S; Serna, D; Prell, R; Stebbings, R; Narayanan, P K

    2014-04-01

    As a result of the CD28 superagonist biotherapeutic monoclonal antibody (TGN 1412) "cytokine storm" incident, cytokine release assays (CRA) have become hazard identification and prospective risk assessment tools for screening novel biotherapeutics directed against targets having a potential risk for eliciting adverse pro-inflammatory clinical infusion reactions. Different laboratories may have different strategies, assay formats, and approaches to the reporting, interpretation, and use of data for either decision making or risk assessment. Additionally, many independent contract research organizations (CROs), academic and government laboratories are involved in some aspect of CRA work. As a result, while some pharmaceutical companies are providing CRA data as part of the regulatory submissions when necessary, technical and regulatory practices are still evolving to provide data predictive of cytokine release in humans and that are relevant to safety. This manuscript provides an overview of different approaches employed by the pharmaceutical industry and CROs, for the use and application of CRA based upon a survey and post survey follow up conducted by ILSI-Health and Environmental Sciences Institute (HESI) Immunotoxicology Committee CRA Working Group. Also discussed is ongoing research in the academic sector, the regulatory environment, current limitations of the assays, and future directions and recommendations for cytokine release assays.

  15. ALPK1 affects testosterone mediated regulation of proinflammatory cytokines production.

    PubMed

    Kuo, Tzer-Min; Yeh, Kun-Tu; Hsu, Hui-Ting; Chiang, Shang-Lun; Chang, Jan-Gowth; Huang, Chung-Ming; Tu, Hung-Pin; Liu, Chiu-Shong; Ko, Ying-Chin

    2015-11-01

    Alpha-protein kinase 1, also known as alpha-kinase 1 (ALPK1), is associated with chronic kidney disease (CKD), myocardial infarction, gout and type 2 diabetes mellitus (DM). In addition to having an inductive effect on the proinflammatory cytokines in monocytic THP1 cells, ALPK1 is expressed abundantly in the mouse testes. Low testosterone levels are commonly associated with arthritis, CKD, type 2 DM, cardiovascular disease and inflammation. The testosterone's anti-inflammatory effect has been demonstrated to reduce proinflammatory cytokines and adhesion molecules. In this study, we found that ALPK1 transgenic mice showed lower levels of testosterone in both the testes and the serum. Decreasing endogenous ALPK1 enhanced testosterone levels and transcripts of testosterone-regulated genes (P450scc, 3beta-HSD, P450C17, 17beta-HSD, StAR, and INSL3) in TM3 Leydig cells. In contrast, increasing testosterone decreased ALPK1 in both TM3 and monocytic THP1 cells. This decrease was accompanied by a reduction of the proinflammatory cytokines. Increased ALPK1 levels attenuated the testosterone effects in THP1 cells. Finally, we also found that ALPK1 increased the release of TNF-alpha and TGF-beta1 in the human embryonic kidney 293 cells, while testosterone inhibited ALPK1 in the primary kidney cells. Taken together, this data suggests that the balance between ALPK1 and testosterone plays a critical role in the testosterone-mediated inhibition of proinflammatory cytokines.

  16. Neonatal infections in Saudi Arabia: Association with cytokine gene polymorphisms.

    PubMed

    Allam, Gamal; Alsulaimani, Adnan A; Alzaharani, Ali K; Nasr, Amre

    2015-01-01

    In recent years, many studies have reported potential associations between cytokine gene polymorphisms and the development, course, and outcome of sepsis, often with apparently conflicting results. The objective of this study was to investigate single nucleotide polymorphism (SNP) in the interleukin (IL)-1β -31 T/C, IL-6 -174 G/C, tumor necrosis factor α (TNF-α) -308 G/A, and interferon γ (IFN-γ) +874 A/T genes for their possible association with susceptibility to early onset sepsis (EOS) in Saudi newborn infants. A total of 205 newborn infants aged 1-2 days were consecutively enrolled onto the study having met the inclusion criteria (as per the research protocol). DNA was extracted from filter papers using the Chelex-100 method. The cytokines SNP were genotyping using Taqman 5' nuclease allelic discrimination. For cytokine measurements we used the commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit. Our results show that the circulating IL-1β, IL-6, TNF-α, and IFN-γ were significantly (p < 0.001) elevated in EOS patients compared to suspected and sepsis-free control groups; and IL-1β -31C, IL-6 -174G, TNF-α -308G, and IFN-γ +874A alleles were associated with EOS in Saudi infants. In conclusion, analysis of cytokines concentrations and SNP for the four tested genes can be used as a predictor of sepsis outcome in newborns.

  17. Circulating Cytokines as Biomarkers of Alcohol Abuse and Alcoholism

    PubMed Central

    Achur, Rajeshwara N.; Freeman, Willard M.; Vrana, Kent E.

    2010-01-01

    There are currently no consistent objective biochemical markers of alcohol abuse and alcoholism. Development of reliable diagnostic biomarkers that permit accurate assessment of alcohol intake and patterns of drinking is of prime importance to treatment and research fields. Diagnostic biomarker development in other diseases has demonstrated the utility of both open, systems biology, screening for biomarkers and more rational focused efforts on specific biomolecules or families of biomolecules. Long term alcohol consumption leads to altered inflammatory cell and adaptive immune responses with associated pathologies and increased incidence of infections. This has led researchers to focus attention on identifying cytokine biomarkers in models of alcohol abuse. Alcohol is known to alter cytokine levels in plasma and a variety of tissues including lung, liver, and very importantly brain. A number of cytokine biomarker candidates have been identified, including: TNF alpha, IL1-alpha, IL1-beta, IL6, IL8, IL12 and MCP-1. This is an emerging and potentially exciting avenue of research in that circulating cytokines may contribute to diagnostic biomarker panels and a combination of multiple biomarkers may significantly increase the sensitivity and specificity of the biochemical tests aiding reliable and accurate detection of excessive alcohol intake. PMID:20020329

  18. Effects of prebiotics on immune system and cytokine expression.

    PubMed

    Shokryazdan, Parisa; Faseleh Jahromi, Mohammad; Navidshad, Bahman; Liang, Juan Boo

    2017-02-01

    Nowadays, use of prebiotics as feed and food additives has received increasing interest because of the beneficial effects of prebiotics on the health of animals and humans. One of the beneficial effects of prebiotics is stimulation of immune system, which can be direct or indirect through increasing population of beneficial microbes or probiotics, especially lactic acid bacteria and bifidobacteria, in the gut. An important mechanism of action of probiotics and prebiotics, by which they can affect the immune system, is changing the expression of cytokines. The present review tried to summarize the findings of studies that investigated the effects of prebiotics on immune system with focusing on their effects on cytokine expression. Generally, most of reviewed studies indicated beneficial effects for prebiotics in terms of improving immune system, by increasing the expression of anti-inflammatory cytokines, while reducing the expressions of proinflammatory cytokines. However, most of studies mainly considered the indirect effects of prebiotics on the immune system (through changing the composition and population of gut microbiota), and their direct effects still need to be further studied using prebiotics with different degree of polymerization in different hosts.

  19. Prognosis Relevance of Serum Cytokines in Pancreatic Cancer

    PubMed Central

    Torres, Carolina; Linares, Ana; Alejandre, Maria José; Palomino-Morales, Rogelio J.; Caba, Octavio; Prados, Jose; Aránega, Antonia; Delgado, Juan R.; Irigoyen, Antonio; Martínez-Galán, Joaquina; Ortuño, Francisco M.; Rojas, Ignacio; Perales, Sonia

    2015-01-01

    The overall survival of patients with pancreatic ductal adenocarcinoma is extremely low. Although gemcitabine is the standard used chemotherapy for this disease, clinical outcomes do not reflect significant improvements, not even when combined with adjuvant treatments. There is an urgent need for prognosis markers to be found. The aim of this study was to analyze the potential value of serum cytokines to find a profile that can predict the clinical outcome in patients with pancreatic cancer and to establish a practical prognosis index that significantly predicts patients' outcomes. We have conducted an extensive analysis of serum prognosis biomarkers using an antibody array comprising 507 human cytokines. Overall survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox's proportional hazard models were used to analyze prognosis factors. To determine the extent that survival could be predicted based on this index, we used the leave-one-out cross-validation model. The multivariate model showed a better performance and it could represent a novel panel of serum cytokines that correlates to poor prognosis in pancreatic cancer. B7-1/CD80, EG-VEGF/PK1, IL-29, NRG1-beta1/HRG1-beta1, and PD-ECGF expressions portend a poor prognosis for patients with pancreatic cancer and these cytokines could represent novel therapeutic targets for this disease. PMID:26346854

  20. Development of specific cytokine and Chemokine ELISAs for Bottlenose Dolphins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Earlier detection of changes in the health status of bottlenose dolphins (Tursiops truncatus) is expected to further improve their medical care. Cytokines and chemokines are critical mediators of the cellular immune response, and studies have suggested that these molecules may serve as important bio...

  1. Cytokine responses in the common cold and otitis media.

    PubMed

    Wine, Todd M; Alper, Cuneyt M

    2012-12-01

    Cytokines are a group of diverse molecules that influence the function of every organ system. They are most well studied in their effects on the immune system and their integral role in mediating inflammation. The common cold and otitis media are two such disease states, and much has been learned about the various effects of cytokines in each disease. Most often the viruses isolated include rhinovirus (RV), respiratory syncytial virus (RSV), adenovirus, coronavirus, and picornavirus. Otitis media, sinusitis, bronchiolitis, pneumonia, and asthma exacerbation are commonly accepted as complications of viral upper respiratory tract infections. Furthermore, otitis media and upper respiratory infections are inextricably linked in that the majority (>70 %) of cases of acute otitis media occur as complications of the common cold. Cytokine polymorphisms have been associated with the severity of colds as well as the frequency of otitis media. This article attempts to update the reader on various studies that have recently been published regarding the role of cytokines in these two disease entities.

  2. Micropatterning of Aptamer Beacons to Create Cytokine-Sensing Surfaces

    PubMed Central

    Tuleuova, Nazgul

    2010-01-01

    Aptamer beacons are DNA or RNA probes that bind proteins or small molecules of interest and emit signal directly upon interaction with the target analyte. This paper describes micropatterning of aptamer beacons for detection of IFN-γ—an important inflammatory cytokine. The beacon consisted of a fluorophore-labeled aptamer strand hybridized with a shorter, quencher-carrying complementary strand. Cytokine molecules were expected to displace quenching strands of the beacon, disrupting FRET effect and resulting in fluorescence signal. The glass substrate was first micropatterned with poly(ethylene glycol) (PEG) hydrogel microwells (35 μm diameter individual wells) so as to define sites for attachment of beacon molecules. PEG microwell arrays were then incubated with avidin followed by biotin-aptamer-fluorophore constructs. Subsequent incubation with quencher-carrying complementary strands resulted in formation of DNA duplex and caused quenching of fluorescence due to FRET effect. When exposed to IFN-γ, microwells changed fluorescence from low (quencher hybridized with fluorophore-carrying strand) to high (quenching strand displaced by cytokine molecules). The fluorescence signal was confined to microwells, was changing in real-time and was dependent on the concentration of IFN-γ. In the future, we plan to co-localize aptamer beacons and cells on micropatterned surfaces in order to monitor in real-time cytokine secretion from immune cells in microwells. PMID:21170394

  3. Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants

    PubMed Central

    Carlo, Waldemar A.; McDonald, Scott A.; Tyson, Jon E.; Stoll, Barbara J.; Ehrenkranz, Richard A.; Shankaran, Seetha; Goldberg, Ronald N.; Das, Abhik; Schendel, Diana; Thorsen, Poul; Skogstrand, Kristin; Hougaard, David M.; Oh, William; Laptook, Abbot R.; Duara, Shahnaz; Fanaroff, Avroy A.; Donovan, Edward F.; Korones, Sheldon B.; Stevenson, David K.; Papile, Lu-Ann; Finer, Neil N.; O’Shea, T. Michael; Poindexter, Brenda B.; Wright, Linda L.; Ambalavanan, Namasivayam; Higgins, Rosemary D.

    2011-01-01

    Objective To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants. Study design Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants. Results IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP. Conclusions CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin. PMID:21798559

  4. Cytokine expression in Peyer's patches following hemorrhage and resuscitation.

    PubMed

    Shenkar, R; Chang, Y H; Abraham, E

    1994-01-01

    Intestinal dysfunction commonly occurs following hemorrhage and injury and appears to contribute to the development of multiple organ system failure in this setting. In order to examine possible mechanisms leading to intestinal dysfunction following blood loss, we investigated mRNA levels for cytokines with proinflammatory and immunoregulatory properties (interleukin 1 beta (IL-1 beta), IL-6, IL-10, TNF-alpha, TGF-beta, IFN-gamma) as well as mRNA expression for inducible nitric oxide synthase (NOS) over the 3 days following hemorrhage and resuscitation. Significantly increased levels of mRNA for IL-1 beta, IL-10, and IFN-gamma were found among cells isolated from Peyer's patches 3 days following hemorrhage. Amounts of mRNA for inducible NOS were not significantly altered 24 or 72 h after blood loss. In addition to being increased 72 h following hemorrhage, levels of mRNA for IL-10 also were increased 1 and 4 h posthemorrhage. No alterations in cytokine or NOS expression were found 24 h following blood loss. These results demonstrate that significant increases in proinflammatory and immunoregulatory cytokine mRNA levels among cellular populations in Peyer's patches are present at late posthemorrhage time points. These alterations in cytokine expression may contribute to the morphologic, immunologic, and functional changes in the intestines which are present following blood loss and injury.

  5. Pro-inflammatory cytokines: Useful markers for the diagnosis of canine mammary tumours?

    PubMed

    Andaluz, Ana; Yeste, Marc; Rodríguez-Gil, Joan E; Rigau, Teresa; García, Félix; Rivera del Álamo, Maria Montserrat

    2016-04-01

    The aim of the present study was to analyse the expression of 60 pro-inflammatory cytokines as possible markers of malignancy in canine mammary tumours using a human cytokine antibody array. The cytokines were grouped into two different categories: (1) cytokines in which expression indicated the presence of a mammary tumour and (2) cytokines in which expression differentiated between simple mammary adenoma, tubulopapillary carcinoma or complex carcinoma. These data suggest that specific pro-inflammatory cytokines could be useful as tools for the diagnosis of canine mammary tumours.

  6. T-Helper Cytokine Profiles in Patients with Kawasaki Disease

    PubMed Central

    Lee, Sang Bum; Kim, Young Hyun; Hyun, Myung Chul; Kim, Yeo Hyang; Kim, Hee Sun

    2015-01-01

    Background and Objectives Kawasaki disease is an acute systemic vasculitis of which pathogenesis suspected is caused by immune dysregulation. The goal of this study is to evaluate the activation pattern of T helper cell type 1 (Th1) and T helper cell type 2 (Th2) in patients with Kawasaki disease. Subjects and Methods Prospective study of 60 patients (male 36, female 24) with diagnosis of Kawasaki disease were enrolled. One hundred and eighty blood samples from these patients were collected according to the different clinical stages {before initial intravenous immunoglobulin (IVIG), 5 days after initial IVIG, 2 months after initial IVIG}. The plasma level of Th1 cytokines; interferon-gamma (IFN-γ) & interleukin (IL)-2 and Th2 cytokines; IL-4 & IL-10 were measured by enzyme-liked immunosorbent assay. Results In all patients, the plasma level of Th1 cytokines (IFN-γ, IL-2) and Th2 cytokines (IL-4 and IL-10) were markedly elevated during the acute stage of Kawasaki disease. Since then, the plasma level of all these cytokines decreased significantly along with the process of clinical stages. Regardless of the existence of coronary artery lesion or no response to initial IVIG treatment, there were no significant differences between them. Conclusion These data suggest that both Th1 and Th2 cells may be activated simultaneously during the acute stage of Kawasaki disease. Further studies are therefore required to establish the difference of activation pattern of T helper cells between Kawasaki disease and other inflammatory diseases. PMID:26617655

  7. Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum.

    PubMed

    Margetts, Peter J; Kolb, Martin; Yu, Lisa; Hoff, Catherine M; Holmes, Clifford J; Anthony, Daniel C; Gauldie, Jack

    2002-06-01

    Peritonitis, a common complication of peritoneal dialysis, is followed by acute changes in the function of the peritoneum. The role of inflammatory cytokines in these processes is not clearly identified. We used adenoviral-mediated gene transfer to transiently overexpress interleukin (IL)-1 beta (AdIL-1 beta) or tumor necrosis factor (TNF)-alpha (AdTNF-alpha) in the rat peritoneum then used a modified equilibrium test to study the histological and functional changes. Overexpression of IL-1 beta or TNF-alpha led to an acute inflammatory response. Both inflammatory cytokines induced an early expression of the angiogenic cytokine, vascular endothelial growth factor, along with increased expression of the profibrotic cytokine, transforming growth factor-beta1, along with fibronectin expression and collagen deposition in peritoneal tissues. Both inflammatory cytokines induced angiogenesis, increased solute permeability, and ultrafiltration dysfunction at earlier time points. Changes in structure and function seen in AdTNF-alpha-treated animals returned to normal by 21 days after infection, whereas AdIL-1 beta-treated animals had persistently increased vasculature with submesothelial thickening and fibrosis. This was associated with up-regulation TIMP-1. TNF-alpha or IL-1 beta both induce acute changes in the peritoneum that mimic those seen in peritoneal dialysis patients who experience an episode of peritonitis. These functional changes were associated with early angiogenesis that resolved rapidly after exposure to TNF-alpha. IL-1 beta exposure, however, led to a different response with sustained vascularization and fibrosis. IL-1 beta inhibition may be a therapeutic goal in acute peritonitis to prevent peritoneal damage.

  8. KSRP: A Checkpoint for Inflammatory Cytokine Production in Astrocytes

    PubMed Central

    LI, XUELIN; LIN, WEI-JYE; CHEN, CHING-YI; SI, YING; ZHANG, XIAOWEN; LU, LIANG; SUSWAM, ESTHER; ZHENG, LEI; KING, PETER H.

    2013-01-01

    Chronic inflammation in the central nervous system (CNS) is a central feature of many neurodegenerative and autoimmune diseases. As an immunologically competent cell, the astrocyte plays an important role in CNS inflammation. It is capable of expressing a number of cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) that promote inflammation directly and through the recruitment of immune cells. Checkpoints are therefore in place to keep tight control over cytokine production. Adenylate/uridylate-rich elements (ARE) in the 3′ untranslated region of cytokine mRNAs serve as a major checkpoint by regulating mRNA stability and translational efficiency. Here, we examined the impact of KH-type splicing regulatory protein (KSRP), an RNA binding protein which destabilizes mRNAs via the ARE, on cytokine expression and paracrine phenotypes of primary astrocytes. We identified a network of inflammatory mediators, including TNF-α and IL-1β, whose expression increased 2 to 4-fold at the RNA level in astrocytes isolated from KSRP−/− mice compared to littermate controls. Upon activation, KSRP−/− astrocytes produced TNF-α and IL-1β at levels that exceeded control cells by 15-fold or more. Conditioned media from KSRP−/− astrocytes induced chemotaxis and neuronal cell death in vitro. Surprisingly, we observed a prolongation of half-life in only a subset of mRNA targets and only after selective astrocyte activation. Luciferase reporter studies indicated that KSRP regulates cytokine gene expression at both transcriptional and post-transcriptional levels. Our results outline a critical role for KSRP in regulating pro-inflammatory mediators and have implications for a wide range of CNS inflammatory and autoimmune diseases. PMID:22847996

  9. Vitamin D and Serum Cytokines in a Randomized Clinical Trial

    PubMed Central

    Yusupov, Eleanor; Li-Ng, Melissa; Pollack, Simcha; Yeh, James K.; Mikhail, Mageda; Aloia, John F.

    2010-01-01

    Background. The role of vitamin D in the body's ability to fight influenza and URI's may be dependent on regulation of specific cytokines that participate in the host inflammatory response. The aim of this study was to test the hypothesis that vitamin D can influence intracellular signaling to regulate the production of cytokines. Subjects and Methods. This study was a 3-month prospective placebo-controlled trial of vitamin D3 supplementation in ambulatory adults [Li-Ng et al., 2009]. 162 volunteers were randomized to receive either 50 μg/d (2000 IU) of vitamin D3 or matching placebo. 25(OH)D and the levels of 10 different cytokines (IL-2, 4, 5, 6, 8, 10, 13, GM-CSF, IFN-γ, TNF-α) were measured in the serum of participants at baseline and the final visit. There were 6 drop-outs from the active vitamin D group and 8 from the placebo group. Results. In the active vitamin D group, we found a significant median percent decline in levels of GM-CSF (−62.9%, P < .0001), IFN-γ (−38.9%, P < .0001), IL-4 (−50.8%, P = .001), IL-8 (−48.4%, P < .0001), and IL-10 (−70.4%, P < .0001). In the placebo group, there were significant declines for GM-CSF (−53.2%, P = .0007) and IFN-γ (−34.4%, P = .0011). For each cytokine, there was no significant difference in the rate of decline between the two groups. 25(OH)D levels increased in the active vitamin D group from a mean of 64.3 ± 25.4 nmol/L to 88.5 ± 23.2 nmol/L. Conclusions. The present study did not show that vitamin D3 supplementation changed circulating cytokine levels among healthy adults. PMID:20871847

  10. Post-Transcriptional Regulation of Cytokine Signaling by AU-Rich and GU-Rich Elements

    PubMed Central

    Bohjanen, Paul R.

    2014-01-01

    Cytokines are necessary for cell communication to enable responses to external stimuli that are imperative for the survival and maintenance of homeostasis. Dysfunction of the cytokine network has detrimental effects on intra- and extracellular environments. Thus, it is critical that the expression of cytokines and the signals transmitted by cytokines to target cells are tightly regulated at numerous levels, including transcriptional and post-transcriptional levels. Here, we briefly summarize the role of AU-rich elements (AREs) in the regulation of cytokine gene expression at the post-transcriptional level and describe a role for GU-rich elements (GREs) in coordinating the regulation of cytokine signaling. GREs function as post-transcriptional regulators of proteins that control cellular activation, growth, and apoptosis. GREs and AREs work in concert to coordinate cytokine signal transduction pathways. The precise regulation of cytokine signaling is particularly important, because its dysregulation can lead to human diseases. PMID:24697201

  11. Taxonomic applicability of inflammatory cytokines in adverse outcome pathway (AOP) development

    EPA Science Inventory

    Cytokines, low-molecular-weight messenger proteins that act as intercellular immunomodulatory signals, have become a mainstream preclinical marker for assessing the systemic inflammatory response to external stressors. The challenge is to quantitate from healthy subjects cytokine...

  12. Effects of rhinovirus species on viral replication and cytokine production

    PubMed Central

    Nakagome, Kazuyuki; Bochkov, Yury A.; Ashraf, Shamaila; Brockman-Schneider, Rebecca A.; Evans, Michael D.; Pasic, Thomas R.; Gern, James E.

    2014-01-01

    Background Epidemiological studies provide evidence of differential virulence of rhinovirus (RV) species. We recently reported that RV-A and RV-C induced more severe illnesses than RV-B, suggesting that the biology of RV-B might be different from RV-A or RV-C. Objective To test the hypothesis that RV-B has lower replication and induces lesser cytokine responses than RV-A or RV-C. Methods We cloned full-length cDNA of RV-A16, A36, B52, B72, C2, C15 and C41 from clinical samples, and grew clinical isolates of RV-A7 and B6 in cultured cells. Sinus epithelial cells were differentiated at air-liquid interface. We tested for differences in viral replication in epithelial cells after infection with purified viruses (108 RNA copies) and measured virus load by quantitative RT-PCR. We measured lactate dehydrogenase (LDH) concentration as a marker of cellular cytotoxicity, and cytokine/chemokine secretion by multiplex ELISA. Results At 24 hours post infection, virus load of RV-B (RV-B52, B72, or B6) in adherent cells was lower than that of RV-A or RV-C. The growth kinetics of infection indicated that RV-B types replicate more slowly. Furthermore, RV-B released less LDH than RV-A or RV-C, and induced lower levels of cytokines and chemokines such as CXCL10, even after correction for viral replication. RV-B replicates to lower levels also in primary bronchial epithelial cells. Conclusions Our results indicate that RV-B types have lower and slower replication, and lower cellular cytotoxicity and cytokine/chemokine production compared to RV-A or RV-C. These characteristics may contribute to reduced severity of illnesses that has been observed with RV-B infections. Clinical implications RV-B types replicate at a lower rate and produce less cytokine/chemokine compared to RV-A or RV-C, which may contribute to the clinical observation that RV-B causes less severe illnesses. Capsule summary RV-B types replicate more slowly and to lower levels, and less cytokine/chemokine production

  13. Pharmacokinetic parameters and biodistribution of soluble cytokine receptors.

    PubMed

    Jacobs, C A; Beckmann, M P; Mohler, K; Maliszewski, C R; Fanslow, W C; Lynch, D H

    1993-01-01

    The potential use of soluble cytokine receptors as therapeutics in disease states when excessive or prolonged cytokine expression leads to pathogenesis is just beginning (Van Brunt, 1989). The inhibitory effects of soluble receptors have been found to be highly potent and specific for their respective cytokines (Maliszewski and Fanslow, 1990; Maliszewski et al., 1990). Recent in vivo data have shown that exogenously administered soluble receptors can function as cytokine antagonists and suppress autoimmune inflammatory responses (Jacobs et al., 1991a), allograft rejection, and alloreactivity (Fanslow et al., 1990b). The proposed frequency of administration and dosage of a therapeutic agent is dependent on the half-life of the agent and the route of administration. The elimination or half-life of a drug usually depends on its physiochemical properties (molecular size, glycosylation, isoelectric point, and hydrophobic/hydrophilic properties) (DiPalma and DiGregorio, 1990; Katzung, 1984). The half-life will also depend on the mechanism of clearance for that specific receptor. Once pharmacokinetic data are available for soluble receptors, the therapeutic potential of these molecules can be better evaluated. Only limited pharmacokinetic data are currently available for soluble cytokine receptors (Jacobs et al., 1991b). For sIL-1R, the majority of an intravenously administered dose was cleared in the second elimination phase, with a reasonably long half-life (6.3 hr), such that the entire dose was not eliminated until 35 hr. If administration is by subcutaneous injection, the half-life was even more prolonged. One explanation for the prolonged half-life is the minimal distribution to liver and kidneys and thus low levels of clearance by these organs. In contrast, elimination of intravenously administered sIL-4R was relatively rapid, with a short half-life (2.3 hr). This appeared mainly due to liver distribution and clearance, which has been the highest observed for any

  14. Cytokine cascade and networks among MSM HIV seroconverters: implications for early immunotherapy

    PubMed Central

    Huang, Xiaojie; Liu, Xinchao; Meyers, Kathrine; Liu, Lihong; Su, Bin; Wang, Pengfei; Li, Zhen; Li, Lan; Zhang, Tong; Li, Ning; Chen, Hui; Li, Haiying; Wu, Hao

    2016-01-01

    The timing, intensity and duration of the cytokine cascade and reorganized interrelations in cytokine networks are not fully understood during acute HIV-1 infection (AHI). Using sequential plasma samples collected over three years post-infection in a cohort of MSM HIV-1 seroconvertors, we determined the early kinetics of cytokine levels during FiebigI-IV stages using Luminex-based multiplex assays. Cytokines were quantified and relationships between cytokines were assessed by Spearman correlation. Compared with HIV-negative MSM, HIV-infected individuals had significantly increased multiple plasma cytokines, including GM-CSF, IFN-α2, IL-12p70, IP-10 and VEGF, during both acute and chronic stages of infection. Furthermore, rapid disease progressors (RDPs) had earlier and more robust cytokine storms, compared with slow disease progressors (SDPs) (49.6 days vs. 74.9 days, respectively; 6.7-fold vs. 3.7-fold change of cytokines, respectively), suggesting the faster and stronger cytokine storm during AHI could promote disease progression. On the other hand, HIV-1 infection induced more interlocked cytokines network, establishing new strong correlations and imposing a higher rigidity. There were, respectively, 146 (44.9%) statistically significant correlations of cytokines in RDPs and 241 (74.2%) in SDPs (p < 0.001). This study suggests that immunomodulatory interventions aimed at controlling cytokine storm in AHI may be beneficial to slow eventual disease progression. PMID:27830756

  15. Research Review: The Role of Cytokines in Depression in Adolescents: A Systematic Review

    ERIC Educational Resources Information Center

    Mills, Natalie T.; Scott, James G.; Wray, Naomi R.; Cohen-Woods, Sarah; Baune, Bernhard T.

    2013-01-01

    Background: While cytokines have been implicated in the pathophysiology of depression in adults, the potential role in younger age groups such as adolescents is less clear. This article therefore reviews the literature (a) to explore the relationship between cytokines and depression in adolescents, and (b) to examine how cytokines may be related…

  16. Quantitative validation and comparison of multiplex cytokine kits.

    PubMed

    Richens, Joanna L; Urbanowicz, Richard A; Metcalf, Rebecca; Corne, Jonathan; O'Shea, Paul; Fairclough, Lucy

    2010-06-01

    The focus of biomarker studies is shifting toward deciphering patterns of biomolecules as they provide a more comprehensive depiction of disease than individual biomarkers. Multiplexing technologies are crucial in deciphering such patterns, but it is essential that they are validated for reproducibility and precision to ensure accurate protein identification. Here the authors examine such properties in Cytokine Bead Array (CBA) and Luminex kits and compare concentration measurements to those obtained using enzyme-linked immunosorbent assay (ELISA). Luminex kits were found to be highly reproducible and reliable; however, CBA kits were not due to aberrant standards. Absolute cytokine concentrations were dependent on the detection kit, but correlations with ELISA were good for all technologies.

  17. Foetal immune programming: hormones, cytokines, microbes and regulatory T cells.

    PubMed

    Hsu, Peter; Nanan, Ralph

    2014-10-01

    In addition to genetic factors, environmental cues play important roles in shaping the immune system. The first environment that the developing foetal immune system encounters is the uterus. Although physically the mother and the foetus are separated by the placental membranes, various factors such as hormones and cytokines may provide "environmental cues" to the foetal immune system. Additionally, increasing evidence suggests that prenatal maternal environmental factors, particularly microbial exposure, might significantly influence the foetal immune system, affecting long-term outcomes, a concept termed foetal immune programming. Here we discuss the potential mediators of foetal immune programming, focusing on the role of pregnancy-related hormones, cytokines and regulatory T cells, which play a critical role in immune tolerance.

  18. Targeting the “Cytokine Storm” for Therapeutic Benefit

    PubMed Central

    Harrison, Kate; Oyston, Petra C.; Lukaszewski, Roman A.; Clark, Graeme C.

    2013-01-01

    Inflammation is the body's first line of defense against infection or injury, responding to challenges by activating innate and adaptive responses. Microbes have evolved a diverse range of strategies to avoid triggering inflammatory responses. However, some pathogens, such as the influenza virus and the Gram-negative bacterium Francisella tularensis, do trigger life-threatening “cytokine storms” in the host which can result in significant pathology and ultimately death. For these diseases, it has been proposed that downregulating inflammatory immune responses may improve outcome. We review some of the current candidates for treatment of cytokine storms which may prove useful in the clinic in the future and compare them to more traditional therapeutic candidates that target the pathogen rather than the host response. PMID:23283640

  19. Cytokines profile in immunocompetent mice during Trichosporon asahii infection.

    PubMed

    Montoya, Alexandra M; González, Gloria M; Martinez-Castilla, Azalia M; Aguilar, Sonia A; Franco-Molina, Moises A; Coronado-Cerda, Erika; Rosas-Taraco, Adrián G

    2017-03-15

    Trichosporon asahii is an opportunistic yeastlike fungus commonly associated with systemic infections in immunocompromised patients. Neutropenia is recognized as the main risk factor in infections by T. asahii; however, little is known about the cytokine response during trichosporonosis. Here, we evaluated systemic and local cytokine production and histological damage in immunocompetent mice during systemic infection with T. asahii. We found a significant increased presence of G-CSF, TNF-α, IFN-γ, and IL-6 in sera samples. High levels of G-CSF were found in organs (kidney, liver and spleen); meanwhile IL-10, IL-17A, IL-2, IL-4 and TNF-α were found in low levels. Neutrophils and fungal structures were found in early stage in analyzed organs. Our results demonstrated that T. asahii induces a systemic inflammatory response and G-CSF environment in infected organs in immunocompetent mice and neutrophil recruitment in analyzed tissue suggests the importance of these cells for fungal control.

  20. Cytokine dependent and independent iNKT cell activation

    PubMed Central

    Reilly, Emma C.; Wands, Jack R.; Brossay, Laurent

    2010-01-01

    Invariant NKT (iNKT) cells have been extensively studied throughout the last decade due to their ability to polarize and amplify the downstream immune response. Only recently however, have the various mechanisms underlying NKT cell activation begun to unfold. iNKT cells have the ability to respond as innate immune cells with minimal TCR involvement as well as through direct TCR recognition of glycolipid antigens. Additionally, the existence of several subsets of iNKT cells creates the potential for other unique pathways, which are not yet clearly defined. Here we provide an overview of the known mechanisms of invariant NKT cell activation, focusing on cytokine driven pathways and the resulting cytokine responses. PMID:20554220

  1. IL-10: A Multifunctional Cytokine in Viral Infections

    PubMed Central

    2017-01-01

    The anti-inflammatory master regulator IL-10 is critical to protect the host from tissue damage during acute phases of immune responses. This regulatory mechanism, central to T cell homeostasis, can be hijacked by viruses to evade immunity. IL-10 can be produced by virtually all immune cells, and it can also modulate the function of these cells. Understanding the effects of this multifunctional cytokine is therefore a complex task. In the present review we discuss the factors driving IL-10 production and the cellular sources of the cytokine during antiviral immune responses. We particularly focus on the IL-10 regulatory mechanisms that impact antiviral immune responses and how viruses can use this central regulatory pathway to evade immunity and establish chronic/latent infections. PMID:28316998

  2. Subversion of cytokine networks by virally encoded decoy receptors

    PubMed Central

    Epperson, Megan L.; Lee, Chung A.; Fremont, Daved H.

    2012-01-01

    Summary During the course of evolution, viruses have captured or created a diverse array of open reading frames that encode for proteins that serve to evade and sabotage the host innate and adaptive immune responses, which would otherwise lead to their elimination. These viral genomes are some of the best textbooks of immunology ever written. The established arsenal of immunomodulatory proteins encoded by viruses is large and growing and includes specificities for virtually all known inflammatory pathways and targets. The focus of this review is on herpes and poxvirus-encoded cytokine and chemokine binding proteins that serve to undermine the coordination of host immune surveillance. Structural and mechanistic studies of these decoy receptors have provided a wealth of information, not only about viral pathogenesis but also about the inner workings of cytokine signaling networks. PMID:23046131

  3. Effects of inactive parapoxvirus ovis on cytokine levels in rats

    PubMed Central

    AVCI, Oguzhan; BULUT, Oya; DIK, Irmak

    2015-01-01

    The aim of this study is to determine the effects of iPPOV on pro-inflammatory and anti-inflammatory cytokine levels in rats. iPPOV (1 ml/rat) was administered intraperitoneal route to 49 rats, except for 7 rats (Control, 0 group). Serum samples were collected from 7 rats at 1st, 2nd, 4th, 8th, 12th, 16th and 24th hr after treatments. Levels of TNF-α, IL-6, IL-12 and IL-10 were determined using ELISA. Administration of iPPOV stimulated TNF-α (16th and 24th hr) and IL-6 (12th, 16th and 24th hr) synthesis and caused fluctuations in IL-10 and IL-12 concentrations. In conclusion, increased cytokine levels could be attributed to immunomodulatory activity of iPPOV, however, detailed studies are required to fully understand effects of iPPOV on immune system. PMID:26290129

  4. Chronic Inflammation and Cytokines in the Tumor Microenvironment

    PubMed Central

    Landskron, Glauben; De la Fuente, Marjorie; Thuwajit, Peti; Thuwajit, Chanitra; Hermoso, Marcela A.

    2014-01-01

    Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma. PMID:24901008

  5. Rheumatoid arthritis, gold therapy, contact allergy and blood cytokines

    PubMed Central

    Svensson, Åke; Möller, Halvor; Björkner, Bert; Bruze, Magnus; Leden, Ido; Theander, Jan; Ohlsson, Kjell; Linder, Carina

    2002-01-01

    Objective To study the clinical and biochemical effects of a low starting dose for gold therapy in rheumatoid arthritis patients with a contact allergy to gold. Methods Serum cytokines were assayed before and 24 h after the first injection of gold sodium thiomalate (GSTM). Results Contact allergy to gold was found in 4 of 19 patients. Compared to gold-negative patients (starting dose: 10 mg GSTM), there was a larger increase in serum TNFalpha (p < 0.05), sTNF-R1 (NS), and IL-1 ra (p < 0.05) in gold-allergic patients. Conclusions Cytokines are released in blood by GSTM in RA patients with gold allergy. To minimize the risk of acute adverse reactions the starting dose of GSTM should be lowered to 5 mg. Alternatively, patients should be patch-tested before gold therapy; in test-positive cases, 5 mg is recommended as the first dose. PMID:11860615

  6. Systems biology of IL-6, IL-12 family cytokines.

    PubMed

    Dittrich, Anna; Hessenkemper, Wiebke; Schaper, Fred

    2015-10-01

    Interleukin-6-type cytokines play important roles in the communication between cells of multicellular organisms. They are involved in the regulation of complex cellular processes such as proliferation and differentiation and act as key player during inflammation and immune response. A major challenge is to understand how these complex non-linear processes are connected and regulated. Systems biology approaches are used to tackle this challenge in an iterative process of quantitative experimental and mathematical analyses. Here we review quantitative experimental studies and systems biology approaches dealing with the function of Interleukin-6-type cytokines in physiological and pathophysiological conditions. These approaches cover the analyses of signal transduction on a cellular level up to pharmacokinetic and pharmacodynamic studies on a whole organism level.

  7. INDUCTION OF CYTOKINE PRODUCTION IN CHEETAH (ACINONYX JUBATUS) PERIPHERAL BLOOD MONONUCLEAR CELLS AND VALIDATION OF FELINE-SPECIFIC CYTOKINE ASSAYS FOR ANALYSIS OF CHEETAH SERUM.

    PubMed

    Franklin, Ashley D; Crosier, Adrienne E; Vansandt, Lindsey M; Mattson, Elliot; Xiao, Zhengguo

    2015-06-01

    Peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood of cheetahs (Acinonyx jubatus ; n=3) and stimulated with lipopolysaccharides (LPS) to induce the production of proinflammatory cytokines TNF-α, IL-1β, and IL-6 for establishment of cross-reactivity between these cheetah cytokines and feline-specific cytokine antibodies provided in commercially available Feline DuoSet® ELISA kits (R&D Systems, Inc., Minneapolis, Minnesota 55413, USA). This study found that feline-specific cytokine antibodies bind specifically to cheetah proinflammatory cytokines TNF-α, IL-1β, and IL-6 from cell culture supernatants. The assays also revealed that cheetah PBMCs produce a measurable, cell concentration-dependent increase in proinflammatory cytokine production after LPS stimulation. To enable the use of these kits, which are designed for cell culture supernatants for analyzing cytokine concentrations in cheetah serum, percent recovery and parallelism of feline cytokine standards in cheetah serum were also evaluated. Cytokine concentrations in cheetah serum were approximated based on the use of domestic cat standards in the absence of cheetah standard material. In all cases (for cytokines TNF-α, IL-1β, and IL-6), percent recovery increased as the serum sample dilution increased, though percent recovery varied between cytokines at a given dilution factor. A 1:2 dilution of serum resulted in approximately 45, 82, and 7% recovery of TNF-α, IL-1β, and IL-6 standards, respectively. Adequate parallelism was observed across a large range of cytokine concentrations for TNF-α and IL-1β; however, a significant departure from parallelism was observed between the IL-6 standard and the serum samples (P=0.004). Therefore, based on our results, the Feline DuoSet ELISA (R&D Systems, Inc.) kits are valid assays for the measurement of TNF-α and IL-1β in cheetah serum but should not be used for accurate measurement of IL-6.

  8. Exercise training and cytokines in breast cancer survivors.

    PubMed

    Gómez, A M; Martínez, C; Fiuza-Luces, C; Herrero, F; Pérez, M; Madero, L; Ruiz, J R; Lucia, A; Ramírez, M

    2011-06-01

    The purpose of this randomized controlled trial was to determine the effects of an 8-week (aerobic+strength) exercise training program (3 sessions/week) on the circulating cytokine levels of breast cancer survivors. We randomly allocated 16 female survivors of breast cancer (mean±SD age: 50±5 years) to an intervention or usual care (control) group (N=8 in each group). The intervention group followed an 8-week exercise program consisting of 3 sessions/week (session duration: 90 min). We measured the levels of the following cytokines before and after the intervention: beta-NGF, CTACK, eotaxin, FGF basic, G-CSF, gmCSFα, HGF, ICAM1, IFNα2, IFNγ, IL1α, IL1ß, IL1ra, IL2, IL2ra, IL3, IL4, IL6, IL7, IL8, IL9, IL10, IL12, IL13, IL15, IL16, IL17, IL18, IP10, LIF, MCS-F, MIP1α, MIP1β, MIF, MCP1, MCP3, MIG, PDGF bb, SCF, SCGFβ, SDF1α, TRAIL, TNFα, TNFβ, VCAM1, and VEGF. We only observed a significant interaction (group*time) effect for CTACK ( P=0.016), with mean values remaining stable in the intervention group but increasing over time in controls. The intervention program did not induce a significant decrease in the main breast cancer-related cytokines such as IL6 and IL8. A combined (aerobic+strength) 8-week exercise training intervention did not induce major changes in the basal cytokine levels of breast cancer survivors.

  9. Cytokine modulation of human blood viscosity from vivax malaria patients.

    PubMed

    Scherer, Edson Fredulin; Cantarini, Déborah Giovanna; Siqueira, Renan; Ribeiro, Elton Brito; Braga, Érika Martins; Honório-França, Adenilda Cristina; França, Eduardo Luzía

    2016-06-01

    Malaria is a major infectious disease in several countries and is caused by protozoa of the genus Plasmodium. In vivax malaria patients, inflammatory processes occur, as well as changes in cytokines and blood flow. The present study analyzed the cytokine modulation of blood viscosity from patients infected with Plasmodium vivax (P. vivax). Blood samples were collected from 42 non-infected individuals (control group) and 37 individuals infected with P. vivax. The IL-2, IL-4, IL-6, IL-10, TNFα, TGF-β and IL-17 cytokine concentrations in the serum were assessed, and the blood rheological properties were determined. The analysis of blood viscosity for shear rates revealed that the blood viscosity of the infected patients was significantly greater than that of the non-infected individuals. The viscosity of the blood was greater in the infected individuals than in the non-infected subjects. The serum from individuals with P. vivax infections exhibited higher IFN-γ and IL-17 concentrations and lower TGF-β levels. Incubation of the blood from infected individuals with IL-17 or IL-17 associated with IFN-γ reduced the viscosity to rates equivalent to the blood from non-infected individuals. Independently of cytokine modulation, no correlation was found between the parasitemia and blood viscosity of the infected patients. These data suggest that the alterations of blood viscosity are relevant as an auxiliary tool for the clinical diagnosis of disease. In malaria, erythrocytes are more sensitive to osmotic shock, and the reduction of viscosity by IL-17 may be related to a possible immunomodulator agent during infection.

  10. Cytokine Profile in Autism Spectrum Disorders in Children.

    PubMed

    Bryn, Vesna; Aass, Hans Christian Dalsbotten; Skjeldal, Ola H; Isaksen, Jørn; Saugstad, Ola Didrik; Ormstad, Heidi

    2017-01-01

    The pathogenesis of autism spectrum disorders (ASD) is not completely understood, but there is evidence of associations with altered immune responses. The aim of this study was to determine the serum levels of various cytokines in children with ASD and in healthy controls, in order to determine their role in ASD and its diagnostic subgroups. Sixty-five ASD patients were enrolled from an epidemiological survey in Norway, of which 30 were diagnosed with childhood autism, 16 with Asperger syndrome, 12 with atypical autism, 1 with Rett syndrome, and 6 with another ASD diagnosis. The serum levels of 12 cytokines were measured in all of the patients and in 30 healthy children. The cytokine levels did not differ significantly between the ASD group and the healthy controls. However, the interleukin-8 (IL-8) level was significantly higher (6.82 vs 4.58 pg/ml, p = 0.017) while that of IL-10 was significantly lower (2.24 vs 6.49 pg/ml, p = 0.009) in patients with childhood autism than in controls. Furthermore, the IL-8 level was significantly higher in childhood autism than in Asperger syndrome (6.82 vs 4.05 pg/ml, p = 0.013). Our study shows that the cytokine profile of children diagnosed with ASD, regardless of the subdiagnosis, does not differ from healthy controls. However, differentiation into different diagnostic subgroups reveals significantly different levels of IL-8 and IL-10. This indicates that different mechanisms may underlie the different ASD subdiagnoses. Future research into the pathophysiological mechanisms of ASD should pay more attention to the different subdiagnoses of ASD.

  11. Plasma Cytokine Levels During Long-Duration Spaceflight

    NASA Technical Reports Server (NTRS)

    Crucian, Brian E.; Zwart, Sara R.; Quiriarte, Heather A.; Smith, Scott M.; Sams, Clarence F.

    2011-01-01

    Reduced T cell, granulocyte, NK and monocyte function have all been reported following both long and short duration spaceflight, however these data indicate crews are generally not experiencing inflammatory or adaptive immune activation during spaceflight. There appear to be varied individual crew responses, and specific relationships between cytokines and markers of iron status and muscle turnover that warrant further evaluation. Increases in growth factors and chemokines may indicate other types of adaptation occurring during spaceflight, such as attempts to overcome diminished immunocyte function.

  12. Chemokine and cytokine levels in inflammatory bowel disease patients.

    PubMed

    Singh, Udai P; Singh, Narendra P; Murphy, E Angela; Price, Robert L; Fayad, Raja; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2016-01-01

    Crohn's disease (CD) and ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), are chronic, relapsing, and tissue destructive lesions that are accompanied by the uncontrolled activation of effector immune cells in the mucosa. Recent estimates indicate that there are 1.3 million annual cases of IBD in the United States, 50% of which consists of CD and 50% of UC. Chemokines and cytokines play a pivotal role in the regulation of mucosal inflammation by promoting leukocyte migration to sites of inflammation ultimately leading to tissue damage and destruction. In recent years, experimental studies in rodents have led to a better understanding of the role played by these inflammatory mediators in the development and progression of colitis. However, the clinical literature on IBD remains limited. Therefore, the aim of this study was to evaluate systemic concentrations of key chemokines and cytokines in forty-two IBD patients with a range of disease activity compared to levels found in ten healthy donors. We found a significant increase in an array of chemokines including macrophage migration factor (MIF), CCL25, CCL23, CXCL5, CXCL13, CXCL10, CXCL11, MCP1, and CCL21 in IBD patients as compared to normal healthy donors (P<0.05). Further, we also report increases in the inflammatory cytokines IL-16, IFN-γ, IL-1β and TNF-α in IBD patients when compared to healthy donors (P<0.05). These data clearly indicate an increase in circulating levels of specific chemokines and cytokines that are known to modulate systemic level through immune cells results in affecting local intestinal inflammation and tissue damage in IBD patients. Blockade of these inflammatory mediators should be explored as a mechanism to alleviate or even reverse symptoms of IBD.

  13. Circulating levels of inflammatory cytokines and risk of colorectal adenomas

    PubMed Central

    Kim, Sangmi; Keku, Temitope O.; Martin, Christopher; Galanko, Joseph; Woosley, John T.; Schroeder, Jane C.; Satia, Jessie A.; Halabi, Susan; Sandler, Robert S.

    2009-01-01

    The association between obesity and colorectal neoplasia may be mediated by inflammation. Circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are elevated in the obese. Adipose tissue can produce and release the inflammatory cytokines that are potentially procarcinogenic. We examined circulating levels of CRP, IL-6, and TNF-α in relation to risk factors and the prevalence of colorectal adenomas. Plasma levels of CRP, IL-6, and TNF-α were quantified in 873 participants (242 colorectal adenoma cases and 631 controls) in a colonoscopy-based cross-sectional study conducted between 1998 and 2002. Multivariable logistic regression was used to estimate associations between levels of inflammatory cytokines, colorectal adenomas, and known risk factors. Several known risk factors for colorectal neoplasia were associated with higher levels of inflammatory cytokines such as older age, current smoking, and increasing adiposity. The prevalence of colorectal adenomas was associated with higher concentrations of IL-6 and TNF-α, and to a lesser degree, with CRP. For IL-6, adjusted odds ratios for colorectal adenomas were 1.78 (95% confidence interval [CI]: 1.18–2.68) for the second highest plasma level, and 1.84 (95% CI: 1.24– 2.74) for the highest level compared with the reference level. A similar association was found with TNF-α, with adjusted odds ratios of 1.54 (95% CI: 1.02–2.33) and 1.65 (95% CI: 1.09–2.50), respectively. Our findings indicate that inflammation might be involved in the early development of colorectal neoplasia, and suggest that systemic inflammatory cytokines might be an indicator of obesity and other risk factors for colorectal neoplasia. PMID:18172326

  14. Cytokine profile and lymphocyte subsets in type 2 diabetes.

    PubMed

    Francisco, C O; Catai, A M; Moura-Tonello, S C G; Arruda, L C M; Lopes, S L B; Benze, B G; Del Vale, A M; Malmegrim, K C R; Leal, A M O

    2016-01-01

    Type 2 diabetes mellitus (T2D) is a metabolic disease with inflammation as an important pathogenic background. However, the pattern of immune cell subsets and the cytokine profile associated with development of T2D are unclear. The objective of this study was to evaluate different components of the immune system in T2D patients' peripheral blood by quantifying the frequency of lymphocyte subsets and intracellular pro- and anti-inflammatory cytokine production by T cells. Clinical data and blood samples were collected from 22 men (51.6±6.3 years old) with T2D and 20 nonsmoking men (49.4±7.6 years old) who were matched for age and sex as control subjects. Glycated hemoglobin, high-sensitivity C-reactive protein concentrations, and the lipid profile were measured by a commercially available automated system. Frequencies of lymphocyte subsets in peripheral blood and intracellular production of interleukin (IL)-4, IL-10, IL-17, tumor necrosis factor-α, and interferon-γ cytokines by CD3+ T cells were assessed by flow cytometry. No differences were observed in the frequency of CD19+ B cells, CD3+CD8+ and CD3+CD4+ T cells, CD16+56+ NK cells, and CD4+CD25+Foxp3+ T regulatory cells in patients with T2D compared with controls. The numbers of IL-10- and IL-17-producing CD3+ T cells were significantly higher in patients with T2D than in controls (P<0.05). The frequency of interferon-γ-producing CD3+ T cells was positively correlated with body mass index (r=0.59; P=0.01). In conclusion, this study shows increased numbers of circulating IL-10- and IL-17-producing CD3+ T cells in patients with T2D, suggesting that these cytokines are involved in the immune pathology of this disease.

  15. TSC for hemorrhagic shock: effects on cytokines and blood pressure.

    PubMed

    Stennett, Amanda K; Gainer, John L

    2004-12-01

    Previous studies have shown that administering trans-sodium crocetinate (TSC) as a treatment of hemorrhagic shock leads to increased whole-body oxygen consumption and survival as well as protection of the liver and kidney. It has been suggested that TSC increases oxygen delivery by increasing the diffusivity of oxygen through plasma. However, as with any novel mechanism of action, there are always questions about whether the results could also be ascribed to other, previously described mechanisms of action. This study was designed to look at some aspects of that by examining the effect of different TSC dosing regimens on the blood pressure and the production of cytokines after hemorrhage because both responses have been reported with compounds that act via other mechanisms. In a constant-pressure rat model of hemorrhagic shock, it was seen that a singe bolus injection of TSC results in an immediate but transient increase in the arterial blood pressure. This is similar to the effect reported previously for using 100% oxygen. It was also found that if the TSC injections were repeated periodically over an hour, a sustained increase in the blood pressure would occur. Because inflammatory cytokines have been implicated in mortality and tissue damage, it has been suggested that TSC may affect the production of cytokines. Thus, the effect of TSC on the production of TNF-alpha and IL-10 was also examined. The data show that treatment with TSC results in lower concentrations of TNF-alpha in the liver and spleen as well as lower concentrations of IL-10 in the spleen. Again, similar effects on other cytokines have been seen with 100% oxygen. These results support the hypothesis that the effects of TSC on hemorrhagic shock are mediated via an effect on oxygen.

  16. Chocolate consumption modulates cytokine production in healthy individuals.

    PubMed

    Netea, Stejara A; Janssen, Sam A; Jaeger, Martin; Jansen, Trees; Jacobs, Liesbeth; Miller-Tomaszewska, Gosia; Plantinga, Theo S; Netea, Mihai G; Joosten, Leo A B

    2013-04-01

    Epidemiological studies suggest that chocolate increases the incidence and severity of acne. Here we demonstrate that chocolate consumption primes human blood mononuclear cells from volunteers to release more interleukin-1β (IL-1β) and IL-10 upon stimulation with Propionibacterium acne or Staphylcoccus aureus, the two microorganisms involved in the pathogenesis of acne. In contrast, production of the Th17-derived cytokine IL-22 was inhibited by chocolate. Modulation of inflammation could represent an important mechanism through which chocolate consumption influences acne.

  17. Cytokine profile and lymphocyte subsets in type 2 diabetes

    PubMed Central

    Francisco, C.O.; Catai, A.M.; Moura-Tonello, S.C.G.; Arruda, L.C.M.; Lopes, S.L.B.; Benze, B.G.; Del Vale, A.M.; Malmegrim, K.C.R.; Leal, A.M.O.

    2016-01-01

    Type 2 diabetes mellitus (T2D) is a metabolic disease with inflammation as an important pathogenic background. However, the pattern of immune cell subsets and the cytokine profile associated with development of T2D are unclear. The objective of this study was to evaluate different components of the immune system in T2D patients' peripheral blood by quantifying the frequency of lymphocyte subsets and intracellular pro- and anti-inflammatory cytokine production by T cells. Clinical data and blood samples were collected from 22 men (51.6±6.3 years old) with T2D and 20 nonsmoking men (49.4±7.6 years old) who were matched for age and sex as control subjects. Glycated hemoglobin, high-sensitivity C-reactive protein concentrations, and the lipid profile were measured by a commercially available automated system. Frequencies of lymphocyte subsets in peripheral blood and intracellular production of interleukin (IL)-4, IL-10, IL-17, tumor necrosis factor-α, and interferon-γ cytokines by CD3+ T cells were assessed by flow cytometry. No differences were observed in the frequency of CD19+ B cells, CD3+CD8+ and CD3+CD4+ T cells, CD16+56+ NK cells, and CD4+CD25+Foxp3+ T regulatory cells in patients with T2D compared with controls. The numbers of IL-10- and IL-17-producing CD3+ T cells were significantly higher in patients with T2D than in controls (P<0.05). The frequency of interferon-γ-producing CD3+ T cells was positively correlated with body mass index (r=0.59; P=0.01). In conclusion, this study shows increased numbers of circulating IL-10- and IL-17-producing CD3+ T cells in patients with T2D, suggesting that these cytokines are involved in the immune pathology of this disease. PMID:27007651

  18. The role of cytokines in human lung fibrosis.

    PubMed

    Vaillant, P; Menard, O; Vignaud, J M; Martinet, N; Martinet, Y

    1996-04-01

    Fibrosis is a disorder characterized by a qualitative and quantitative alteration of the deposition of extracellular matrix with accumulation of mesenchymal cells in replacement of normal tissue. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in this area. A similar sequence of events occurs in wound healing with formation of normal, limited and transient granulation tissue, while in fibrosis, a maladaptive repair leads to an extensive, exaggerated process with functional impairment. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of several human fibrotic lung diseases, five diffuse (idiopathic pulmonary fibrosis (IPF); adult respiratory distress syndrome (ARDS); coal workers' pneumoconiosis (CWP); Hermansky-Pudlak syndrome (HPS); systemic sclerosis (SS)) and two focal (tumour stroma in lung cancer; and obliterative bronchiolitis (OB) after lung transplantation), has shown that several cytokines participate in the local injury and inflammatory reaction (interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-alpha)), while other cytokines are involved in tissue repair and fibrosis (platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)). A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches.

  19. Changes in inflammatory cytokine networks in myasthenia gravis

    PubMed Central

    Uzawa, Akiyuki; Kanai, Tetsuya; Kawaguchi, Naoki; Oda, Fumiko; Himuro, Keiichi; Kuwabara, Satoshi

    2016-01-01

    Myasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation-inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late-onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology. PMID:27172995

  20. Cytokine gene polymorphisms and outcome after traumatic brain injury.

    PubMed

    Waters, Ryan J; Murray, Gordon D; Teasdale, Graham M; Stewart, Janice; Day, Ian; Lee, Robert J; Nicoll, James A R

    2013-10-15

    Clinical outcome after traumatic brain injury (TBI) is variable and cannot easily be predicted. There is increasing evidence to suggest that there may be genetic influences on outcome. Cytokines play an important role in mediating the inflammatory response provoked within the central nervous system after TBI. This study was designed to identify associations between cytokine gene polymorphisms and clinical outcome 6 months after head injury. A prospectively identified cohort of patients (n=1096, age range 0-93 years, mean age 37) was used. Clinical outcome at 6 months was assessed using the Glasgow Outcome Scale. In an initial screen of 11 cytokine gene single nucleotide polymorphisms (SNPs) previously associated with disease susceptibility or outcome (TNFA -238 and -308, IL6 -174, -572 and -597, IL1A -889, IL1B -31, -511 and +3953, and TGFB -509 and -800), TNFA -308 was identified as having a likely association. The TNFA -308 SNP was further evaluated, and a significant association was identified, with 39% of allele 2 carriers having an unfavorable outcome compared with 31% of non-carriers (adjusted odds ratio 1.67, confidence interval 1.19-2.35, p=0.003). These findings are consistent with experimental and clinical data suggesting that neuroinflammation has an impact on clinical outcome after TBI and that tumor necrosis factor alpha plays an important role in this process.

  1. Regulation of NF-κB by TNF family cytokines.

    PubMed

    Hayden, Matthew S; Ghosh, Sankar

    2014-06-01

    The NF-κB family of inducible transcription factors is activated in response to a variety of stimuli. Amongst the best-characterized inducers of NF-κB are members of the TNF family of cytokines. Research on NF-κB and TNF have been tightly intertwined for more than 25 years. Perhaps the most compelling examples of the interconnectedness of NF-κB and the TNF have come from analysis of knock-out mice that are unable to activate NF-κB. Such mice die embryonically, however, deletion of TNF or TNFR1 can rescue the lethality thereby illustrating the important role of NF-κB as the key regulator of transcriptional responses to TNF. The physiological connections between NF-κB and TNF cytokines are numerous and best explored in articles focusing on a single TNF family member. Instead, in this review, we explore general mechanisms of TNF cytokine signaling, with a focus on the upstream signaling events leading to activation of the so-called canonical and noncanonical NF-κB pathways by TNFR1 and CD40, respectively.

  2. T-lymphocyte cytokine profiles in compositae airborne dermatitis.

    PubMed

    Stingeni, L; Agea, E; Lisi, P; Spinozzi, F

    1999-10-01

    Compositae airborne dermatitis is a well-recognized disorder characterized by erythematosquamous lesions and papules on light-exposed areas. The presence of positive patch test reactions and the absence of specific serum IgE suggest delayed-type hypersensitivity, the murine model of which is characterized by a Th1 cytokine production profile [high amounts of interferon (IFN)-gamma and interleukin (IL)-2; little or no IL-4 and IL-5]. The aim of this study was to evaluate the cytokine profile of T-cell lines and T-cell clones from peripheral blood in a 38-year-old non-atopic male woodcutter affected by seasonal airborne contact dermatitis. The patient showed positive patch test reactions to several Compositae extracts (Achillea millefolium, Chamomilla recutita, Tanacetum parthenium, T. vulgare) and sesquiterpene lactone mix. On prick testing with Compositae and other plants, serum-specific IgE levels and phototesting were negative or normal. Allergen-specific T-cell lines produced with Compositae extracts showed a good in vitro cell proliferation only to C. recutita extract. Serial cloning performed using the C. recutita-specific T-cell lines revealed an alphabeta+CD4+ phenotype with high amounts of IFN-gamma and IL-4 in T-cell clones. Thus, these cells expressed a preferential Th0 phenotype. These data suggest that in addition to IFN-gamma, other T-cell derived cytokines, such as IL-4, may play a part in the immunopathogenesis of contact dermatitis.

  3. [Methotrexate as inducer of proinflammatory cytokines by epithelial cells].

    PubMed

    Morón-Medina, Alejandra; Viera, Ninoska; de Morales, Thaís Rojas; Alcocer, Sirley; Bohorquez, Dinorath

    2014-03-01

    Methotrexate (MTX), a drug commonly used in childhood cancer, has also been indicated as a cytotoxic agent of the oral mucosa, which can trigger the inflammatory process and increase the vascularity of epithelial tissues during the early stages of oral mucositis. The aim of this study was to determine the production of proinflammatory cytokines IL-1beta, IL-6 y TNF-alpha in epithelial cell cultures treated with MTX. Epithelial cells of human larynx, obtained from the cell line Hep-2, were cultured with different doses of MTX during different incubation times. The drug cytotoxicity was analyzed by means of the colorimetric test, which is based on the metabolic reduction of the bromide of 3-(4, 5-dimetiltiazol-2-ilo)-2,5-difeniltetrazol (MTT); and the proinflammatory cytokines production by the test enzyme-linked immunosorbent assay (ELISA). Cultures of HEp-2 cells showed increased production of proinflammatory cytokines at 72 hours with 0.32 microM of MTX. These results suggest that depending on the dose and exposure time, MTX alters the physiology of human epithelial cells, which may play an important role during the phases of initiation and development of oral mucositis.

  4. Cytokine-like factor 1 (CLF1): life after development?

    PubMed

    Kass, Daniel J

    2011-09-01

    Cytokine-like factor 1 (CLF1) is a secreted receptor belonging to the interleukin-6 family of cytokines. CLF1 and its physiologic partner, cardiotrophin-like cytokine (CLC) are secreted as a heterodimer and engage the tripartite signaling complex of ciliary neurotrophic factor receptor (CNTFR), leukemia inhibitory factor (LIFR) and gp130. Ligation of this receptor complex leads to activation of the STAT3 and MAPK pathways and mediates survival pathways in neurons. Mutations in CLF1, CLC, or CNTFR in mice lead to the birth of mice that die on post-natal day 1 because of an inability to nurse. These animals exhibit significant decreases in the number of motor neurons in the facial nucleus and the spinal cord. CLF1 or CLC deficiency is associated with the development of the human cold-induced sweating syndromes. A growing body of research suggests that CLF1 expression may be associated with several post-natal disease processes. In this review, we summarize the current understanding of CLF1 expression and suggest future studies to understand the potentially important role of CLF1 in postnatal life and disease.

  5. Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis

    PubMed Central

    Mortensen, Martin B.; Kjolby, Mads; Gunnersen, Stine; Larsen, Jakob V.; Palmfeldt, Johan; Falk, Erling; Nykjaer, Anders; Bentzon, Jacob F.

    2014-01-01

    Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (SORT1) has been implicated as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort1 did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-γ, but not of other measured cytokines. Transfer of sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that sortilin influences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and reduces atherosclerosis. PMID:25401472

  6. Proinflammatory cytokines and procalcitonin in children with acute pyelonephritis.

    PubMed

    Gürgöze, Metin Kaya; Akarsu, Saadet; Yilmaz, Erdal; Gödekmerdan, Ahmet; Akça, Zehra; Ciftçi, Ismail; Aygün, A Denizmen

    2005-10-01

    This prospective study, performed in 76 children with a urinary tract infection (UTI), evaluates the diagnostic value of procalcitonin (PCT) and proinflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) in children with acute pyelonephritis documented by dimercaptosuccinic acid scintigraphy (DMSA). Renal parenchymal involvement was assessed by (99m )Tc-DMSA scintigraphy within 7 days of admission. The diagnosis of acute pyelonephritis was confirmed only in patients with reversible lesions on scintigraphy. According to DMSA scan results, patients were divided into two groups, lower UTI or acute pyelonephritis. In acute pyelonephritis, serum PCT level was found to be significantly higher than it is in the lower UTI (p <0.001). Also, significantly higher serum proinflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) levels were detected in those with acute pyelonephritis than those with lower UTI (p <0.001). We conclude that both serum PCT and proinflammatory cytokine levels may be used as accurate markers for diagnosis of acute pyelonephritis.

  7. Cytokines as biomarkers of Crimean-Congo hemorrhagic fever.

    PubMed

    Papa, Anna; Tsergouli, Katerina; Çağlayık, Dilek Yağcı; Bino, Silvia; Como, Najada; Uyar, Yavuz; Korukluoglu, Gulay

    2016-01-01

    Crimean-Congo hemorrhagic fever (CCHF) is a potentially severe disease caused by CCHF virus. As in other viral hemorrhagic fevers, it is considered that the course and outcome of the disease depend on the viral load and the balance among the immune response mediators, and that a fatal outcome is the result of a "cytokine storm." The level of 27 cytokines was measured in serum samples taken from 29 patients during the acute phase of the disease. Two cases were fatal. Among survivors, significant differences between severe and non-severe cases were observed in the levels of IP-10, and MCP-1, while the levels of IL-1b, IL-5, IL-6, IL-8, IL-9, IL-10, IL-15, IP-10, MCP-1, TNF-α, and RANTES differed significantly between fatal and non-fatal cases (P < 0.05). RANTES was negatively correlated with the outcome of the disease. A striking similarity with the cytokine patterns seen in Ebola virus disease was observed. A weak Th1 immune response was seen. The viral load was positively correlated with IL-10, IP-10, and MCP-1 levels, and negatively correlated with the ratio IL-12/IL-10. Especially IP-10 and MCP-1 were significantly associated with the viral load, the severity and outcome of the disease, and they could act as biomarkers and, probably, as potential targets for treatment strategies design.

  8. Role of cytokines in gonarthrosis and knee prosthesis aseptic loosening.

    PubMed

    Loria, Maria Paola; Dambra, Porzia; Moretti, Biagio; Patella, Vittorio; Capuzzimati, Laura; Cavallo, Elsa; Nettis, Eustachio; Pesce, Vito; Dell'Osso, Adriana; Simone, Carmelo; Tursi, Alfredo

    2004-01-01

    Cytokines, which have been demonstrated in synovial fluids during various joint diseases, play an important role in mediating synovial inflammation and in regulating the immune response of many inflammatory processes. We studied synovial fluid, serum, and synovial fragments obtained from 33 patients--10 affected by serious gonarthrosis re-quiring a prosthetic implant, 8 with knee prosthesis aseptic loosening, and (as controls) 15 affected by degenerative meniscopathies--to evaluate the degree of inflammation and level of interleukins (IL-2, IL-4, IL-6, IL-10) and interferon gamma secretion. Histological analysis revealed slightly more infiltration by inflammatory cells in the synovial tissue of patients with gonarthrosis and knee prosthesis aseptic loosening than in that of the control group, with a high prevalence of macrophages. Moreover, we observed enhanced production of the studied cytokines, especially in synovial fluid as compared to serum, indicating that in the pathological conditions examined the inflammatory events are mainly localized. Because the role of these cytokines is to modulate inflammation, better knowledge of the involvement of cells and their soluble mediators in articular damage could guide immunomodulating treatment.

  9. Dysregulation of cytokine mediated chemotherapy induced cognitive impairment.

    PubMed

    Ren, Xiaojia; St Clair, Daret K; Butterfield, D Allan

    2017-03-01

    One of the major complaints patients who survive cancer often make is chemotherapy induced cognitive impairment (CICI), which survivors often call "chemo brain." CICI is a side effect of chemotherapy due to the cytotoxicity and neurotoxicity of anti-cancer drugs causing structural and functional changes in brain, even when drugs that do not cross the blood brain barrier (BBB) are used. Diminished cognitive functions including diminution of learning and memory, concentration and attention, processing speed and executive functions that reduce quality of life and ability to work are common signs and symptoms of CICI. There still is not a clarified and complete mechanism for CICI, but researchers have pointed to several biochemical candidates. Chemotherapy-induced, cytokine-mediated involvement in CICI will be mainly discussed in this review paper with emphasis on different types of cytokines, correlated with BBB and epigenetic changes. Mechanisms of ROS-generating, anti-cancer drugs and their relation to cytokine-mediated CICI will be emphasized.

  10. Noninvasive assessment of cytokines in occupational respiratory diseases.

    PubMed

    Akpinar-Elci, Muge; Yucesoy, Berran; Elci, Omur Cinar; Weissman, David N

    2007-06-01

    A major goal in studying occupational respiratory diseases is to show relationships between occupational exposures and health outcomes. Due to the nature of these diseases, accurate, practical, and objective measurement techniques are needed in field investigations. Pulmonary function tests, such as spirometry, are important objective health outcome measures. However, they reflect the functional changes of the lung, often in relatively late stages, which may be irreversible. Direct monitoring of airways inflammations, in response to occupational exposures, are receiving an increasing attention since they may pick up inflammatory changes before the injury becomes irreversible. Invasive approaches such as bronchoalveolar lavage and bronchial biopsies have been used to assess airways inflammation: but these methods are not practical for use in occupational field investigations. Thus, much work has focused on the development of noninvasive methods for monitoring inflammation in occupational respiratory diseases. The three recent most commonly used noninvasive techniques in occupational respiratory diseases investigations are induced sputum, exhaled breath condensate, and nasal lavage. In this review, we discuss the practical application of these techniques, patents and cytokines measured with them. Since variation of cytokine genes contribute to the inflammatory processes, we briefly discuss the genetic polymorphisms on the expression of occupational respiratory diseases. Details of genetic polymorphism were beyond the focus of this review. Our primary focus was cytokines measured with these three noninvasive techniques in occupational respiratory investigations.

  11. Regulation of NF-κB by TNF Family Cytokines

    PubMed Central

    Hayden, Matthew S; Ghosh, Sankar

    2014-01-01

    The NF-κB family of inducible transcription factors is activated in response to a variety of stimuli. Amongst the best-characterized inducers of NF-κB are members of the TNF family of cytokines. Research on NF-κB and TNF have been tightly intertwined for more than 25 years. Perhaps the most compelling examples of the interconnectedness of NF-κB and the TNF have come from analysis of knock-out mice that are unable to activate NF-kB. Such mice die embryonically, however, deletion of TNF or TNFR1 can rescue the lethality thereby illustrating the important role of NF-κB as the key regulator of transcriptional responses to TNF. The physiological connections between NF-κB and TNF cytokines are numerous and best explored in articles focusing on a single TNF family member. Instead, in this review, we explore general mechanisms of TNF cytokine signaling, with a focus on the upstream signaling events leading to activation of the socalled canonical and noncanonical NF-κB pathways by TNFR1 and CD40 respectively. PMID:24958609

  12. Rituximab-Induced Splenic Rupture and Cytokine Release

    PubMed Central

    Nair, Ranjit; Gheith, Shereen; Lamparella, Nicholas

    2016-01-01

    Patient: Female, 55 Final Diagnosis: Mantle cell lymphoma Symptoms: Cytokine release syndrome • hypoglycemia • hypotension • splenic rupture • splenomegaly • vision loss Medication: — Clinical Procedure: Case Report Specialty: Oncology Objective: Unusual clinical course Background: Rituximab is a therapeutic monoclonal antibody that is used for many different lymphomas. Post-marketing surveillance has revealed that the risk of fatal reaction with rituximab use is extremely low. Splenic rupture and cytokine release syndrome are rare fatal adverse events related to the use of therapeutic monoclonal antibodies, especially in aggressive malignancies with high tumor burden. Case Report: A 55-year-old woman presented with abdominal pain and type B symptoms and was diagnosed with mantle cell lymphoma. Initial peripheral blood flow cytometry showed findings that mimicked features of chronic lymphocytic leukemia. Further treatment with rituximab led to catastrophic treatment complications that proved to be fatal for the patient. Conclusions: Severe cytokine release syndrome associated with biologics carries a very high morbidity and case fatality rate. With this case report we aim to present the diagnostic challenge with small B-cell neoplasms, especially mantle cell lymphoma and chronic lymphocytic lymphomas, and underscore the importance of thorough risk assessment for reactions prior to treatment initiation. PMID:26972227

  13. Characterising Cytokine Gene Expression Signatures in Patients with Severe Sepsis

    PubMed Central

    Grealy, Robert; White, Mary; Stordeur, Patrick; Kelleher, Dermot; Doherty, Derek G.; McManus, Ross; Ryan, Thomas

    2013-01-01

    Introduction. Severe sepsis in humans may be related to an underlying profound immune suppressive state. We investigated the link between gene expression of immune regulatory cytokines and the range of illness severity in patients with infection and severe sepsis. Methods. A prospective observational study included 54 ICU patients with severe sepsis, 53 patients with infection without organ failure, and 20 healthy controls. Gene expression in peripheral blood mononuclear cells (PBMC) was measured using real-time polymerase chain reaction. Results. Infection differed from health by decreased expression of the IL2, and IL23 and greater expression of IL10 and IL27. Severe sepsis differed from infection by having decreased IL7, IL23, IFNγ, and TNFα gene expression. An algorithm utilising mRNA copy number for TNFα, IFNγ, IL7, IL10, and IL23 accurately distinguished sepsis from severe sepsis with a receiver operator characteristic value of 0.88. Gene expression was similar with gram-positive and gram-negative infection and was similar following medical and surgical severe sepsis. Severity of organ failure was associated with serum IL6 protein levels but not with any index of cytokine gene expression in PBMCs. Conclusions. Immune regulatory cytokine gene expression in PBMC provides a robust method of modelling patients' response to infection. PMID:23935244

  14. Cytokine and Chemokine Regulation of Sensory Neuron Function

    PubMed Central

    Miller, Richard J.; Jung, Hosung; Bhangoo, Sonia K.; White, Fletcher A.

    2009-01-01

    Pain normally subserves a vital role in the survival of the organism, prompting the avoidance of situations associated with tissue damage. However, the sensation of pain can become dissociated from its normal physiological role. In conditions of neuropathic pain, spontaneous or hypersensitive pain behavior occurs in the absence of the appropriate stimuli. Our incomplete understanding of the mechanisms underlying chronic pain hypersensitivity accounts for the general ineffectiveness of currently available options for the treatment of chronic pain syndromes. Despite its complex pathophysiological nature, it is clear that neuropathic pain is associated with short- and long-term changes in the excitability of sensory neurons in the dorsal root ganglia (DRG) as well as their central connections. Recent evidence suggests that the upregulated expression of inflammatory cytokines in association with tissue damage or infection triggers the observed hyperexcitability of pain sensory neurons. The actions of inflammatory cytokines synthesized by DRG neurons and associated glial cells, as well as by astrocytes and microglia in the spinal cord, can produce changes in the excitability of nociceptive sensory neurons. These changes include rapid alterations in the properties of ion channels expressed by these neurons, as well as longer-term changes resulting from new gene transcription. In this chapter we review the diverse changes produced by inflammatory cytokines in the behavior of sensory neurons in the context of chronic pain syndromes. PMID:19655114

  15. Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection.

    PubMed

    Kedzierski, Lukasz; Linossi, Edmond M; Kolesnik, Tatiana B; Day, E Bridie; Bird, Nicola L; Kile, Benjamin T; Belz, Gabrielle T; Metcalf, Donald; Nicola, Nicos A; Kedzierska, Katherine; Nicholson, Sandra E

    2014-05-01

    Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influenza virus (PR8) and are hypersusceptible to infection with the less virulent H3N2 (X31) strain. In SOCS4-deficient animals, this led to substantially greater weight loss, dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This was associated with impaired trafficking of influenza-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity.

  16. Suppressor of Cytokine Signaling 4 (SOCS4) Protects against Severe Cytokine Storm and Enhances Viral Clearance during Influenza Infection

    PubMed Central

    Kedzierski, Lukasz; Linossi, Edmond M.; Kolesnik, Tatiana B.; Day, E. Bridie; Bird, Nicola L.; Kile, Benjamin T.; Belz, Gabrielle T.; Metcalf, Donald; Nicola, Nicos A.; Kedzierska, Katherine; Nicholson, Sandra E.

    2014-01-01

    Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influenza virus (PR8) and are hypersusceptible to infection with the less virulent H3N2 (X31) strain. In SOCS4-deficient animals, this led to substantially greater weight loss, dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This was associated with impaired trafficking of influenza-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity. PMID:24809749

  17. Proallergic cytokines and group 2 innate lymphoid cells in allergic nasal diseases.

    PubMed

    Matsushita, Kazufumi; Kato, Yukinori; Akasaki, Shoko; Yoshimoto, Tomohiro

    2015-07-01

    Recent advances in our understanding of proallergic cytokines and group 2 innate lymphoid cells (ILC2s) indicate their critical roles in type 2 immunity-mediated disorders. Proallergic cytokines, interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin, are released from epithelial cells in inflamed tissues and drive type 2 inflammation by acting on innate and acquired immune systems. ILC2s are an innate immune population that responds to proallergic cytokines by producing type 2 cytokines. In line with allergic disorders in the lung, skin, and intestine, emerging evidence suggests the involvement of proallergic cytokines and ILC2s in allergic nasal diseases such as chronic rhinosinusitis with polyps (CRSwNP), allergic fungal rhinosinusitis, and allergic rhinitis (AR). In CRSwNP patients, both proallergic cytokine levels and ILC2s frequency are increased in the nasal mucosa. Increased proallergic cytokine levels correlate with poorer disease outcomes in CRSwNP. Levels of nasal proallergic cytokines are also elevated in AR patients. In addition, animal studies demonstrate that cytokines are essential for the development of AR. It is becoming clear that the proallergic cytokine/ILC2s axis participates in allergic diseases by multiple mechanisms dependent upon the inflammatory context. Thus, a thorough understanding of these cytokines and ILC2s including their tissue- and disease-specific roles is essential for targeting the pathways to achieve therapeutic applications.

  18. T cell cytokines and the risk of blood stream infection in extremely low birth weight infants

    PubMed Central

    Schelonka, Robert L.; Maheshwari, Akhil; Carlo, Waldemar A.; Taylor, Sarah; Hansen, Nellie I.; Schendel, Diana E.; Thorsen, Poul; Skogstrand, Kristin; Hougaard, David M.; Higgins, Rosemary D.

    2010-01-01

    Cytokines mediate the host immune response to infectious microorganisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6 and IL-10) and inflammatory cytokines (Interferon- [INF- ], tumor necrosis factor- [TNF- ], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the 5 sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (P=0.01), and higher levels of the regulatory cytokines, IL-6 (P=0.01) and IL-10 (P<0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population. PMID:21145756

  19. Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member cytokines with selectable target spectrum.

    PubMed

    Nata, Toshie; Basheer, Asjad; Cocchi, Fiorenza; van Besien, Richard; Massoud, Raya; Jacobson, Steven; Azimi, Nazli; Tagaya, Yutaka

    2015-09-11

    The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases.

  20. Altered cytokine network in gestational diabetes mellitus affects maternal insulin and placental-fetal development.

    PubMed

    Wedekind, Lauren; Belkacemi, Louiza

    2016-01-01

    Pregnancy is characterized by an altered inflammatory profile, compared to the non-pregnant state with an adequate balance between pro-and anti-inflammatory cytokines needed for normal development. Cytokines are small secreted proteins expressed mainly in immunocompetent cells in the reproductive system. From early developmental stages onward, the secretory activity of placenta cells clearly contributes to increase local as well as systemic levels of cytokines. The placental production of cytokines may affect mother and fetus independently. In turn because of this unique position at the maternal fetal interface, the placenta is also exposed to the regulatory influence of cytokines from maternal and fetal circulations, and hence, may be affected by changes in any of these. Gestational diabetes mellitus (GDM) is associated with an overall alteration of the cytokine network. This review discusses the changes that occur in cytokines post GDM and their negative effects on maternal insulin and placental-fetal development.

  1. Association of 22 cytokine gene polymorphisms with rheumatoid arthritis in population of ethnic Macedonians.

    PubMed

    Trajkov, Dejan; Mishevska-Perchinkova, Snezhana; Karadzova-Stojanoska, Anzelika; Petlichkovski, Aleksandar; Strezova, Ana; Spiroski, Mirko

    2009-11-01

    To examine the possible role of 22 cytokine gene polymorphisms in host susceptibility to or protection against RA in Macedonians. In this study, 301 healthy unrelated individuals and 85 patients with RA were studied. Cytokine genotyping was performed by PCR with sequence-specific priming (PCR-SSP) (Heidelberg kit). Results showed susceptible association for four cytokine alleles, six cytokine genotypes, one haplotype, and four combinations of haplotypes, while protective associations were found for four cytokine alleles, three cytokine genotypes, three haplotypes, and only one combination of haplotypes. These results suggest that IL-4 -1098, IL-4 -590, IL-10 -1082, IL-10 -819, IL-2 -330, IL-6 -174, and TNF-alpha -238 cytokine gene polymorphisms might be significantly associated and affect host susceptibility and/or resistance to RA in Macedonians.

  2. The Role of Cytokine PF4 in the Antiviral Immune Response of Shrimp

    PubMed Central

    Chen, Yulei; Cao, Jiao; Zhang, Xiaobo

    2016-01-01

    During viral infection in vertebrates, cytokines play important roles in the host defense against the virus. However, the function of cytokines in invertebrates has not been well characterized. In this study, shrimp cytokines involved in viral infection were screened using a cytokine antibody microarray. The results showed that three cytokines, the Fas receptor (Fas), platelet factor 4 (PF4) and interleukin-22 (IL-22), were significantly upregulated in the white spot syndrome virus (WSSV)-challenged shrimp, suggesting that these cytokines played positive regulatory roles in the immune response of shrimp against the virus. Further experiments revealed that PF4 had positive effects on the antiviral immunity of shrimp by enhancing the shrimp phagocytic activity and inhibiting the apoptotic activity of virus-infected hemocytes. Therefore, our study presented a novel mechanism of cytokines in the innate immunity of invertebrates. PMID:27631372

  3. A proinflammatory cytokine interleukin-32beta promotes the production of an anti-inflammatory cytokine interleukin-10.

    PubMed

    Kang, Jeong-Woo; Choi, Seung-Chul; Cho, Min-Chul; Kim, Hee-Jong; Kim, Jae-Hwa; Lim, Jong-Seok; Kim, Soo-Hyun; Han, Jae-Yong; Yoon, Do-Young

    2009-09-01

    A new proinflammatory cytokine interleukin-32 (IL-32) has six isoforms. Although IL-32 can be detected in sera from patients suffering from Crohn's disease and rheumatoid arthritis, it is unclear which isoforms are involved. To this end, we investigated the functions of the most abundant IL-32beta by generating K562-IL-32beta stable cell lines. This report confirms, using IL-32 small interfering RNA, that IL-32beta induces an anti-inflammatory cytokine IL-10 in K562-IL-32beta cells and U937 promonocytic cells, which express endogenous IL-32beta upon phorbol 12-myristate 13-acetate (PMA) treatment, and monocyte-derived dendritic cells (DC) upon lipopolysaccharide (LPS) treatment. Interleukin-32beta was induced in monocyte-derived macrophages by LPS and in monocyte-derived DC by LPS, poly(I:C), or anti-CD40 antibody, but was not induced by PMA. We showed that IL-32beta expression was increased in a time-dependent manner in monocyte-derived DC upon LPS treatment and peaked at 24 hr. Production of IL-10 was exactly coincident with IL-32beta expression, but IL-1beta and tumour necrosis factor-alpha production peaked at 6 hr after LPS treatment, then steeply declined. Interleukin-12 p40 was induced at 9 hr and gradually increased until 48 hr, at which time IL-32beta and IL-10 were no longer increased. Knock-down of IL-32beta by IL-32 small interfering RNA led to the decrease of IL-10, but the increase of IL-12 in monocyte-derived DC, which means that IL-32beta promotes IL-10 production, but limits IL-12 production. We also showed that IL-10 neutralization increases IL-12, IL-1beta and tumour necrosis factor-alpha production, which implies that IL-10 suppresses such proinflammatory cytokines. Taken together, our results suggest that IL-32beta upregulates the production of an anti-inflammatory cytokine IL-10, and then IL-10 suppresses proinflammatory cytokines.

  4. Tamm-Horsfall protein regulates circulating and renal cytokines by affecting glomerular filtration rate and acting as a urinary cytokine trap.

    PubMed

    Liu, Yan; El-Achkar, Tarek M; Wu, Xue-Ru

    2012-05-11

    Although few organ systems play a more important role than the kidneys in cytokine catabolism, the mechanism(s) regulating this pivotal physiological function and how its deficiency affects systemic cytokine homeostasis remain unclear. Here we show that elimination of Tamm-Horsfall protein (THP) expression from mouse kidneys caused a marked elevation of circulating IFN-γ, IL1α, TNF-α, IL6, CXCL1, and IL13. Accompanying this were enlarged spleens with prominent white-pulp macrophage infiltration. Lipopolysaccharide (LPS) exacerbated the increase of serum cytokines without a corresponding increase in their urinary excretion in THP knock-out (KO) mice. This, along with the rise of serum cystatin C and the reduced inulin and creatinine clearance from the circulation, suggested that diminished glomerular filtration may contribute to reduced cytokine clearance in THP KO mice both at the baseline and under stress. Unlike wild-type mice where renal and urinary cytokines formed specific in vivo complexes with THP, this "trapping" effect was absent in THP KO mice, thus explaining why cytokine signaling pathways were activated in renal epithelial cells in such mice. Our study provides new evidence implicating an important role of THP in influencing cytokine clearance and acting as a decoy receptor for urinary cytokines. Based on these and other data, we present a unifying model that underscores the role of THP as a major regulator of renal and systemic immunity.

  5. Potential pharmacokinetic interactions of therapeutic cytokines or cytokine modulators on small-molecule drugs: mechanistic understanding via studies using in vitro systems.

    PubMed

    Zhou, Jin; Li, Feng

    2014-01-01

    The potential pharmacokinetic interactions between macromolecules and small-molecule drugs have received more and more attention with the increasing development of macromolecule therapeutics. Studies have shown that cytokines can differentially modulate drug-metabolizing enzymes and transporters, which raises concerns on the potential interactions of therapeutic cytokines and cytokine modulators on the disposition of small-molecule drugs. Although many in vitro studies have been conducted to characterize the effects of cytokines on drug-metabolizing enzymes and transporters, these studies were limited to only a handful of cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-α, and interferon. It is also challenging to translate these in vitro results to in vivo. In addition, information on the impact of cytokine modulators on drug-metabolizing enzymes and transporters is rather limited. More research is needed in this area. The present review is to provide a summary of the in vitro findings on the pharmacokinetic interactions of therapeutic cytokines and cytokine modulators on small-molecule drugs. Discussion on current challenges in assessing these interactions is also included.

  6. The role of cytokines in the pathogenesis of rheumatoid arthritis--Practical and potential application of cytokines as biomarkers and targets of personalized therapy.

    PubMed

    Brzustewicz, Edyta; Bryl, Ewa

    2015-12-01

    Rheumatoid arthritis (RA), as a common chronic disease leading to severe disability, requires early diagnosis and introduction of proper treatment. Deregulation in the cytokine network plays an undoubtedly crucial role in the pathogenesis of RA. The understanding of the role of cytokines in RA can be used for patients' benefit. Technological advances had already allowed introduction of the tailor-made cytokine-targeted therapies (so far anti-TNF, anti-IL-1 and anti-IL-6) into clinical practice. This type of treatment is currently developing very fast. Moreover, cytokines are considered to be potential powerful biomarkers of RA with roles predicted to grow in the future. Detailed understanding of the cytokine balance in RA may assist both the diagnostic process and therapy.

  7. Inflammatory Response to Burn Trauma: Nicotine Attenuates Proinflammatory Cytokine Levels

    PubMed Central

    Papst, S.; Reimers, K.; Stukenborg-Colsman, C.; Steinstraesser, L.; Vogt, P. M.; Kraft, T.; Niederbichler, A. D.

    2014-01-01

    Objective: The immune response to an inflammatory stimulus is balanced and orchestrated by stimulatory and inhibitory factors. After a thermal trauma, this balance is disturbed and an excessive immune reaction with increased production and release of proinflammatory cytokines results. The nicotine-stimulated anti-inflammatory reflex offsets this. The goal of this study was to verify that transdermal administration of nicotine downregulates proinflammatory cytokine release after burn trauma. Methods: A 30% total body surface area full-thickness rat burn model was used in Sprague Dawley rats (n = 35, male). The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham + nicotine group with 5 experimental animals per group. The last 2 groups received a transdermal nicotine administration of 1.75 mg. The concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 were determined in homogenates of hearts, livers, and spleens 12 or 24 hours after burn trauma. Results: Experimental burn trauma resulted in a significant increase in cytokine levels in hearts, livers, and spleens. Nicotine treatment led to a decrease of the effect of the burn trauma with significantly lower concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 compared to the trauma group. Conclusions: This study confirms in a standardized burn model that stimulation of the nicotinic acetylcholine receptor is involved in the regulation of effectory molecules of the immune response. Looking at the results of our study, further experiments designed to explore and evaluate the potency and mechanisms of the immunomodulating effects of this receptor system are warranted. PMID:25671045

  8. T helper cell cytokine profiles after endurance exercise.

    PubMed

    Kakanis, Michael W; Peake, Jonathan; Brenu, Ekua W; Simmonds, Michael; Gray, Bon; Marshall-Gradisnik, Sonya M

    2014-09-01

    Endurance exercise can cause immunosuppression and increase the risk of upper respiratory illness. The present study examined changes in the secretion of T helper (Th) cell cytokines after endurance exercise. Ten highly trained road cyclists [mean±SEM: age 24.2±1.7 years; height 1.82±0.02 m; body mass 73.8±2.0 kg; peak oxygen uptake 65.9±2.3 mL/(kg•min)] performed 2 h of cycling exercise at 90% of the second ventilatory threshold. Peripheral blood mononuclear cells were isolated and stimulated with phytohemagglutinin. Plasma cortisol concentrations and the concentration of Th1/Th2/Th17 cell cytokines were examined. Data were analyzed using both traditional statistics and magnitude-based inferences. Results revealed a significant decrease in plasma cortisol at 4-24 h postexercise compared with pre-exercise values. Qualitative analysis revealed postexercise changes in concentrations of plasma cortisol, IL-2, TNF, IL-4, IL-6, IL-10, and IL-17A compared with pre-exercise values. A Th1/Th2 shift was evident immediately postexercise. Furthermore, for multiple cytokines, including IL-2 and TNF (Th1), IL-6 and IL-10 (Th2), and IL-17 (Th17), no meaningful change in concentration occurred until more than 4 h postexercise, highlighting the duration of exercise-induced changes in immune function. These results demonstrate the importance of considering "clinically" significant versus statistically significant changes in immune cell function after exercise.

  9. A cascade of cytokines mediates mechanical inflammatory hypernociception in mice

    PubMed Central

    Cunha, T. M.; Verri, W. A.; Silva, J. S.; Poole, S.; Cunha, F. Q.; Ferreira, S. H.

    2005-01-01

    The hypernociceptive effects of cytokines [TNF-α, keratinocyte-derived chemokine (KC), and IL-1β] and their participation in carrageenan (Cg)-induced inflammatory hypernociception in mice were investigated. Nociceptor sensitization (hypernociception) was quantified with an electronic version of the von Frey filament test in WT and TNF receptor type 1 knockout mice (TNF-R1–/–). TNF-α-induced hypernociception was abolished in TNF-R1–/– mice, partially inhibited by pretreatment with IL-1 receptor antagonist (IL-1ra) or indomethacin and unaffected by Ab against KC (AbKC) or guanethidine. IL-1ra and indomethacin pretreatment strongly inhibited the hypernociception induced by IL-1β, which was not altered by AbKC or guanethidine or by knocking out TNF-R1. KC-induced hypernociception was abolished by AbKC, inhibited by pretreatment with indomethacin plus guanethidine, and partially inhibited by IL-1ra, indomethacin, or guanethidine. In contrast, KC-induced hypernociception was not altered by knocking out TNF-R1. Cg-induced hypernociception was abolished by administration of indomethacin plus guanethidine, diminished in TNF-R1–/– mice, and partially inhibited in WT mice pretreated with AbKC, IL-1ra, indomethacin, or guanethidine. TNF-α, KC, and IL-1β concentrations were elevated in the skin of Cg-injected paws. The TNF-α and KC concentrations rose concomitantly and peaked before that of IL-1β. In mice, the cytokine cascade begins with the release of TNF-α (acting on TNF-R1 receptor) and KC, which stimulate the release of IL-1β. As in rats, the final mediators of this cascade were prostaglandins released by IL-1β and sympathetic amines released by KC. These results extend to mice the concept that the release of primary mediators responsible for hypernociception is preceded by a cascade of cytokines. PMID:15665080

  10. Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines.

    PubMed

    Mordue, D G; Monroy, F; La Regina, M; Dinarello, C A; Sibley, L D

    2001-10-15

    Virulence in Toxoplasma gondii is strongly influenced by the genotype of the parasite. Type I strains uniformly cause rapid death in mice regardless of the host genotype or the challenge dose. In contrast, the outcome of infections with type II strains is highly dependent on the challenge dose and the genotype of the host. To understand the basis of acute virulence in toxoplasmosis, we compared low and high doses of the RH strain (type I) and the ME49/PTG strain (type II) of T. gondii in outbred mice. Differences in virulence were reflected in only modestly different growth rates in vivo, and both strains disseminated widely to different tissues. The key difference in the virulent RH strain was the ability to reach high tissue burdens rapidly following a low dose challenge. Lethal infections caused by type I (RH) or type II (PTG) strain infections were accompanied by extremely elevated levels of Th1 cytokines in the serum, including IFN-gamma, TNF-alpha, IL-12, and IL-18. Extensive liver damage and lymphoid degeneration accompanied the elevated levels of cytokines produced during lethal infection. Increased time of survival following lethal infection with the RH strain was provided by neutralization of IL-18, but not TNF-alpha or IFN-gamma. Nonlethal infections with a low dose of type II PTG strain parasites were characterized by a modest induction of Th1 cytokines that led to control of infection and minimal damage to host tissues. Our findings establish that overstimulation of immune responses that are normally necessary for protection is an important feature of acute toxoplasmosis.

  11. Cytokine and Growth Factor Responses After Radiotherapy for Localized Ependymoma

    SciTech Connect

    Merchant, Thomas E. Li Chenghong; Xiong Xiaoping; Gaber, M. Waleed

    2009-05-01

    Purpose: To determine the time course and clinical significance of cytokines and peptide growth factors in pediatric patients with ependymoma treated with postoperative radiotherapy (RT). Methods and Materials: We measured 15 cytokines and growth factors (fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor [VEGF], interleukin [IL]-1{beta}, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-{gamma}, tumor necrosis factor-{alpha}, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and macrophage inflammatory protein-{alpha}) from 30 patients before RT and 2 and 24 h, weekly for 6 weeks, and at 3, 6, 9, and 12 months after the initiation of RT. Two longitudinal models for the trend of log-transformed measurements were fitted, one during treatment and one through 12 months. Results: During RT, log IL-8 declined at a rate of -0.10389/wk (p = 0.0068). The rate of decline was greater (p = 0.028) for patients with an infratentorial tumor location. The decline in IL-8 after RT was significant when stratified by infratentorial tumor location (p = 0.0345) and more than one surgical procedure (p = 0.0272). During RT, the decline in log VEGF was significant when stratified by the presence of a ventriculoperitoneal shunt. After RT, the log VEGF declined significantly at a rate of -0.06207/mo. The decline was significant for males (p = 0.0222), supratentorial tumors (p = 0.0158), one surgical procedure (p = 0.0222), no ventriculoperitoneal shunt (p = 0.0005), and the absence of treatment failure (p = 0.0028). Conclusion: The pro-inflammatory cytokine IL-8 declined significantly during RT and the decline differed according to tumor location. The angiogenesis factor VEGF declined significantly during the 12 months after RT. The decline was greater in males, those without a ventriculoperitoneal shunt, and in those with favorable disease factors, including one surgical procedure, supratentorial tumor location, and

  12. Autoimmunity and Cytokine Imbalance in Inherited Epidermolysis Bullosa

    PubMed Central

    Esposito, Susanna; Guez, Sophie; Orenti, Annalisa; Tadini, Gianluca; Scuvera, Giulietta; Corti, Laura; Scala, Alessia; Biganzoli, Elia; Berti, Emilio; Principi, Nicola

    2016-01-01

    In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB) types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls (p = 0.008, p < 0.001, p < 0.001, p < 0.001 and p < 0.001 for desmoglein 1 (DSG1) desmoglein 3 (DSG3), bullous pemphigoid 180 (BP180), BP230 and type VII collagen (COL7), respectively). The same trend was observed for interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-β, and interferon-γ (p < 0.001, p < 0.001, p < 0.001, p = 0.008, p < 0.001 and p = 0.002, respectively). Increases in anti-skin antibodies and cytokine concentrations were higher in patients with recessive dystrophic EB than in those with different types of EB, in generalized cases than in localized ones, and in patients with higher Birmingham Epidermolysis Bullosa Severity (BEBS) scores than in those with a lower score. The BEBS score was directly correlated with BP180, BP230, COL7 (p = 0.015, p = 0.008 and p < 0.001, respectively) and IL-6 (p = 0.03), whereas IL-6 appeared significantly associated with DSG1, DSG3, BP180, BP230 and COL7 (p = 0.015, p = 0.023, p = 0.023, p = 0.015 and p = 0.005, respectively). This study showed that autoimmunity and inflammatory responses are frequently activated in EB, mainly in severe forms, suggesting the use of immunosuppressive drugs or biologicals that are active against pro-inflammatory cytokines to reduce clinical signs and symptoms of disease. PMID:27669234

  13. Cytokine production in patients with cirrhosis and TLR4 polymorphisms

    PubMed Central

    Nieto, Juan Camilo; Sánchez, Elisabet; Román, Eva; Vidal, Silvia; Oliva, Laia; Guarner-Argente, Carlos; Poca, Maria; Torras, Xavier; Juárez, Cándido; Guarner, Carlos; Soriano, German

    2014-01-01

    AIM: To analyze the cytokine production by peripheral blood cells from cirrhotic patients with and without TLR4 D299G and/or T399I polymorphisms. METHODS: The study included nine patients with cirrhosis and TLR4 D299G and/or T399I polymorphisms, and 10 wild-type patients matched for age, sex and degree of liver failure. TLR4 polymorphisms were determined by sequence-based genotyping. Cytokine production by peripheral blood cells was assessed spontaneously and also after lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation. RESULTS: Patients with TLR4 polymorphisms had a higher incidence of previous hepatic encephalopathy than wild-type patients (78% vs 20%, P = 0.02). Spontaneous production of interleukin (IL)-6 and IL-10 was lower in patients with TLR4 polymorphisms than in wild-type patients [IL-6: 888.7 (172.0-2119.3) pg/mL vs 5540.4 (1159.2-26053.9) pg/mL, P < 0.001; IL-10: 28.7 (6.5-177.1) pg/mL vs 117.8 (6.5-318.1) pg/mL, P = 0.02]. However, the production of tumor necrosis factor-α, IL-6 and IL-10 after LPS and LTA stimulation was similar in the two groups. CONCLUSION: TLR4 polymorphisms were associated with a distinctive pattern of cytokine production in cirrhotic patients, suggesting that they play a role in the development of cirrhosis complications. PMID:25516666

  14. Cytokines and Metabolic Patterns in Pediatric Patients with Critical Illness

    PubMed Central

    Briassoulis, George; Venkataraman, Shekhar; Thompson, Ann

    2010-01-01

    It is not known if cytokines, which are cell-derived mediators released during the host immune response to stress, affect metabolic response to stress during critical illness. The aim of this prospective study was to determine whether the metabolic response to stress is related to the inflammatory interleukin-6 (IL-6), 10 (IL-10), and other stress mediators' responses and to assess their relationships with different feeding patterns, nutritional markers, the severity of illness as assessed by the Multiple Organ System Failure (MOSF), the Pediatric Risk of Mortality Score (PRISM), systemic inflammatory response syndrome (SIRS), and mortality in critically ill children. Patients were classified as hypermetabolic, normometabolic, and hypometabolic when the measured resting energy expenditures (REE) were >110%, 90–110% and, <90% of the predicted basal metabolic rate, respectively. The initial predominance of the hypometabolic pattern (48.6%) declined within 1 week of acute stress (20%), and the hypermetabolic patterns dominated only after 2 weeks (60%). Only oxygen consumption (VO2) and carbon dioxide production (VCO2) (P < .0001) but none of the cytokines and nutritional markers, were independently associated with a hypometabolic pattern. REE correlated with the IL-10 but not PRISM. In the presence of SIRS or sepsis, CRP, IL-6, IL-10, Prognostic Inflammatory and Nutritional Index (NI), and triglycerides—but not glucose, VO2, or VCO2 increased significantly. High IL-10 levels (P = .0000) and low measured REE (P = .0000) were independently associated with mortality (11.7%), which was higher in the hypometabolic compared to other metabolic patterns (P < .005). Our results showed that only VO2 and VCO2, but not IL-6 or IL-10, were associated with a hypometabolic pattern which predominated the acute phase of stress, and was associated with increased mortality. Although in SIRS or sepsis, the cytokine response was reliably reflected by increases in NI and

  15. Cytokine orchestration in post-operative peritoneal adhesion formation

    PubMed Central

    Cahill, Ronan A; Redmond, H Paul

    2008-01-01

    Peritoneal adhesions are a near inevitable occurrence after laparotomy and a major cause of both patient and physician misery. To date, clinical attempts at their amelioration have concentrated on manipulating the physical factors that affect their development despite a wealth of experimental data elucidating the molecular mechanisms that underlie their initiation, development and maturation. However, the advent of targeted, specific anti-cytokine agents as directed therapy for inflammatory and neoplastic conditions raises the prospect of a new era for anti-adhesion strategies. To harness this potential will require considerable cross-disciplinary collaboration and that surgeon-scientists propel themselves to the forefront of this emerging field. PMID:18756592

  16. [Cytokines and proteases involved in pathogenesis of COPD].

    PubMed

    Yamaya, Atsuyo; Osanai, Kazuhiro

    2011-10-01

    COPD is characterized by persistence of chronic inflammation in small airways and alveoli. Macrophages, neutrophils, and a specialized subset of T lymphocytes orchestrate the mild inflammation. This article focuses on humoral factors such as cytokines and chemokines that recruit these inflammatory and immune cells to the lungs, and proteases/antiproteases that ultimately cause structural derangement in the terminal respiratory zones. In addition to the classical protease and antiprotease imbalance hypothesis, alveolar homeostasis abnormality that comes from imbalance of lung constitutional cell apoptosis and regeneration may play a role in emphysema development. Also, autoimmunity to elastin degradation products may take part in the disease.

  17. Effect of grepafloxacin on cytokine production in vitro.

    PubMed

    Ono, Y; Ohmoto, Y; Ono, K; Sakata, Y; Murata, K

    2000-07-01

    The effect of a new quinolone antibacterial agent, grepafloxacin, on the production of cytokines was investigated using lipopolysaccharide-stimulated human peripheral blood cells. Grepafloxacin 1-30 mg/L inhibited the production of interleukin 1alpha (IL-1alpha) and IL-1beta, and the expression of IL-1alpha, IL-1beta, tumour necrosis factor alpha (TNFalpha), IL-6 and IL-8 mRNA. These results suggest that the inhibitory effect of grepafloxacin is exerted, in part, at the gene transcription level.

  18. MICROFLUIDIC MODULES FOR ISOLATION OF RECOMBINANT CYTOKINE FROM BACTERIAL LYSATES

    SciTech Connect

    Retterer, Scott T; Doktycz, Mitchel John

    2014-01-01

    The portability and personalization of health-care diagnostics and treatments benefits from advancements and applications of micro and nanotechnology. Modularization and miniaturization of standardized biochemical processes and tests facilitates the advancement and customization of analyte detection and diagnosis on-chip. The goal of our work here is to develop modular platforms for on-chip biochemical processing of synthesized biologics for a range of on-demand applications. Our report focuses on the initial development, characterization and application of microfluidic size exclusion/gel filtration and ion exchange protein concentration modules for cytokine isolation from spiked cell extracts.

  19. Modulation of cytokine expression in human macrophages by endocrine-disrupting chemical Bisphenol-A

    SciTech Connect

    Liu, Yanzhen; Mei, Chenfang; Liu, Hao; Wang, Hongsheng; Zeng, Guoqu; Lin, Jianhui; Xu, Meiying

    2014-09-05

    Highlights: • Effects of BPA on the cytokines expression of human macrophages were investigated. • BPA increased pro-inflammation cytokines TNF-α and IL-6 production. • BPA decreased anti-inflammation IL-10 and TGF-β production. • ERα/β/ERK/NF-κB signaling involved in BPA-mediated cytokines expression. - Abstract: Exposure to environmental endocrine-disrupting chemical Bisphenol-A (BPA) is often associated with dysregulated immune homeostasis, but the mechanisms remain unclear. In the present study, the effects of BPA on the cytokines responses of human macrophages were investigated. Treatment with BPA increased pro-inflammation cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production, but decreased anti-inflammation cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) production in THP1 macrophages, as well as in primary human macrophages. BPA effected cytokines expression through estrogen receptor α/β (ERα/β)-dependent mechanism with the evidence of ERα/β antagonist reversed the expression of cytokines. We also identified that activation of extracellular regulated protein kinases (ERK)/nuclear factor κB (NF-κB) signal cascade marked the effects of BPA on cytokines expression. Our results indicated that BPA effected inflammatory responses of macrophages via modulating of cytokines expression, and provided a new insight into the link between exposure to BPA and human health.

  20. B cells responses and cytokine production are regulated by their immune microenvironment.

    PubMed

    Vazquez, Monica I; Catalan-Dibene, Jovani; Zlotnik, Albert

    2015-08-01

    The adaptive immune system consists of two types of lymphocytes: T and B cells. These two lymphocytes originate from a common precursor, yet are fundamentally different with B cells mediating humoral immunity while T cells mediate cell mediated immunity. In cytokine production, naïve T cells produce multiple cytokines upon activation while naïve activated B cells do not. B cells are capable of producing cytokines, but their cytokine production depends on their differentiation state and activation conditions. Hence, unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines. Many cytokines act on B cells as well. Here, we discuss several cytokines and their effects on B cells including: Interleukins, IL-7, IL-4, IL-6, IL-10, and Interferons, IFN-α, IFN-β, IFN-γ. These cytokines play important roles in the development, survival, differentiation and/or proliferation of B cells. Certain chemokines also play important roles in B cell function, namely antibody production. As an example, we discuss CCL28, a chemokine that directs the migration of plasma cells to mucosal sites. We conclude with a brief overview of B cells as cytokine producers and their likely functional consequences on the immune response.

  1. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis.

    PubMed

    Mateen, Somaiya; Zafar, Atif; Moin, Shagufta; Khan, Abdul Qayyum; Zubair, Swaleha

    2016-04-01

    Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anti-citrullinated peptide antibodies. Initial phase of RA involves the activation of both T and B cells. Cytokines have a crucial role in the pathophysiology of RA as pro-inflammatory cytokines such as TNFα, IL-1, IL-17 stimulates inflammation and degradation of bone and cartilage. There occurs an imbalance between the pro- and anti-inflammatory cytokine activities which leads to multisystem immune complications. There occurs a decline in the number of Treg cells which may also play an important role in pathophysiology of the disease. In RA patients, serum or plasma level of cytokines may indicate the severity of disease. Cytokine gene polymorphism could be used as markers of susceptibility and severity of RA. Anti-cytokine agents seem to emerge as potent drug molecules to treat RA. Many clinical trials are ongoing and several positive results have been obtained. There is a need to develop potential anti-cytokine agents that target numerous pathways involved in the pathogenesis of RA. This review article describes the effector functions of pro- and anti-inflammatory cytokines and the role of cytokine gene polymorphism in the pathogenesis of RA. Anti-cytokine agents that are currently available and those that are still in clinical trials have also been summarized.

  2. Comparison of cytokine responses between dogs with sepsis and dogs with immune-mediated hemolytic anemia.

    PubMed

    Johnson, Valerie; Burgess, Brandy; Morley, Paul; Bragg, Ryan; Avery, Anne; Dow, Steven

    2016-11-01

    Cytokine abnormalities have been described previously in dogs with varied immune mediated and inflammatory conditions such as IMHA and sepsis. The purpose of this study was to establish references ranges for cytokine levels in dogs and to compare cytokine levels in normal dogs and dogs with two common inflammatory diseases (sepsis and IMHA). We hypothesized that cytokine response profiles in dogs with sepsis would be significantly different from those in dogs with IMHA due to the very different etiologies of the two diseases. Concentrations of 14 different cytokines in serum were measured and values grouped according to cytokine function. Serum from clinically normal dogs was used to establish cytokine concentration reference ranges. Rank values for each of the 4 cytokine groups were then compared statistically between healthy control, septic and IMHA dogs. This analysis revealed differences in cytokine groups between dogs with sepsis and IMHA when compared to healthy control dogs but no difference between dogs with either of these conditions. In conclustion, dogs in the early stage of sepsis and IMHA have similar circulating cytokines despite different etiologies suggesting activation of common immunologic pathways. This may have implications for immunotherapy of immune mediated diseases in dogs of varying etiology.

  3. A whole blood in vitro cytokine release assay with aqueous monoclonal antibody presentation for the prediction of therapeutic protein induced cytokine release syndrome in humans.

    PubMed

    Wolf, Babette; Morgan, Hannah; Krieg, Jennifer; Gani, Zaahira; Milicov, Adriana; Warncke, Max; Brennan, Frank; Jones, Stewart; Sims, Jennifer; Kiessling, Andrea

    2012-12-01

    The administration of several monoclonal antibodies (mAbs) to humans has been associated with acute adverse events characterized by clinically significant release of cytokines in the blood. The limited predictive value of toxicology species in this field has triggered intensive research to establish human in vitro assays using peripheral blood mononuclear cells or blood to predict cytokine release in humans. A thorough characterization of these assays is required to understand their predictive value for hazard identification and risk assessment in an optimal manner, and to highlight potential limitations of individual assay formats. We have characterized a whole human blood cytokine release assay with only minimal dilution by the test antibodies (95% v/v blood) in aqueous presentation format, an assay which has so far received less attention in the scientific world with respect to the evaluation of its suitability to predict cytokine release in humans. This format was compared with a human PBMC assay with immobilized mAbs presentation already well-characterized by others. Cytokine secretion into plasma or cell culture supernatants after 24h incubation with the test mAbs (anti-CD28 superagonist TGN1412-like material (TGN1412L), another anti-CD28 superagonistic mAb (ANC28.1), a T-cell depleting mAb (Orthoclone™), and a TGN1412 isotype-matched control (Tysabri™) not associated with clinically-relevant cytokine release) was detected by a multiplex assay based on electrochemiluminescent excitation. We provide proof that this whole blood assay is a suitable new method for hazard identification of safety-relevant cytokine release in the clinic based on its ability to detect the typical cytokine signatures found in humans for the tested mAbs and on a markedly lower assay background and cytokine release with the isotype-matched control mAb Tysabri™ - a clear advantage over the PBMC assay. Importantly, quantitative and qualitative differences in the relative cytokine

  4. Cytokine profile in human eyes: contribution of a new cytokine combination for differential diagnosis between intraocular lymphoma or uveitis.

    PubMed

    Fisson, Sylvain; Ouakrim, Hanane; Touitou, Valérie; Baudet, Sylvie; Ben Abdelwahed, Rym; Donnou, Sabrina; Miloudi, Amine; Galand, Claire; Bodaghi, Bahram; Lehoang, Phuc; Brissard, Martine; Le Garff-Tavernier, Magali; Fridman, Wolf Herman; Sautès-Fridman, Catherine; Cassoux, Nathalie; Merle-Béral, Hélène

    2013-01-01

    Primary intraocular lymphoma (PIOL), also called primary vitreoretinal lymphomas, often masquerades as uveitis. This misdiagnosis can result in subsequent brain involvement and oculocerebral lymphoma (OCL). In this study, we sought to characterize the helper T-cell type 1 (Th1)/Th2 cytokine profile in vitreous samples from patients with PIOL, OCL, uveitis and controls with non-inflammatory disease. Vitreous and aqueous humor samples from 87 patients with PIOL (n = 30), OCL (n = 12), uveitis (n = 34), and retinal detachment (RD) without hemorrhage (n = 11) were analyzed and their concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were determined by flow cytometric bead arrays (CBA). The IL-10 levels determined by CBA were compared with those by ELISA. IL-10 concentrations measured by CBA and ELISA were highly correlated. IL-2, IL-4, and TNFα were not detected in any sample. The only cytokine detected at a significant level in samples from RD vitreous was IL-6. The IL-10/IL-6 ratio, as previously reported, was slightly higher in PIOL than in uveitis samples, but not for all patients. Cytokine profiles from PIOL and OCL samples did not differ. The combination of the IL-10/IL-6 and IL-10/IFNγ ratios was highly informative for discriminating PIOL/OCL from uveitis samples and for therapeutic follow up of PIOL. This strategy might be very helpful as an initial screening to rule out PIOL in patients thought to have uveitis.

  5. Evaluation of cytokines as adjuvants of infectious bovine keratoconjunctivitis vaccines.

    PubMed

    di Girolamo, Fabio A; Sabatini, Diego Jorge; Fasan, Raúl A; Echegoyen, Maia; Vela, Mauro; Pereira, Claudio A; Maure, Pablo

    2012-01-15

    In this work two cytokines were used in combination with inactivated bacteria (bacterin) to test the bovine conjuctival immune response to the pathogen Moraxella bovis, the causative agent of Infectious bovine keratoconjunctivitis (IBK). Treatments using the bacterin vaccine combined with interleukin-2 and interferon-α as adjuvants (Group A), the bacterin vaccine only (Group B), and controls without treatment (Group C), were applied by ocular spraying to evaluate the local immune response in the corneal structure of cattle experimentally infected with M. bovis. Six weeks after infection, 14 out of a total of 34 animals presented different corneal lesions; 9 corresponding to the control group C, 4 to the group B and only one to the group A. According to the clinical manifestations, a numeric score was calculated. Control animals presented the highest score value (12 points), followed by group B (7.5 points) and group A (1 point). These results suggest that the addition of cytokines to M. bovis treatments can reduce not only eye injuries caused by IBK but also the number of diseased animals.

  6. New immunological approaches and cytokine targets in asthma and allergy.

    PubMed

    Stirling, R G; Chung, K F

    2000-12-01

    The aims of current asthma treatment are to suppress airway inflammation and control symptoms, and corticosteroids maintain a commanding position in this role. Steroids effectively suppress inflammation in the majority of patients but have little impact on the natural history of this disease. In severe asthmatics, corticosteroids may have relatively less beneficial effects. Recent advances in understanding the inflammatory and immunological mechanisms of asthma have indicated many potential therapeutic avenues that may prevent or reverse abnormalities that underlie asthma. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which may provide valuable flexibility in the therapeutic approach to asthma. The novel immunological approaches include the prevention of T-cell activation, attempts to influence the balance of T-helper cell (Th) populations to inhibit or prevent Th2-derived cytokine expression, and the inhibition or blockade of the downstream actions of these cytokines such as effects on immunoglobulin-E and eosinophils. These approaches provide broad as well as highly specific targeting, and also prospects for prevention and reversal of immunological and inflammatory abnormalities associated with asthma. Hopefully, the development of effective antiasthma agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of asthma.

  7. Role of various cytokines and growth factors in pubertal development.

    PubMed

    Casazza, Krista; Hanks, Lynae J; Alvarez, Jessica A

    2010-01-01

    Historical data suggest that body composition is intricately involved in pubertal development. Progression through puberty is dependent on the interaction between the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis, reproductive and metabolic hormones as well as pro- and anti-inflammatory cytokines which induce alterations in feedback mechanisms and therefore mediate body composition and growth. Simultaneous increases in GH and IGF-1, and the concomitant changes in the hormonal milieu (i.e. reproductive hormones, testosterone and estrogen, and insulin)are the major contributors to anabolic effects seen throughout the pubertal transition, and are affected by various factors including (but not limited to) energy status and body composition. Orexigenic agents (i.e. ghrelin and leptin) also play a role at the level of the hypothalamus affecting not only energy intake, but also pubertal onset and progression. Effects of cytokines, many of which may be considered catabolic, extend beyond their traditionally viewed role involving the immune system, accompanying reproductive maturity further regulating aspects of energy and bone metabolism. As such, the signal(s) initiating the hypothalamic response that triggers puberty is likely reliant on a number of neural, metabolic and endocrine networks, all of which are at least partially influenced by pubertal growth factors, and act independently, antagonistically and/or synergistically to regulate anabolic pathways, therefore modifying body composition trajectory and growth during adolescence.

  8. Deficient cytokine control modulates temporomandibular joint pain in rheumatoid arthritis.

    PubMed

    Ahmed, Neveen; Catrina, Anca I; Alyamani, Ahmed O; Mustafa, Hamid; Alstergren, Per

    2015-08-01

    The aim was to investigate how endogenous cytokine control of tumor necrosis factor (TNF) influences temporomandibular joint (TMJ) pain in relation to the role of anti-citrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis (RA). Twenty-six consecutive patients with TMJ RA were included. Temporomandibular joint pain intensity was assessed at rest, on maximum mouth opening, on chewing, and on palpation. Mandibular movement capacity and degree of anterior open bite (a clinical sign of structural destruction of TMJ tissues) were also assessed. Systemic inflammatory activity was assessed using the Disease Activity Score in 28 joints (DAS28) for rheumatoid arthritis. Samples of TMJ synovial fluid and blood were obtained and analyzed for TNF, its soluble receptor, soluble TNF receptor II (TNFsRII), and ACPA. A high concentration of TNF in relation to the concentration of TNFsRII in TMJ synovial fluid was associated with TMJ pain on posterior palpation on maximum mouth opening. The ACPA concentration correlated significantly to the TNF concentration, but not to the TNFsRII concentration, indicating that increased inflammatory activity is mainly caused by an insufficient increase in anti-inflammatory mediators. This study indicates that TMJ pain on palpation in patients with RA is related to a deficiency in local cytokine control that contributes to increased inflammatory activity, including sensitization to mechanical stimuli over the TMJ.

  9. Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms

    PubMed Central

    Hoermann, Gregor; Greiner, Georg; Valent, Peter

    2015-01-01

    The term myeloproliferative neoplasms (MPN) refers to a heterogeneous group of diseases including not only polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), but also chronic myeloid leukemia (CML), and systemic mastocytosis (SM). Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application. PMID:26543328

  10. Expression of class II cytokine genes in children's skin.

    PubMed

    Reemann, Paula; Reimann, Ene; Suutre, Siim; Paavo, Maarjaliis; Loite, Ulvi; Porosaar, Orm; Abram, Kristi; Silm, Helgi; Vasar, Eero; Kõks, Sulev; Kingo, Külli

    2014-07-01

    Immune regulation of the skin plays an important role in susceptibility and development of illnesses. The aim of our study was to localise the interleukin (IL)-10 family of cytokines, in children's skin and to determine possible age-related differences in the expression level. The mRNA expression level of IL10, IL19, IL20, IL22, IL24, IL26, IL28B, IL29 and their receptors IL10RA, IL10RB, IL20RA, IL20RB, IL22RA1, IL22RA2, IL28RA was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time PCR (qRT-PCR). Immunohistochemistry was performed to confirm the qRT-PCR findings. We found age-related differences in the expression of IL10RB, IL20, IL20RA, IL22RA1, IL22RA2, IL26 and IL28RA genes. Cell type-dependent expression of IL10 family cytokines was apparent in the skin. In addition to previously known differences in systemic immunological response of adults and children, the present results reveal differences in immune profile of adult and juvenile skin.

  11. Evaluation of plasma inflammatory cytokine concentrations in racing sled dogs.

    PubMed

    von Pfeil, Dirsko J F; Cummings, Bethany P; Loftus, John P; Levine, Corri B; Mann, Sabine; Downey, Robert L; Griffitts, Caroline; Wakshlag, Joseph J

    2015-12-01

    In human athletes significant changes in cytokine concentrations secondary to exercise have been observed. This prospective study evaluated the effect of a multi-day stage sled dog race on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10). Samples from 20 dogs were harvested prior to and on days 2 and 8 of an 8-day race. Exercise resulted in significantly decreased TNF-α and IL-8 as well as increases of MCP-1, IL-6, and IL-10 concentrations (P-value between 0.01 and < 0.0001 for all parameters). The proportion of values for IL-2 that were below the detection limit increased from 40% on day 0 to 75% on day 2 and decreased on day 8 to 40% (P = 0.04). Racing sled dogs show cytokine-concentration changes that are different from those in humans.

  12. Evaluation of plasma inflammatory cytokine concentrations in racing sled dogs

    PubMed Central

    von Pfeil, Dirsko J. F.; Cummings, Bethany P.; Loftus, John P.; Levine, Corri B.; Mann, Sabine; Downey, Robert L.; Griffitts, Caroline; Wakshlag, Joseph J.

    2015-01-01

    In human athletes significant changes in cytokine concentrations secondary to exercise have been observed. This prospective study evaluated the effect of a multi-day stage sled dog race on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10). Samples from 20 dogs were harvested prior to and on days 2 and 8 of an 8-day race. Exercise resulted in significantly decreased TNF-α and IL-8 as well as increases of MCP-1, IL-6, and IL-10 concentrations (P-value between 0.01 and < 0.0001 for all parameters). The proportion of values for IL-2 that were below the detection limit increased from 40% on day 0 to 75% on day 2 and decreased on day 8 to 40% (P = 0.04). Racing sled dogs show cytokine-concentration changes that are different from those in humans. PMID:26663920

  13. Blastocyst-endometrium interaction: intertwining a cytokine network.

    PubMed

    Castro-Rendón, W A; Castro-Alvarez, J F; Guzmán-Martinez, C; Bueno-Sanchez, J C

    2006-11-01

    The successful implantation of the blastocyst depends on adequate interactions between the embryo and the uterus. The development of the embryo begins with the fertilized ovum, a single totipotent cell which undergoes mitosis and gives rise to a multicellular structure named blastocyst. At the same time, increasing concentrations of ovarian steroid hormones initiate a complex signaling cascade that stimulates the differentiation of endometrial stromal cells to decidual cells, preparing the uterus to lodge the embryo. Studies in humans and in other mammals have shown that cytokines and growth factors are produced by the pre-implantation embryo and cells of the reproductive tract; however, the interactions between these factors that converge for successful implantation are not well understood. This review focuses on the actions of interleukin-1, leukemia inhibitory factor, epidermal growth factor, heparin-binding epidermal growth factor, and vascular endothelial growth factor, and on the network of their interactions leading to early embryo development, peri-implantatory endometrial changes, embryo implantation and trophoblast differentiation. We also propose therapeutical approaches based on current knowledge on cytokine interactions.

  14. Future therapeutic treatment of COPD: Struggle between oxidants and cytokines

    PubMed Central

    de Boer, Willem I; Yao, Hongwei; Rahman, Irfan

    2007-01-01

    Chronic obstructive pulmonary disease (COPD) is a global health problem. Being a progressive disease characterized by inflammation and predominantly caused by tobacco smoking, it deteriorates pulmonary and skeletal muscle functioning, and reduces physical behavior, societal participation and quality of life. During the last two decades studies were focused on the airway and systemic inflammation, oxidative stress, and airway and/or parenchymal remodeling. Macrophages, neutrophils and T cells are thought to be important key players, as well as structural cells like fibroblasts, epithelial, endothelial and smooth muscle cells. Mediators and proteins including cytokines, chemokines, growth factors, proteinases, and oxidants seem to be involved differentially in its pathogenesis. Current pharmacological treatments are directed to reducing airway inflammation, boosting the endogenous levels of anti-oxidants and relieving airway contraction and sputum production. Most agents were primarily used for treating asthma. But in contrast to asthma, these treatments are not very effective in COPD. As a result, novel more specifically acting interventional drugs with less side effects are being developed to treat chronic inflammatory diseases, including COPD. This review highlights studies on novel or potential drug antioxidants such as dietary antioxidants supplementation, N-acetyl-L-cysteine, N-acystelyn, endosteine, antioxidant enzyme mimetics, and anti-inflammatory agents like antagonists of cytokines, such as tumor necrosis factor (TNF)-α, CXCL8, and CCL2, and inhibitors of signal transduction proteins including phosphodiesterase 4, MAPK p38, Pl-3k, and NFκB. PMID:18229560

  15. Circadian disruption, Per3, and human cytokine secretion.

    PubMed

    Guess, Jaclyn; Burch, James B; Ogoussan, Kisito; Armstead, Cheryl A; Zhang, Hongmei; Wagner, Sara; Hebert, James R; Wood, Patricia; Youngstedt, Shawn D; Hofseth, Lorne J; Singh, Udai P; Xie, Dawen; Hrushesky, William J M

    2009-12-01

    Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70). Adjusted mean serum cytokine concentrations (IL-6, TNF-alpha, gamma-INF, IL-1ra, IL-1-beta, VEGF) were compared among patients with high and low scores for fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory II), or sleep disruption (Pittsburgh Sleep Quality Index), or among patients with different Per3 clock gene variants. Poor sleep was associated with elevated VEGF, and fatigue-related reduced activity was associated with elevated TNF-alpha concentrations. Participants with the 4/5 or 5/5 Per3 variable tandem repeat sequence had elevated IL-6 concentrations compared to those with the 4/4 genotype. Biological processes linking circadian disruption with cancer remain to be elucidated. Increased inflammatory cytokine secretion may play a role.

  16. JAK/STAT Pathways in Cytokine Signaling and Myeloproliferative Disorders

    PubMed Central

    Jatiani, Shashidhar S.; Baker, Stacey J.; Silverman, Lewis R.; Reddy, E. Premkumar

    2010-01-01

    Hematopoiesis is the cumulative result of intricately regulated signaling pathways that are mediated by cytokines and their receptors. Studies conducted over the past 10 to 15 years have revealed that hematopoietic cytokine receptor signaling is largely mediated by a family of tyrosine kinases termed Janus kinases (JAKs) and their downstream transcription factors, termed STATs (signal transducers and activators of transcription). Aberrations in these pathways, such as those caused by the recently identified JAK2V617F mutation and translocations of the JAK2 gene, are underlying causes of leukemias and other myeloproliferative disorders. This review discusses the role of JAK/STAT signaling in normal hematopoiesis as well as genetic abnormalities associated with myeloproliferative and myelodisplastic syndromes. This review also summarizes the status of several small molecule JAK2 inhibitors that are currently at various stages of clinical development. Several of these compounds appear to improve the quality of life of patients with myeloproliferative disorders by palliation of disease-related symptoms. However, to date, these agents do not seem to significantly affect bone marrow fibrosis, alter marrow histopathology, reverse cytopenias, reduce red cell transfusion requirements, or significantly reduce allele burden. These results suggest the possibility that additional mutational events might be associated with the development of these neoplasms, and indicate the need for combination therapies as the nature and significance of these additional molecular events is better understood. PMID:21442038

  17. Cytokine-mediated PGE2 expression in human colonic fibroblasts.

    PubMed

    Kim, E C; Zhu, Y; Andersen, V; Sciaky, D; Cao, H J; Meekins, H; Smith, T J; Lance, P

    1998-10-01

    We investigated prostanoid biogenesis in human colonic fibroblasts (CCD-18Co and 5 primary fibroblast cultures) and epithelial cell lines (NCM460, T84, HT-29, and LS 174T) and the effect of PGE2 on fibroblast morphology. Cytokine-stimulated PGE2 production was measured. PGH synthase-1 and -2 (PGHS-1 and -2) protein and mRNA expression were evaluated. Basal PGE2 levels were low in all cell types (0.15-6.47 ng/mg protein). Treatment for 24 h with interleukin-1beta (IL-1beta; 10 ng/ml) or tumor necrosis factor-alpha (50 ng/ml), respectively, elicited maximal 25- and 6-fold inductions of PGE2 synthesis in CCD-18Co cultures and similar results in primary fibroblast cultures; maximal inductions with IL-1beta in colonic epithelial cell lines were from zero to fivefold. Treatment of CCD-18Co fibroblasts with IL-1beta caused maximal 21- and 53-fold increases, respectively, in PGHS-2 protein and mRNA levels without altering PGHS-1 expression. PGE2 (0.1 micromol/l) elicited a dramatic shape change in selected fibroblasts. Colonic fibroblasts are potentially important as cytokine targets and a source of and target for colonic prostanoids in vivo.

  18. Tenocytes, pro-inflammatory cytokines and leukocytes: a relationship?

    PubMed Central

    Al-Sadi, Onays; Schulze-Tanzil, Gundula; Kohl, Benjamin; Lohan, Anke; Lemke, Marion; Ertel, Wolfgang; John, Thilo

    2011-01-01

    Summary Leukocyte derived pro-inflammatory mediators could be involved in tendon healing and scar formation. Hence, the effect of autologous leukocytes (PBMCs, peripheral blood mononuclear cells and neutrophils) on primary rabbit Achilles tenocytes gene expression was tested in insert assisted co-cultures. Subsequently, tenocytes gene expression of extra-cellular matrix (ECM) components (type I collagen, decorin, fibronectin), the cell-ECM receptor β1-integrin, the angiogenic factor myodulin, ECM degrading matrix-metalloproteinase (MMP)1 and pro-inflammatory cytokines (interleukin [IL]-1β, tumour necrosis factor [TNFα] and IL-6) was analysed. The only significant effect of leukocytes on tenocytes ECM genes expression was a suppression of type I collagen by neutrophils combined with TNFα stimulation. The same effect could be observed analysing the β1-integrin and myodulin gene expression. However, PBMCs up-regulated significantly cytokine and MMP1 gene expression in tenocytes. These in vitro results suggest that mononuclear cells could present an exogenic stimulus for the induction of pro-inflammatory and catabolic mediators in tendon. PMID:23738251

  19. Flavonoids as Cytokine Modulators: A Possible Therapy for Inflammation-Related Diseases

    PubMed Central

    Leyva-López, Nayely; Gutierrez-Grijalva, Erick P.; Ambriz-Perez, Dulce L.; Heredia, J. Basilio

    2016-01-01

    High levels of cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6, are associated with chronic diseases like rheumatoid arthritis, asthma, atherosclerosis, Alzheimer’s disease and cancer; therefore cytokine inhibition might be an important target for the treatment of these diseases. Most drugs used to alleviate some inflammation-related symptoms act by inhibiting cyclooxygenases activity or by blocking cytokine receptors. Nevertheless, these drugs have secondary effects when used on a long-term basis. It has been mentioned that flavonoids, namely quercetin, apigenin and luteolin, reduce cytokine expression and secretion. In this regard, flavonoids may have therapeutical potential in the treatment of inflammation-related diseases as cytokine modulators. This review is focused on current research about the effect of flavonoids on cytokine modulation and the description of the way these compounds exert their effect. PMID:27294919

  20. Cytokine Synergy: an underappreciated contributor to innate anti-viral immunity

    PubMed Central

    Bartee, Eric; McFadden, Grant

    2013-01-01

    Inflammatory cytokines, such as tumor necrosis factor and the members of the interferon family, are potent mediators of the innate anti-viral immune response. The intracellular anti-viral states resulting from treatment of cultured cells with each of these molecules independently has been well studied; but, within complex tissues, the early inflammatory response is likely mediated by simultaneously expressed mixures of these, and other, protective anti-viral cytokines. Such cytokine mixtures have been shown to induce potently synergistic anti-viral responses in vitro which are more complex than the simple summation of the individual cytokine response profiles. The physiological role of this ‘cytokine synergy’, however, remains largely unappreciated in vivo. This brief commentary will attempt to summarize the potential effects and mechanisms of anti-viral cytokine synergy as well as present several ‘real-world’ applications where this phenomenon might play an important role. PMID:23693158

  1. Suppression of Proinflammatory Cytokines in Functionalized Fullerene-Exposed Dermal Keratinocytes

    DOE PAGES

    Gao, Jun; Wang, Hsing-Lin; Iyer, Rashi

    2010-01-01

    Initial experiments using differentially functionalized fullerenes, CD-, hexa-, and tris-, suggested a properties dependent effect on cytotoxic and proliferative responses in human skin keratinocytes. In the present study we investigated the cytokine secretion profile of dermal epithelial cells exposed to functionalized fullerenes. Keratinocyte-derived cytokines affect homing and trafficking of normal and malignant epidermal immune as well as nonimmune cells in vivo. These cytokines are critical for regulating activation, proliferation, and differentiation of epidermal cells. Our results indicate that tris- (size range <100 nm) significantly reduces inflammatory cytokine release in a dose- and time-dependent manner. In contrast CD- demonstrated a relatively pro-inflammatorymore » cytokine response, while hexa- did not significantly perturb cytokine responses. Physical and chemical characterizations of these engineered nanomaterials suggest that the disparate biological responses observed may potentially be a function of the aggregation properties of these fullerenes.« less

  2. Cytokine production and dysregulation in HIV pathogenesis: lessons for development of therapeutics and vaccines.

    PubMed

    Reuter, Morgan A; Pombo, Carolina; Betts, Michael R

    2012-01-01

    Numerous studies have characterized the cytokine modulation observed in human immunodeficiency virus (HIV) infected individuals, from initial infection through chronic disease. Progressive and non-progressive HIV infection models show the cytokine milieu differs in terms of production and responsiveness in these two groups, suggesting an understanding of the role cytokines play during infection is necessary for directing the immune response toward viral control. This review will cover cytokine induction and dysfunction during HIV pathogenesis, with a focus on the interplay between cytokines and transcription factors, T cell activation, and exhaustion. We highlight cytokines that have either vaccine adjuvant or therapeutic potential and discuss the need to identify key factors required for prevention of progression, clearance of infection, or protection from acquisition.

  3. The Role of Osteoblast-Derived Cytokines in Bone Metastatic Breast Cancer

    DTIC Science & Technology

    2009-01-01

    osteoblasts no longer produce non-collagenous bone matrix proteins. The focus of this project was to determine how osteoblast-derived cytokine production ...PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Karen M. Bussard 5e. TASK NUMBER E-Mail: kmb337@psu.edu 5f. WORK UNIT NUMBER 7...cytokines influence BC metastases to bone. Goals include investigating the production of OB-derived cytokines in response to BC cells or their

  4. Taxonomic applicability of inflammatory cytokines in adverse outcome pathway (AOP) development.

    PubMed

    Angrish, Michelle M; Pleil, Joachim D; Stiegel, Matthew A; Madden, Michael C; Moser, Virginia C; Herr, David W

    2016-01-01

    Cytokines, low-molecular-weight messenger proteins that act as intercellular immunomodulatory signals, have become a mainstream preclinical marker for assessing the systemic inflammatory response to external stressors. The challenge is to quantitate from healthy subjects cytokine levels that are below or at baseline and relate those dynamic and complex cytokine signatures of exposures with the inflammatory and repair pathways. Thus, highly sensitive, specific, and precise analytical and statistical methods are critically important. Investigators at the U.S. Environmental Protection Agency (EPA) have implemented advanced technologies and developed statistics for evaluating panels of inflammatory cytokines in human blood, exhaled breath condensate, urine samples, and murine biological media. Advanced multiplex, bead-based, and automated analytical platforms provided sufficient sensitivity, precision, and accuracy over the traditional enzyme-linked immunosorbent assay (ELISA). Thus, baseline cytokine levels can be quantified from healthy human subjects and animals and compared to an in vivo exposure response from an environmental chemical. Specifically, patterns of cytokine responses in humans exposed to environmental levels of ozone and diesel exhaust, and in rodents exposed to selected pesticides (such as fipronil and carbaryl), were used as case studies to generally assess the taxonomic applicability of cytokine responses. The findings in this study may aid in the application of measureable cytokine markers in future adverse outcome pathway (AOP)-based toxicity testing. Data from human and animal studies were coalesced and the possibility of using cytokines as key events (KE) to bridge species responses to external stressors in an AOP-based framework was explored.

  5. [Role of cytokines and their blocking in immune-mediated inflammatory diseases].

    PubMed

    Matikainen, Sampsa; Jokiranta, Sakari; Eklund, Kari K

    2016-01-01

    Rheumatoid arthritis, inflammatory bowel diseases and psoriasis are examples of immune-mediated inflammatory diseases. They involve activation of a partly similar cytokine network that has an essential role in the disease pathogenesis. Biological drugs have been developed for the inhibition of single cytokines, and good therapeutic responses have been achieved by using them. For instance, TNF blockers are used in the treatment of several inflammatory diseases. The use of the blockers of certain other cytokines is more limited. Other important target molecules include certain interleukins. New bispecific antibodies enabling inhibition of the action of two distinct cytokines are currently undergoing clinical studies.

  6. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases.

    PubMed

    Raphael, Itay; Nalawade, Saisha; Eagar, Todd N; Forsthuber, Thomas G

    2015-07-01

    CD4(+) T helper (Th) cells are critical for proper immune cell homeostasis and host defense, but are also major contributors to pathology of autoimmune and inflammatory diseases. Since the discovery of the Th1/Th2 dichotomy, many additional Th subsets were discovered, each with a unique cytokine profile, functional properties, and presumed role in autoimmune tissue pathology. This includes Th1, Th2, Th17, Th22, Th9, and Treg cells which are characterized by specific cytokine profiles. Cytokines produced by these Th subsets play a critical role in immune cell differentiation, effector subset commitment, and in directing the effector response. Cytokines are often categorized into proinflammatory and anti-inflammatory cytokines and linked to Th subsets expressing them. This article reviews the different Th subsets in terms of cytokine profiles, how these cytokines influence and shape the immune response, and their relative roles in promoting pathology in autoimmune and inflammatory diseases. Furthermore, we will discuss whether Th cell pathogenicity can be defined solely based on their cytokine profiles and whether rigid definition of a Th cell subset by its cytokine profile is helpful.

  7. Buffering Capacity and Size of siRNA Polyplexes Influence Cytokine Levels

    PubMed Central

    Leng, Qixin; Chou, Szu-Ting; Scaria, Puthupparampil V; Woodle, Martin C; Mixson, A James

    2012-01-01

    Induction of cytokines by small interfering RNA (siRNA) polyplexes has been a significant concern of researchers attempting to minimize the toxicity of this promising therapy. Although cationic carriers of siRNA are known to increase cytokine levels, few systematic studies have been done to determine what properties of the carrier are important to modulate cytokines. Because branched histidine-lysine (HK) peptides are effective carriers of siRNA and their sequence can be readily modified, we selected this class of carrier to determine which sequences of the peptide were important for cytokine induction. With the use of peripheral blood mononuclear cells (PBMCs), the HK peptide with a higher number of histidines (H3K(+H)4b) in complex with siRNA induced lower levels of cytokines compared with other HK (e.g., H2K4b, H3K4b, H3K(+N)4b) siRNA nanoplexes. Notably, these peptides' siRNA polyplexes showed a similar pattern of cytokine induction when injected intravenously in a mouse model, i.e., the HK with higher content of histidines induced cytokines the least. As indicated by the pH-sensitive dye within acidic endosomes, the greater pH-buffering capacity of H3K(+H)4b compared with other HK peptides may explain why cytokine levels were reduced. In addition to buffering capacity, the size of HK polyplexes markedly influenced cytokine production. PMID:23032972

  8. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness?

    PubMed

    Jeon, Sang Won; Kim, Yong Ku

    2016-09-22

    Depression results from changes in the central nervous system (CNS) that may result from immunological abnormalities. The immune system affects the CNS through cytokines, which regulate brain activities and emotions. Cytokines affect two biological systems that are most associated with the pathophysiology of depression: The hypothalamic-pituitary-adrenal axis and the catecholamine/sympathetic nervous system. Neuroinflammation and cytokines affect the brain signal patterns involved in the psychopathology of depression and the mechanisms of antidepressants, and they are associated with neurogenesis and neural plasticity. These observations suggest that neuroinflammation and cytokines might cause and/or maintain depression, and that they might be useful in the diagnosis and prognosis of depression. This psychoneuroimmunologic perspective might compensate for some of the limitations of the monoamine theory by suggesting that depression is a result of a failure to adapt to stress and that inflammatory responses and cytokines are involved in this process. In this review, the interactions of cytokines with the CNS, neuroendocrine system, neurotransmitters, neurodegeneration/neurogenesis, and antidepressants are discussed. The roles of cytokines in the etiology and psychopathology of depression are examined. The use of cytokine inhibitors or anti-inflammatory drugs in depression treatment is explored. Finally, the significance and limitations of the cytokine hypothesis are discussed.

  9. Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology.

    PubMed

    Hermanns, Heike M

    2015-10-01

    Oncostatin M (OSM) and interleukin-31 (IL-31) are two cytokines belonging to the IL-6 family which share a common signaling receptor subunit, the OSM receptor beta (OSMRβ). Both of them are released by monocytes/macrophages, dendritic cells and T lymphocytes in inflammatory situations and upon binding to their respective receptor complexes they signal mainly via the JAK/STAT pathway. Besides sharing many biochemical properties, both display divergent physiological functions. This review summarizes aspects of cytokine transcription and biosynthesis, cytokine-receptor interactions, cross-species activities, signal transduction and physiology delineated from recent findings in genetic mouse models for both cytokines, OSM and IL-31.

  10. Fetal exposure to chlordane and permethrin mixtures in relation to inflammatory cytokines and birth outcomes

    PubMed Central

    Neta, Gila; Goldman, Lynn R.; Barr, Dana; Apelberg, Benjamin J.; Witter, Frank R.; Halden, Rolf U.

    2011-01-01

    We sought to characterize the relationships between cord serum concentrations of chlordane and permethrin pesticides, inflammatory cytokines, gestational age, and size at birth. Umbilical cord serum levels of trans-nonachlor, oxychlordane, cis- and trans-permethrin, piperonyl butoxide, and cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, GMCSF), were quantified in 300 newborns at the Johns Hopkins Hospital in Baltimore, MD (2004–2005). Principal component analyses were used to quantitate chlordane and permethrin mixtures, and to identify independent cytokine components. Five cytokine components described 87% of the variance in cord serum cytokine levels; these (and predominant loadings) were: (1) all 9 cytokines; (2) acute phase (IL-1β, IL-6); (3) anti-inflammatory (IL-10) (4) TNF-α; and (5) IL-1β. Of these, the TNF-α component was significantly associated with a 2-day decrease in gestational age. Chlordane was associated with lower levels of the pro-inflammatory IL-1β [β: −0.11 (−0.20, −0.02)]. Permethrin was negatively associated with the anti-inflammatory cytokine IL-10 [β: −0.14 (−0.22, −0.05)]. Neither pesticides nor cytokines were significantly associated with birthweight, length or head circumference, and pesticides were not associated with gestational age. Our findings suggest that chlordane and permethrin concentrations in cord blood may be associated with levels of inflammatory cytokines in the fetus. PMID:21235202

  11. Impact of Exogenous Gonadotropin Stimulation on Circulatory and Follicular Fluid Cytokine Profiles

    PubMed Central

    Baskind, N. Ellissa; Orsi, Nicolas M.; Sharma, Vinay

    2014-01-01

    Background. The natural cycle is the prototype to which we aspire to emulate in assisted reproduction techniques. Increasing evidence is emerging that controlled ovarian hyperstimulation (COH) with exogenous gonadotropins may be detrimental to oogenesis, embryo quality, and endometrial receptivity. This research aimed at assessing the impact of COH on the intrafollicular milieu by comparing follicular fluid (FF) cytokine profiles during stimulated in vitro fertilization (IVF) and modified natural cycle (MNC) IVF. Methods. Ten women undergoing COH IVF and 10 matched women undergoing MNC IVF were recruited for this pilot study. 40 FF cytokine concentrations from individual follicles and plasma were measured by fluid-phase multiplex immunoassay. Demographic/cycle/cytokine data were compared and correlations between cytokines were computed. Results. No significant differences were found between COH and MNC groups for patient and cycle demographics, including outcome. Overall mean FF cytokine levels were higher in the MNC group for 29/40 cytokines, significantly so for leukaemia inhibitory factor and stromal cell-derived factor-1α. Furthermore, FF MNC cytokine correlations were significantly stronger than for COH data. Conclusions. These findings suggest that COH perturbs intrafollicular cytokine networks, in terms of both cytokine levels and their interrelationships. This may impact oocyte maturation/fertilization and embryo developmental competence. PMID:25763393

  12. Cytokine assays: an assessment of the preparation and treatment of blood and tissue samples.

    PubMed

    Keustermans, Genoveva C E; Hoeks, Sanne B E; Meerding, Jenny M; Prakken, Berent J; de Jager, Wilco

    2013-05-15

    Cytokines are key components of the innate and adaptive immune system. As pivotal players in the progression or regression of a pathological process, these molecules provide a window through which diseases can be monitored and can thus act as biomarkers. In order to measure cytokine levels, a plethora of protocols can be applied. These methods include bioassays, protein microarrays, high-performance liquid chromatography (HPLC), sandwich enzyme-linked immunosorbent assay (ELISA), Meso Scale Discovery (MSD) electrochemiluminescence and bead based multiplex immunoassays (MIA). Due to the interaction and activity of cytokines, multiplex immunoassays are at the forefront of cytokine analysis by allowing multiple cytokines to be measured in parallel. However, even with optimized protocols, sample standardization needs to occur before these proteins can optimally act as biomarkers. This review describes various factors influencing the levels of cytokines measured in plasma, serum, dried blood spots and tissue biopsies, focusing on sample collection and handling, long term storage and the repetitive use of samples. By analyzing how each of these factors influences protein levels, it is concluded that samples should be stored at low temperatures in order to maintain cytokine stability. In addition, within a study, sample manipulations should be kept the same, with measurement protocols being chosen for their compatibility with the research in question. By having a clear understanding of what factors influence cytokine levels and how to overcome these technical issues, minimally confounded data can be obtained and cytokines can achieve optimal biomarker activity.

  13. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness?

    PubMed Central

    Jeon, Sang Won; Kim, Yong Ku

    2016-01-01

    Depression results from changes in the central nervous system (CNS) that may result from immunological abnormalities. The immune system affects the CNS through cytokines, which regulate brain activities and emotions. Cytokines affect two biological systems that are most associated with the pathophysiology of depression: The hypothalamic-pituitary-adrenal axis and the catecholamine/sympathetic nervous system. Neuroinflammation and cytokines affect the brain signal patterns involved in the psychopathology of depression and the mechanisms of antidepressants, and they are associated with neurogenesis and neural plasticity. These observations suggest that neuroinflammation and cytokines might cause and/or maintain depression, and that they might be useful in the diagnosis and prognosis of depression. This psychoneuroimmunologic perspective might compensate for some of the limitations of the monoamine theory by suggesting that depression is a result of a failure to adapt to stress and that inflammatory responses and cytokines are involved in this process. In this review, the interactions of cytokines with the CNS, neuroendocrine system, neurotransmitters, neurodegeneration/neurogenesis, and antidepressants are discussed. The roles of cytokines in the etiology and psychopathology of depression are examined. The use of cytokine inhibitors or anti-inflammatory drugs in depression treatment is explored. Finally, the significance and limitations of the cytokine hypothesis are discussed. PMID:27679767

  14. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases.

    PubMed Central

    Lucey, D R; Clerici, M; Shearer, G M

    1996-01-01

    In the mid-1980s, Mosmann, Coffman, and their colleagues discovered that murine CD4+ helper T-cell clones could be distinguished by the cytokines they synthesized. The isolation of human Th1 and Th2 clones by Romagnani and coworkers in the early 1990s has led to a large number of reports on the effects of Th1 and Th2 on the human immune system. More recently, cells other than CD4+ T cells, including CD8+ T cells, monocytes, NK cells, B cells, eosinophils, mast cells, basophils, and other cells, have been shown to be capable of producing "Th1" and "Th2" cytokines. In this review, we examine the literature on human diseases, using the nomenclature of type 1 (Th1-like) and type 2 (Th2-like) cytokines, which includes all cell types producing these cytokines rather than only CD4+ T cells. Type 1 cytokines include interleukin-2 (IL-2), gamma interferon, IL-12 and tumor necrosis factor beta, while type 2 cytokines include IL-4, IL-5, IL-6, IL-10, and IL-13. In general, type 1 cytokines favor the development of a strong cellular immune response whereas type 2 cytokines favor a strong humoral immune response. Some of these type 1 and type 2 cytokines are cross-regulatory. For example, gamma interferon and IL-12 decrease the levels of type 2 cytokines whereas IL-4 and IL-10 decrease the levels of type 1 cytokines. We use this cytokine perspective to examine human diseases including infections due to viruses, bacteria, parasites, and fungi, as well as selected neoplastic, atopic, rheumatologic, autoimmune, and idiopathic-inflammatory conditions. Clinically, type 1 cytokine-predominant responses should be suspected in any delayed-type hypersensitivity-like granulomatous reactions and in infections with intracellular pathogens, whereas conditions involving hypergammaglobulinemia, increased immunoglobulin E levels, and/or eosinophilia are suggestive of type 2 cytokine-predominant conditions. If this immunologic concept is relevant to human diseases, the potential exists for

  15. Nasal cytokine responses to natural colds in asthmatic children

    PubMed Central

    Lewis, Toby C.; Henderson, Tiffany A.; Carpenter, Ashley R.; Ramirez, Ixsy A.; McHenry, Christina L.; Goldsmith, Adam M.; Ren, Xiaodan; Mentz, Graciela B.; Mukherjee, Bhramar; Robins, Thomas G.; Joiner, Terence A.; Mohammad, Layla S.; Nguyen, Emily R.; Burns, Mark A.; Burke, David T.; Hershenson, Marc B.

    2014-01-01

    Background The mechanisms by which viruses induce asthma exacerbations are not well-understood. Objective We characterized fluctuations in nasal aspirate cytokines during naturally-occurring respiratory viral infections in children with asthma. Methods Sixteen children underwent home collections of nasal aspirates when they were without cold symptoms and again during self-reported respiratory illnesses. The presence of viral infection was ascertained by multiplex PCR. Cytokines were measured by multiplex immune assay. mRNA expression for selected markers of viral infection was measured by RT-PCR. A cumulative respiratory symptom score was calculated for each day of measurement. Generalized estimated equations were used to evaluate associations between viral infection and marker elevation, and between marker elevation and symptom score. Results The 16 patients completed a total of 37 weeks of assessment (15 “well” weeks; 22 self-assessed “sick” weeks). Viral infections were detected in three of the “well” weeks and 17 of the “sick” weeks (10 rhinovirus, 3 coronavirus, 2 influenza A, 2 influenza B, 2 respiratory syncytial virus, 1 parainfluenza). Compared to virus-negative well weeks, nasal aspirate IFN-γ, CXCL8/IL-8, CXCL10/IP-10, CCL5/RANTES, CCL11/eotaxin-1, CCL2/MCP-1, CCL4/MIP-1β, CCL7/MCP-3 and CCL20/MIP3α protein levels increased during virus-positive sick weeks. Only a subset of cytokines (IFN-γ, CXCL8, CCL2, CCL4, CCL5 and CCL20) correlated with self-reported respiratory tract symptoms. While many aspirates were dilute and showed no mRNA signal, viral infection significantly increased the number of samples that were positive for IFN-λ1, IFN-λ2/3, TLR3, RIG-I and IRF7 mRNA. Conclusions & Clinical Relevance We conclude that, in children with asthma, naturally-occurring viral infections apparently induce a robust innate immune response including expression of specific chemokines, IFNs and IFN-responsive genes. PMID:23181789

  16. Lipopolysaccharide-induced lethality and cytokine production in aged mice.

    PubMed Central

    Tateda, K; Matsumoto, T; Miyazaki, S; Yamaguchi, K

    1996-01-01

    This study was designed to define the lipopolysaccharide (LPS) sensitivity of aged mice in terms of lethality and cytokine production and to determine down-regulating responses of corticosterone and interleukin 10 (IL-10). The 50% lethal doses of LPS in young (6- to 7-week-old) and aged (98- to 102-week-old) mice were 601 and 93 microg per mouse (25.6 and 1.6 mg per kg of body weight), respectively. Aged mice were approximately 6.5-fold more sensitive to the lethal toxicity of LPS in micrograms per mouse (16-fold more sensitive in milligrams per kilogram) than young mice. Levels in sera of tumor necrosis factor-alpha (TNF-alpha) IL-1alpha, and IL-6 after intraperitoneal injection of 100 microg of LPS peaked at 1.5, 3, and 3 h, respectively, and declined thereafter in both groups of mice. However, the peak values of these cytokines were significantly higher in aged than in young mice (P < 0.05). Gamma interferon (IFN-gamma) was detectable at 3 h, and sustained high levels were still detected after 12 h in both age groups. Although there were no significant differences in levels of IFN-gamma in sera from both groups, aged mice showed higher IFN-gamma levels throughout the 3- to 12-h study period. Administration of increasing doses of LPS revealed that aged mice had a lower threshold to IL-1alpha production than young mice. In addition, aged mice were approximately 4-fold more sensitive to the lethal toxicity of exogenous TNF in units per mouse (10-fold more sensitive in units per kilogram) than young mice. With regard to down-regulating factors, corticosterone amounts were similar at basal levels and no differences in kinetics after the LPS challenge were observed, whereas IL-10 levels in sera were significantly higher in aged mice at 1.5 and 3 h than in young mice (P < 0.01). These results indicate that aged mice are more sensitive to the lethal toxicities of LPS and TNF than young mice. We conclude that a relatively activated, or primed, state for LPS

  17. [Antistaphylococcal activity of the complex of natural cytokines].

    PubMed

    Koval'chuk, L V; Gankovskaia, L V; Moroz, A F; Avedova, T A; Ukhina, T V

    2004-01-01

    The in vitro study of the action of the complex of natural cytokines (CNC), or preparation Superlymph, on different microbial test strains (Staphylococcus aureus, Escherichia coli, yeast-like fungi of the genus Candida) was carried out. CNC suppressed the growth of S. aureus test culture, depending on the concentration of the preparation. The inhibiting effect was observed in the presence of Ca and Mg bivalent cations in the medium. Under the chosen conditions of the experiment CNC did not inhibit the growth of E. coli test cultures, as well as test cultures of yeast-like fungi of the genus Candida. In addition to its antibacterial effect, Superlymph also produced some effect on the release of cathepsin G, the lysosomal enzyme of human leukocyte granules.

  18. IL-1 family cytokines trigger sterile inflammatory disease

    PubMed Central

    Lukens, John R.; Gross, Jordan M.; Kanneganti, Thirumala-Devi

    2012-01-01

    Inflammation plays vital roles in protective responses against pathogens and tissue repair, however, improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases. Extensive advances have been made in recent years to define the inflammatory processes that are required for pathogen clearance, however, in comparison, less is known about the regulation of inflammation in sterile settings. Over the past decade non-communicable chronic diseases that are potentiated by sterile inflammation have replaced infectious diseases as the major threat to global human health. Thus, improved understanding of the sterile inflammatory process has emerged as one of the most important areas of biomedical investigation during our time. In this review we highlight the central role that interleukin-1 family cytokines play in sterile inflammatory diseases. PMID:23087690

  19. Immunomodulatory properties of mesenchymal stem cells: cytokines and factors.

    PubMed

    Soleymaninejadian, Ehsan; Pramanik, Krishna; Samadian, Esmaeil

    2012-01-01

    Mesenchymal stem cells (MSCs) are defined as undifferentiated cells that are capable of self renewal and differentiation into several cell types such as chondrocyte, adipocyte, osteocyte, myocyte, hepatocyte, and neuron-like cells. MSC can be isolated from bone marrow, umbilical cord blood, adipose tissue, placenta, periosteum, trabecular bone, synovium, skeletal muscle, and deciduous teeth. Immunomodulatory of MSCs is one of the important issues nowadays, because this aspect can be clinically applied for graft-versus-host and autoimmune diseases. In this review, we tried to discuss in detail about cytokines and factors such as members of the transforming growth factor superfamily (transforming growth factor-β), hepatic growth factors (HGF), prostaglandin E2 (PGE2), IL-10, indolamine 2,3-dioxygenase (IDO), nitric oxide (NO), heme oxygenase-1 (HO-1), and human leukocyte antigen-G (HLA-G) that are involved in immunomodulatory of MSCs.

  20. Cytokines and effector T cell subsets causing autoimmune CNS disease.

    PubMed

    Petermann, Franziska; Korn, Thomas

    2011-12-01

    Although experimental autoimmune encephalomyelitis (EAE) is limited in its potency to reproduce the entirety of clinical and histopathologic features of multiple sclerosis (MS), this model has been successfully used to prove that MS like autoimmunity in the CNS is orchestrated by autoantigen specific T cells. EAE was also very useful to refute the idea that IFN-γ producing T helper type 1 (Th1) cells were the sole players within the pathogenic T cell response. Rather, "new" T cell lineages such as IL-17 producing Th17 cells or IL-9 producing Th9 cells have been first discovered in the context of EAE. Here, we will summarize new concepts of early and late T cell plasticity and the cytokine network that shapes T helper cell responses and lesion development in CNS specific autoimmunity.

  1. Cytokine gene-mediated immunotherapy: current status and future perspectives.

    PubMed

    Jinushi, Masahisa; Tahara, Hideaki

    2009-08-01

    Recent understanding of the molecular events crucial in overcoming immunosuppressive tumor microenvironments and generating effective antitumor immunity provides us with the wreath opportunity to manipulate genes that have a key role in antitumor immune responses. Granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-12 (IL-12) are two indispensable cytokines for activating dendritic cells and boosting the strong immune responses against cancer. In this review, we describe the antitumor mechanisms and clinical application of gene-modified tumor cells and dendritic cells to secrete GM-CSF or IL-12, respectively, in various preclinical and clinical settings. The principles operative in these vaccination strategies may prove applicable to other immunotherapy strategies, especially in combination with other therapeutic modalities, such as chemotherapy and targeted therapy.

  2. Pyoderma gangrenosum with increased levels of serum cytokines.

    PubMed

    Kozono, Kana; Nakahara, Takeshi; Kikuchi, Satoko; Itoh, Eriko; Kido-Nakahara, Makiko; Furue, Masutaka

    2015-12-01

    A 66-year-old woman presented after an episode of accidental trauma with a painful ulcer on her scalp which rapidly enlarged in size, accompanied by central necrosis and undermining ulceration. The patient's past history was negative for underlying systemic disease, although she had had a similar post-traumatic intractable leg ulcer 3 years prior, which was unresponsive to surgical management but successfully treated with systemic steroids. A biopsied specimen from the scalp showed marked neutrophilic infiltrates in the dermis, compatible with a diagnosis of pyoderma gangrenosum (PG). The large ulcerative lesion responded very well to oral steroid therapy, showing rapid epithelialization. Serum levels of granulocyte colony-stimulating factor and interleukin-6 were significantly elevated prior to treatment, with decrease to normal levels after treatment. Serum tumor necrosis factor (TNF)-α and granulocyte macrophage colony-stimulating factor levels were within normal limits. The significance and pathogenic role of cytokine burst in PG is reviewed and discussed.

  3. Cytokine levels affected by gamma-linolenic acid.

    PubMed

    Dirks, J; van Aswegen, C H; du Plessis, D J

    1998-10-01

    This study was undertaken to assess whether gamma-linolenic acid (GLA) in the form of evening primrose oil (EPO) could affect rat serum cytokines, interferon-gamma (IFN-gamma), monocyte chemotactic protein-1 (MCP-1) and tumour necrosis factor-alpha (TNF-alpha). The following diets were administered: control, glucan, Freund's adjuvant and glucan plus Freund's adjuvant with and without GLA. In the presence of GLA, the IFN-gamma and MCP-1 levels were significantly decreased in contrast to the control group of TNF-alpha, which was significantly stimulated. On account of interaction between diets and GLA, the remaining diet groups of TNF-alpha were either not affected or were inhibited in the presence of GLA. The observations indicate that GLA may modulate the level of serum IFN-gamma, MCP-1 and TNF-alpha, which may be a worthwhile line of treatment in certain human diseases.

  4. Viral mimicry of cytokines, chemokines and their receptors.

    PubMed

    Alcami, Antonio

    2003-01-01

    Viruses have evolved elegant mechanisms to evade detection and destruction by the host immune system. One of the evasion strategies that have been adopted by large DNA viruses is to encode homologues of cytokines, chemokines and their receptors--molecules that have a crucial role in control of the immune response. Viruses have captured host genes or evolved genes to target specific immune pathways, and so viral genomes can be regarded as repositories of important information about immune processes, offering us a viral view of the host immune system. The study of viral immunomodulatory proteins might help us to uncover new human genes that control immunity, and their characterization will increase our understanding of not only viral pathogenesis, but also normal immune mechanisms. Moreover, viral proteins indicate strategies of immune modulation that might have therapeutic potential.

  5. Cytokines: Roles in atherosclerosis disease progression and potential therapeutic targets

    PubMed Central

    Moss, Joe W. E.; Ramji, Dipak P.

    2017-01-01

    Atherosclerosis, the primary cause of cardiovascular disease (CVD), is a chronic inflammatory disorder in the walls of medium and large arteries. CVD is currently responsible for about one in three global deaths and this is expected to rise in the future due to an increase in the prevalence of obesity and diabetes. Current therapies for atherosclerosis mainly modulate lipid homeostasis and whilst successful at reducing the risk of a CVD-related death, they are associated with considerable residual risk and various side effects. There is therefore a need for alternative therapies aimed at regulating inflammation in order to reduce atherogenesis. This review will highlight the key role cytokines play during disease progression as well as potential therapeutic strategies to target them. PMID:27357616

  6. Cytokine treatment of macrophage suppression of T cell activation.

    PubMed

    Silberman, Daniel; Bucknum, Amanda; Kozlowski, Megan; Matlack, Robin; Riggs, James

    2010-01-01

    High Mphi:T cell ratios suppress the immune response to the retroviral superantigen Mls by IFNgamma-triggered production of the arg- and trp-consuming enzymes iNOS and IDO. Attempts to reverse suppression by treatment with pro-inflammatory cytokines revealed that IL-6 improved the T cell response to Mls and the pro-hematopoietic cyokines IL-3 and GM-CSF increased suppression. GM-CSF treatment increased Mphi expression of CD80, a ligand for the immune suppressive B7H1 and CTLA-4 receptors. These results illustrate potential strategies for reversing the suppression of cell-mediated immunity characteristic of the high Mphi:T cell ratios found in many tumors.

  7. CP-115,953 stimulates cytokine production by lymphocytes.

    PubMed Central

    Riesbeck, K; Forsgren, A

    1995-01-01

    The cytotoxic quinolone CP-115,953 specifically exerts its inhibitory effect upon eukaryotic topoisomerase II. CP-115,953 stimulates DNA cleavage mediated by topoisomerase II with a potency approximately 600 times greater than that of ciprofloxacin, a quinolone antibacterial agent that currently is in clinical use. Because ciprofloxacin has been reported to strongly enhance interleukin-2 production, we considered it important to study the effect of CP-115,953 on interleukin-2 and gamma interferon (IFN-gamma) mRNA and protein expression in mitogen-stimulated human peripheral blood lymphocytes. For comparison, novobiocin and the antineoplastic drug etoposide were also included in the study. CP-115,953 (25 microM) enhanced interleukin-2 mRNA levels up to 8-fold and IFN-gamma mRNA concentrations up to 6.5-fold. In contrast, ciprofloxacin (282 microM) induced mRNAs for interleukin-2 and IFN-gamma up to 20-fold and 7.8-fold, respectively. However, CP-115,953 showed more prolonged kinetics of IFN-gamma mRNA production than ciprofloxacin. At high concentrations (> or = 141 microM), ciprofloxacin was a greater inducer of interleukin-2 production and exhibited a higher level of stimulatory action than CP-115,953 on IFN-gamma synthesis. At low concentrations, however, CP-115,953 (< or = 25 microM) was more potent than ciprofloxacin in inducing interleukin-2 and IFN-gamma synthesis. Etoposide or novobiocin did not influence cytokine mRNA expression. Thus, among the topoisomerase II inhibitors tested, fluoroquinolones are unique in stimulating cytokine synthesis in lymphocyte cultures. PMID:7726518

  8. Alveolar macrophage cytokine response to air pollution particles: Oxidant mechanisms

    SciTech Connect

    Imrich, Amy; Ning Yaoyu; Lawrence, Joy; Coull, Brent; Gitin, Elena; Knutson, Mitchell; Kobzik, Lester . E-mail: lkobzik@hsph.harvard.edu

    2007-02-01

    Alveolar macrophages (AMs) primed with LPS and treated with concentrated ambient air particles (CAPs) showed enhanced release of tumor necrosis factor (TNF) and provide an in vitro model for the amplified effects of air pollution particles seen in people with preexisting lung disease. To investigate the mechanism(s) by which CAPs mediate TNF release in primed rat AMs, we first tested the effect of a panel of antioxidants. N-Acetyl-L-cysteine (20 mM), dimethyl thiourea (20 mM) and catalase (5 {mu}M) significantly inhibited TNF release by primed AMs incubated with CAPs. Conversely, when LPS-primed AMs were treated with CAPs in the presence of exogenous oxidants (H{sub 2}O{sub 2} generated by glucose oxidase, 10 {mu}M/h), TNF release and cell toxicity was significantly increased. The soluble fraction of CAPs suspensions caused most of the increased bioactivity in the presence of exogenous H{sub 2}O{sub 2}. The metal chelator deferoxamine (DFO) strongly inhibited the interaction of the soluble fraction with H{sub 2}O{sub 2} but had no effect on the bioactivity of the insoluble CAPs fraction. We conclude that CAPs can mediate their effects in primed AMs by acting on oxidant-sensitive cytokine release in at least two distinct ways. In the primed cell, insoluble components of PM mediate enhanced TNF production that is H{sub 2}O{sub 2}-dependent (catalase-sensitive) yet independent of iron (DFO-insensitive). In the presence of exogenous H{sub 2}O{sub 2} released by AMs, PMNs, or other lung cells within an inflamed alveolar milieu, soluble iron released from air particles can also mediate cytokine release and cell toxicity.

  9. The Role of Proinflammatory Cytokine Interleukin-18 in Radiation Injury

    PubMed Central

    Xiao, Mang

    2016-01-01

    Abstract Massive radiation-induced inflammatory factors released from injured cells may cause innate and acquired immune reactions that can further result in stress response signal activity-induced local and systemic damage. IL‐1 family members IL‐1β, IL‐18, and IL‐33 play key roles in inflammatory and immune responses and have been recognized to have significant influences on the pathogenesis of diseases. IL‐1β, IL‐18, and IL‐33 share similarities of cytokine biology, but differences exist in signaling pathways. A key component of the inflammatory reaction is the inflammasome, which is a caspase‐1‐containing multiprotein oligomer. Pathological stimuli such as radiation can induce inflammasome and caspase‐1 activation, and subsequently cause maturation (activation) of pro-forms of IL‐1 and IL‐18 upon caspase‐1 cleavage. This caspase‐1 dependent and IL‐1 and IL‐18 associated cell damage is defined as pyroptosis. Activated IL‐1 and IL‐18 as proinflammatory cytokines drive pathology at different immune and inflammatory disorders through Toll-like receptor (TLR) signaling. While the mechanisms of IL‐1β-induced pathophysiology of diseases have been well studied, IL‐18 has received less attention. The author recently reported that gamma radiation highly increased IL‐1β, IL‐18 and IL‐33 expression in mouse thymus, spleen and/or bone marrow cells; also circulating IL‐18 can be used as a radiation biomarker to track radiation injury in mice, minipigs, and nonhuman primates. This mini-review focuses on the role of IL‐18 in response to gamma radiation-induced injury. PMID:27356067

  10. Urinary cytokines for assessing inflammation in HIV-associated wasting.

    PubMed

    Rivera, S; Sattler, F R; Boyd, H; Auffenberg, T; Nakao, S; Moldawer, L L

    2001-03-07

    The relationship between cytokines and HIV-related weight loss has not been well established. Unlike most cytokines that are secreted in a paracrine manner, IL-6, sTNFR-II, and IL-1ra are readily detected in the systemic circulation and serve as markers of the inflammatory response. Twenty-four-hour urine concentrations of these proteins are believed to provide an integrative assessment of their systemic levels over the preceding hours. We sought to determine whether spot measurements of IL-6, sTNFR-II, and IL-1ra could be related to subsequent 24 h concentrations and prior weight loss. Eighteen subjects with severe wasting (average BMI=18+/-3 kg/m2with 19+/-13 kg of weight loss) and six HIV-negative healthy subjects were tested. Compared to values in controls, 24-h urinary concentrations of the three proteins adjusted for creatinine excreted were elevated in 44%, 89%, and 72% of patients, respectively. Twenty-four-hour concentrations were highly correlated with the spot concentrations (r=0.80, 0.87, 0.84, respectively, P<0.001). IL-1ra concentrations (24 h and spot) were correlated with weight loss in the previous 6 months, lifetime rate of weight loss and the 6 month rate of weight loss (spot: r=0.66, 0.73, 0.68, respectively, P< or =0.001). These data suggest that spot urinary collections can be used to estimate 24 h excretion rates. This strategy may be useful in assessing the inflammatory response in HIV-associated wasting.

  11. Association between Prediagnostic Allergy-Related Serum Cytokines and Glioma.

    PubMed

    Schwartzbaum, Judith; Seweryn, Michal; Holloman, Christopher; Harris, Randall; Handelman, Samuel K; Rempala, Grzegorz A; Huang, Ruo-Pan; Burkholder, Brett; Brandemihl, Adam; Kallberg, Henrik; Johannesen, Tom Borge; Ahlbom, Anders; Feychting, Maria; Grimsrud, Tom K

    2015-01-01

    Allergy is inversely related to glioma risk. To determine whether prediagnostic allergy-related serum proteins are associated with glioma, we conducted a nested case-control study of seven cytokines (IL4, IL13, IL5, IL6, IL10, IFNG, TGFB2), two soluble cytokine receptors (sIL4RA, sIL13RA2) and three allergy-related transcription factors (FOXP3, STAT3, STAT6) using serum specimens from the Janus Serum Bank Cohort in Oslo, Norway. Blood donors subsequently diagnosed with glioma (n = 487) were matched to controls (n = 487) on age and date of blood draw and sex. We first estimated individual effects of the 12 serum proteins and then interactions between IL4 and IL13 and their receptors using conditional logistic regression. We next tested equality of case-control inter-correlations among the 12 serum proteins. We found that TGFB2 is inversely related to glioblastoma (Odds Ratio (OR) = 0.87, 95% Confidence Interval (CI)) = 0.76, 0.98). In addition, ≤ 5 years before diagnosis, we observed associations between IL4 (OR = 0.82, 95% CI = 0.66, 1.01), sIL4RA (OR = 0.80, 95% CI = 0.65, 1.00), their interaction (OR = 1.06, 95% CI = 1.01, 1.12) and glioblastoma. This interaction was apparent > 20 years before diagnosis (IL4-sIL4RA OR = 1.20, 95% CI = 1.05, 1.37). Findings for glioma were similar. Case correlations were different from control correlations stratified on time before diagnosis. Five years or less before diagnosis, correlations among case serum proteins were weaker than were those among controls. Our findings suggest that IL4 and sIL4RA reduce glioma risk long before diagnosis and early gliomagenesis affects circulating immune function proteins.

  12. Cytokines and Prognostic Factors in Epithelial Ovarian Cancer

    PubMed Central

    Jammal, Millena Prata; Martins-Filho, Agrimaldo; Silveira, Thales Parenti; Murta, Eddie Fernando Candido; Nomelini, Rosekeila Simões

    2016-01-01

    INTRODUCTION Ovarian cancer has a high mortality and delayed diagnosis. Inflammation is a risk factor for ovarian cancer, and the inflammatory response is involved in almost all stages of tumor development. Immunohistochemical staining in stroma and epithelium of a panel of cytokines in benign and malignant ovarian neoplasm was evaluated. In addition, immunostaining was related to prognostic factors in malignant tumors. METHOD The study group comprised 28 ovarian benign neoplasias and 28 ovarian malignant neoplasms. A panel of cytokines was evaluated by immunohistochemistry (Th1: IL-2 and IL-8; Th2: IL-5, IL-6, and IL-10; and TNFR1). Chi-square test with Yates’ correction was used, which was considered significant if less than 0.05. RESULTS TNFR1, IL-5, and IL-10 had more frequent immunostaining 2/3 in benign neoplasms compared with malignant tumors. Malignant tumors had more frequent immunostaining 2/3 for IL-2 in relation to benign tumors. The immunostaining 0/1 of IL 8 was more frequent in the stroma of benign neoplasms compared with malignant neoplasms. Evaluation of the ovarian cancer stroma showed that histological grade 3 was significantly correlated with staining 2/3 for IL-2 (P = 0.004). Women whose disease-free survival was less than 2.5 years had TNFR1 stromal staining 2/3 (P = 0.03) more frequently. CONCLUSION IL-2 and TNFR1 stromal immunostaining are related prognostic factors in ovarian cancer and can be the target of new therapeutic strategies. PMID:27512342

  13. Distinct Cytokine and Chemokine Profiles in Autism Spectrum Disorders

    PubMed Central

    Han, Yvonne M. Y.; Cheung, Winnie K. Y.; Wong, Chun Kwok; Sze, Sophia L.; Cheng, Timmy W. S.; Yeung, Michael K.; Chan, Agnes S.

    2017-01-01

    Previous studies have shown that immunological factors are involved in the pathogenesis of autism spectrum disorders (ASDs). However, this research has been conducted almost exclusively in Western contexts, and only a handful of studies on immune measures have been conducted in Asian populations, such as Chinese populations. The present study examined whether immunological abnormalities are associated with cognitive deficits and problem behaviors in Chinese children with ASD and whether these children show different immunological profiles. Thirteen typically developing (TD) children and 22 children with ASD, aged 6–17 years, participated voluntarily in the study. Executive functions and short-term memory were measured using neuropsychological tests, and behavioral measures were assessed using parent ratings. The children were also assessed on immunological measures, specifically, the levels of cytokines and chemokines in the blood serum. Children with ASD showed greater deficits in cognitive functions, as well as altered levels of immunological measures, including CCL2, CCL5, and CXCL9 levels, compared to TD children, and the cognitive functions and associated behavioral deficits of children with ASD were significantly associated with different immunological measures. The children were further sub-classified into ASD with only autistic features (ASD-only) or ASD comorbid with attention deficit hyperactivity disorder (ASD + ADHD). The comorbidity results showed that there were no differences between the two groups of ASD children in any of the cognitive or behavioral measures. However, the results pertaining to immunological measures showed that the children with ASD-only and ASD + ADHD exhibited distinct cytokine and chemokine profiles and that abnormal immunologic function was associated with cognitive functions and inattention/hyperactivity symptoms. These results support the notion that altered immune functions may play a role in the selective

  14. Cytokines and growth factors cross-link heparan sulfate

    PubMed Central

    Migliorini, Elisa; Thakar, Dhruv; Kühnle, Jens; Sadir, Rabia; Dyer, Douglas P.; Li, Yong; Sun, Changye; Volkman, Brian F.; Handel, Tracy M.; Coche-Guerente, Liliane; Fernig, David G.; Lortat-Jacob, Hugues; Richter, Ralf P.

    2015-01-01

    The glycosaminoglycan heparan sulfate (HS), present at the surface of most cells and ubiquitous in extracellular matrix, binds many soluble extracellular signalling molecules such as chemokines and growth factors, and regulates their transport and effector functions. It is, however, unknown whether upon binding HS these proteins can affect the long-range structure of HS. To test this idea, we interrogated a supramolecular model system, in which HS chains grafted to streptavidin-functionalized oligoethylene glycol monolayers or supported lipid bilayers mimic the HS-rich pericellular or extracellular matrix, with the biophysical techniques quartz crystal microbalance (QCM-D) and fluorescence recovery after photobleaching (FRAP). We were able to control and characterize the supramolecular presentation of HS chains—their local density, orientation, conformation and lateral mobility—and their interaction with proteins. The chemokine CXCL12α (or SDF-1α) rigidified the HS film, and this effect was due to protein-mediated cross-linking of HS chains. Complementary measurements with CXCL12α mutants and the CXCL12γ isoform provided insight into the molecular mechanism underlying cross-linking. Fibroblast growth factor 2 (FGF-2), which has three HS binding sites, was also found to cross-link HS, but FGF-9, which has just one binding site, did not. Based on these data, we propose that the ability to cross-link HS is a generic feature of many cytokines and growth factors, which depends on the architecture of their HS binding sites. The ability to change matrix organization and physico-chemical properties (e.g. permeability and rigidification) implies that the functions of cytokines and growth factors may not simply be confined to the activation of cognate cellular receptors. PMID:26269427

  15. Moxonidine modulates cytokine signalling and effects on cardiac cell viability.

    PubMed

    Aceros, Henry; Farah, Georges; Noiseux, Nicolas; Mukaddam-Daher, Suhayla

    2014-10-05

    Regression of left ventricular hypertrophy and improved cardiac function in SHR by the centrally acting imidazoline I1-receptor agonist, moxonidine, are associated with differential actions on circulating and cardiac cytokines. Herein, we investigated cell-type specific I1-receptor (also known as nischarin) signalling and the mechanisms through which moxonidine may interfere with cytokines to affect cardiac cell viability. Studies were performed on neonatal rat cardiomyocytes and fibroblasts incubated with interleukin (IL)-1β (5 ng/ml), tumor necrosis factor (TNF)-α (10 ng/ml), and moxonidine (10(-7) and 10(-5) M), separately and in combination, for 15 min, and 24 and 48 h for the measurement of MAPKs (ERK1/2, JNK, and p38) and Akt activation and inducible NOS (iNOS) expression, by Western blotting, and cardiac cell viability/proliferation and apoptosis by flow cytometry, MTT assay, and Live/Dead assay. Participation of imidazoline I1-receptors and the signalling proteins in the detected effects was identified using imidazoline I1-receptor antagonist and signalling protein inhibitors. The results show that IL-1β, and to a lower extent, TNF-α, causes cell death and that moxonidine protects against starvation- as well as IL-1β -induced mortality, mainly by maintaining membrane integrity, and in part, by improving mitochondrial activity. The protection involves activation of Akt, ERK1/2, p38, JNK, and iNOS. In contrast, moxonidine stimulates basal and IL-1β-induced fibroblast mortality by mechanisms that include inhibition of JNK and iNOS. Thus, apart from their actions on the central nervous system, imidazoline I1-receptors are directly involved in cardiac cell growth and death, and may play an important role in cardiovascular diseases associated with inflammation.

  16. Endothelin Regulates Porphyromonas gingivalis-Induced Production of Inflammatory Cytokines

    PubMed Central

    Kim, Ji-Hye; Lee, Dong Eun; Kang, Si-Mook; Lee, So Yun; Choi, Lin; Sun, Ji Su; Kim, Seul Ki; Park, Wonse; Kim, Baek Il; Yoo, Yun-Jung; Chang, Inik; Shin, Dong Min

    2016-01-01

    Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1β, TNFα, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis

  17. Differential regulation of cytokine and cytokine receptor mRNA expression upon infection of bone marrow-derived macrophages with Listeria monocytogenes.

    PubMed Central

    Demuth, A; Goebel, W; Beuscher, H U; Kuhn, M

    1996-01-01

    Cytokine and cytokine receptor mRNA expression was analyzed by PCR-assisted amplification of RNA extracted from bone marrow-derived macrophages (BMM phi) at different time points after infection with Listeria monocytogenes. The mRNAs for the cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) were induced early after infection, whereas IL-6 mRNA appeared later and even nonhemolytic Listeria strains, which are unable to grow inside eukaryotic cells, induced the same cytokine mRNAs at levels similar to those of the wild-type strain. In most cases, the amounts of cytokines determined by various bioassays correlated with the level of mRNA induction. Inhibition of phagocytic uptake of L. monocytogenes by cytochalasin D treatment resulted in adherent bacteria which still induced the proinflammatory cytokines. In BMM phi, the level of IL-1 receptor II mRNA was unaffected, whereas mRNA expression of the two subtypes of tumor necrosis factor receptors (TNF-RI and TNF-RII) was differentially regulated upon infection: transcription of TNF-RI was reduced, and that of TNF-RII mRNA was induced. Similar to the decreased TNF-RI mRNA expression, gamma interferon receptor mRNA was downregulated in L. monocytogenes-infected BMM phi. This dose- and time-dependent induction or downregulation of cytokine receptor mRNA following L. monocytogenes infection of BMM phi was not observed upon infection of established macrophage-like cell lines J774 and P388D1. Induction of IL-6 mRNA as well as IL-1 alpha/beta and TNF-alpha mRNAs upon L. monocytogenes infection of BMM phi occurs independently of autocrine TNF-alpha signaling via TNF-RI or TNF-RII, as shown by infection of TNF-RI- and TNF-RII-deficient macrophages derived from mutant B6 x 129 mice. In contrast to gamma interferon receptor mRNA, both TNF receptor subtype mRNAs were not influenced by L. monocytogenes infection of hybrid (B6 x 129) mouse macrophages. Whereas the proinflammatory

  18. Circulating Cytokines and Cytokine Receptors in Infliximab Treatment Failure Due to TNF-α Independent Crohn Disease.

    PubMed

    Steenholdt, Casper; Coskun, Mehmet; Buhl, Sine; Bendtzen, Klaus; Ainsworth, Mark A; Brynskov, Jørn; Nielsen, Ole H

    2016-04-01

    The inflammatory response at infliximab (IFX) treatment failure due to tumor necrosis factor (TNF)-α-independent Crohn disease activity is unknown. This is an exploratory, hypothesis-generating study based on samples collected in a clinical trial among patients failing conventional IFX dosages and treated with an intensified IFX regimen for 12 weeks. Patients with clinical response at week 12, as defined by a reduction of Crohn disease activity index by ≥70, were considered to suffer from nonimmune pharmacokinetic (PK) treatment failure (n = 18), and nonresponders had a presumed pharmacodynamic (PD) failure due to non-TNF-driven disease (n = 8). Patients failing IFX due to functional anti-IFX antibodies (n = 2) were excluded. The study population also comprised a group of 12 patients in long-term remission on IFX. A functional cell-based reporter gene assay was applied to measure IFX and anti-IFX antibodies. Circulating cytokines and cytokine receptors were assessed by enzyme-linked immunosorbent assay: granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1α, IL-1β, IL-1Ra, IL-6, IL-10, IL-12p70, soluble TNF receptor (sTNF-R) 1, sTNF-R2, IL-17A, and monocyte chemotactic protein 1. The IFX levels were similar between patients with IFX failure caused by nonimmune PK or PD at treatment failure (median 1.4 vs 2.4 μg/mL; P = 0.52), during treatment intensification (8.1 vs 5.6; P = 0.85), and after 12 weeks (8.8 vs 7.7; P = 0.93), congruent with nonresponders failing IFX due to predominantly TNF-α-independent signaling pathways in their disease. Cytokine and cytokine receptor levels were comparable between patients with nonimmune PK failure and PD failure at time of manifestation of IFX failure, but with higher IL-6 and sTNF-R2 levels among IFX treatment failures as compared with patients in remission (IL-6 median 3.6 vs <3.1 pg/mL; P = 0.03; sTNF-R2 3207 vs 2547 pg/mL; P = 0.01). IL-6 and sTNF-R2

  19. CYTOKINE PROFILES DO NOT PREDICT ANTIBODY RESPONSES AND RESPIRATORY HYPERRESPONSIVENESS FOLLOWING DERMAL EXPOSURE TO ISOCYANATES

    EPA Science Inventory

    Rationale: Cytokine profiling of local lymph node responses following dermal exposure has been proposed as a test to identify chemicals that pose a risk of occupational asthma. The present study tested the hypothesis that relative differences in cytokine profiles for dini...

  20. Comparative Assessment of Cytokine Pattern in Early and Late Onset of Neonatal Sepsis

    PubMed Central

    Khaertynov, Kh. S.; Andreeva, A. A.; Satrutdinov, M. A.; Agafonova, E. A.

    2017-01-01

    Neonatal sepsis is a significant health issue associated with high mortality. Immune responses associated with neonatal sepsis, such as proinflammatory cytokine production, are believed to play a central role in the pathogenesis of this disease. In the present study, serum levels of the proinflammatory cytokines TNF-α, IL1-β, and IL-6 and the anti-inflammatory cytokines IL-4 and IL-10 were evaluated for 25 subjects with neonatal sepsis. We observed that subjects with late onset of sepsis (LOS), as well as those with early onset of sepsis (EOS), had a substantial increase in serum TNF-α. In contrast to EOS, subjects with LOS demonstrated a significant increase in serum levels IL-6 and IL-10. Additionally, we observed a significant difference in cytokine profiles between acute and postacute cases of neonatal sepsis. For instance, the level of proinflammatory cytokines, such as TNF-α and IL-6, was elevated in the acute phase, whereas the production of anti-inflammatory cytokines, such as IL-10, became substantially upregulated during the postacute phase. Additionally, no correlation was observed between cytokine levels and CRP levels or lymphocyte counts. Thus, in contrast to CRP levels and lymphocyte counts, examination of the cytokine profile can provide valuable information when determining the most effective therapy for treating neonatal sepsis. This information may be useful to physicians when determining if anti-inflammatory or immune stimulatory therapy is warranted. PMID:28367457

  1. The Effect of a Bio-Behavioral Intervention on the Release of Cytokines

    DTIC Science & Technology

    2012-04-04

    intravenous lidocaine demonstrated less increase in levels of pro-inflammatory cytokines to include IL-8 and lesser severity of postoperative pain than...Comparison of the effects of thoracic epidural analgesia and i.v. infusion with lidocaine on cytokine response, postoperative pain and bowel

  2. Stage-dependent alterations of the serum cytokine pattern in colorectal carcinoma

    PubMed Central

    Kantola, T; Klintrup, K; Väyrynen, J P; Vornanen, J; Bloigu, R; Karhu, T; Herzig, K-H; Näpänkangas, J; Mäkelä, J; Karttunen, T J; Tuomisto, A; Mäkinen, M J

    2012-01-01

    Background: Inflammation contributes to the pathogenesis of colorectal cancer (CRC), and cytokine levels are altered during colorectal carcinogenesis. Methods: The serum levels of 13 cytokines and their relation to clinical and pathological parameters, and systemic inflammatory response (mGPS, CRP and neutrophil–lymphocyte ratio), were analysed from a prospective series of 148 CRC patients and 86 healthy age- and sex-matched controls. Results: CRC patients had higher serum platelet-derived growth factor, interleukin (IL)-6, IL-7, and IL-8 levels and lower monocyte chemotactic protein-1 (MCP-1) levels than the controls. A logistic regression model for discriminating the patients from the controls – including the five most predictive cytokines (high IL-8, high IL-6, low MCP-1, low IL-1ra, and low IP-10) – yielded an area under curve value of 0.890 in receiver operating characteristics analysis. Serum cytokines showed distinct correlation with other markers of systemic inflammatory response, and advanced CRCs were associated with higher levels of IL-8, IL-1ra, and IL-6. A metastasised disease was accompanied by an orientation towards Th2 cytokine milieu. Conclusion: CRC is associated with extensive alterations in serum cytokine environment, highlighting the importance of studying relative cytokine level alterations. Serum cytokine profile shows promise in separating CRC patients from healthy controls but its clinical value is yet to be confirmed. PMID:23059742

  3. Distinct cytokine pattern in response to different bacterial pathogens in human brain abscess.

    PubMed

    Bajpai, Anamika; Prasad, Kashi Nath; Mishra, Priyanka; Singh, Aloukick Kumar; Gupta, Rakesh Kumar; Ojha, Bal Krishan

    2014-08-15

    Brain abscess is a focal suppurative process. Host inflammatory response in Gram type and specific bacteria has not been studied in brain abscess. A total of 57 brain abscess patients with monomicrobial infections were studied for Th1 (TNF-α, IFN-γ, IL1-β), Th2 (IL-4, IL-10) and Th17 (IL-17, IL-23) cytokine response by reverse-transcriptase PCR and ELISA. Th1 and Th17 cytokines were significantly elevated in Gram positive (Staphylococcus aureus and Streptococcus intermedius) and Th2 cytokine (IL-10) in Gram negative (Bacteroides fragilis and Escherichia coli) infections (p<0.05). Cytokine levels were significantly higher in abscess than blood (p<0.001). Elevated levels of several inflammatory cytokines (TNF-α, IFN-γ, IL1-β, IL-17 and IL-23) were associated with the duration of symptoms; predisposing factors also influenced the levels of several cytokines. The expression of inflammatory cytokines in abscess was influenced by the bacterial pathogen, duration of symptoms and predisposing factors. Local milieu of brain plays significant role in secretion of various cytokines.

  4. [Prognostication of acute-pancreatitis-associated pulmonary injury based on determination of cytokines levels].

    PubMed

    Fedorkiv, M B; Hudz, I M; Shevchuk, I M

    2013-07-01

    The results of examination of 68 patients, admitted to hospital for an acute pancreatitis during 48 h from its occurrence, were analyzed. In all the patients the cytokines (IL-8, IL-10, TNF-alpha) content was determined in the blood, using immunoenzymal analysis. Algorithm of prognostication of an acute pancreatitis-associated pulmonary injury, basing on determination of the cytokines contents, was elaborated.

  5. Exposure to Polycyclic Aromatic Hydrocarbons, Plasma Cytokines, and Heart Rate Variability.

    PubMed

    Yang, Binyao; Deng, Qifei; Zhang, Wangzhen; Feng, Yingying; Dai, Xiayun; Feng, Wei; He, Xiaosheng; Huang, Suli; Zhang, Xiao; Li, Xiaohai; Lin, Dafeng; He, Meian; Guo, Huan; Sun, Huizhen; Yuan, Jing; Lu, Jiachun; Hu, Frank B; Zhang, Xiaomin; Wu, Tangchun

    2016-01-13

    Epidemiological studies have suggested associations between polycyclic aromatic hydrocarbons (PAHs) and heart rate variability (HRV). However, the roles of plasma cytokines in these associations are limited. In discovery stage of this study, we used Human Cytokine Antibody Arrays to examine differences in the concentrations of 280 plasma cytokines between 8 coke-oven workers and 16 community residents. We identified 19 cytokines with significant different expression (fold change ≥2 or ≤-2, and q-value <5%) between exposed workers and controls. 4 cytokines were selected to validate in 489 coke-oven workers by enzyme-linked immunosorbent assays in validation stage. We found OH-PAHs were inversely associated with brain-derived neurotrophic factor (BDNF) (p < 0.05), and interquartile range (IQR) increases in OH-PAHs were associated with >16% BDNF decreases. Additionally, OH-PAHs were positively associated with activated leukocyte cell adhesion molecule (ALCAM) and C-reactive protein (CRP) (p < 0.05), and IQR increases in OH-PAHs were associated with >20% increases in CRP. We also found significant associations between these cytokines and HRV (p < 0.05), and IQR increases in BDNF and CRP were associated with >8% decreases in HRV. Our results indicated PAH exposure was associated with plasma cytokines, and higher cytokines were associated with decreased HRV, but additional human and potential mechanistic studies are needed.

  6. Molecular identification of duck and quail common cytokine receptor gamma chain genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Common cytokine receptor gamma chain family cytokines play crucial roles in the regulation of innate and adaptive immune responses. Unlike mammals, chickens possess two different gamma chains transcripts. To determine if this difference is present in other avian species, gamma chain cDNA and genomic...

  7. Hostility is related to clusters of T-cell cytokines and chemokines in healthy men.

    PubMed

    Mommersteeg, Paula M C; Vermetten, Eric; Kavelaars, Annemieke; Geuze, Elbert; Heijnen, Cobi J

    2008-09-01

    Hostility is a risk factor for adverse health outcomes as diverse as cardiovascular disease and post-traumatic stress disorder (PTSD). Cytokines have been suggested to mediate this relationship. We investigated whether in healthy men a relation existed between hostility and T-cell mitogen-induced cytokines and chemokines. Male Dutch military personnel (n=304) were included before deployment. Eleven cytokines and chemokines were measured in supernatants of T-cell mitogen-stimulated whole blood cultures by multiplex immunoassay. Factor analysis was used to identify clusters of cytokines and chemokines. In a regression analysis hostility was related to the cytokine/chemokine clusters, and the potential risk factors age, BMI, smoking, drinking, previous deployment, early life trauma and depression. Explorative factor analysis showed four functional clusters; a pro-inflammatory factor (IL-2, TNFalpha, IFNgamma), an anti-inflammatory factor (IL-4, IL-5, IL-10), IL-6/chemokine factor (IL-6, MCP-1, RANTES, IP-10), and MIF. Hostility was significantly related to decreased IL-6/chemokine secretion and increased pro- and anti-inflammatory cytokines. There was an inverse relation between age and hostility scores. Early life trauma and depression were positively and independently related to hostility as well. This study represents a novel way of investigating the relation between cytokines and psychological characteristics. Cytokines/chemokines clustered into functional factors, which were related to hostility in healthy males. Moreover this relation appeared to be independent of reported depression and early trauma.

  8. Association of genetic variants, ethnicity and preterm birth with amniotic fluid cytokine concentrations.

    PubMed

    Menon, Ramkumar; Fortunato, Stephen J; Edwards, Digna R Velez; Williams, Scott M

    2010-03-01

    We examined the association of 166 single nucleotide polymorphisms (SNPs) in cytokines and cytokine related genes with cytokine concentrations (IL-1beta, IL-8, and IL-10) in the amniotic fluid (AF). These cytokines have been associated with spontaneous preterm birth (PTB) and their genetic regulation may play a role in disease risk. These associations were studied in both PTB and term births in African Americans and Caucasians; maternal and fetal genotypes were studied separately. Analyses modeled genotype, pregnancy status, and marker by pregnancy status (case/control) interaction with cytokine concentration as outcome. Our results indicate that AF cytokines (IL-1beta and IL-10) were associated with interactions between pregnancy status and both maternal and fetal SNPs, with the most significant interactions being observed for African Americans with IL-1beta concentration (maternal at IL1RAP rs1024941 p < 10(-3), fetal IL1RAP rs3773953 p < 10(-3)). AF IL-10 concentrations also showed evidence for association with SNPs in both ethnicities with the most significant interaction in Caucasian maternal samples (IL10 rs1800896 p < 10(-3)). Our data indicate that the genetic regulation of cytokine concentrations in PTB likely differs by ethnicity. AF cytokine concentrations were associated with interactions between genotype and PTB in African Americans, but less so in Caucasians.

  9. Serum cytokine profiles of children with human enterovirus 71-associated hand, foot, and mouth disease.

    PubMed

    Han, Jun; Wang, Ying; Gan, Xing; Song, Juan; Sun, Peng; Dong, Xiao-Ping

    2014-08-01

    Cytokine profiles may impact the pathogenicity and severity of hand, foot, and mouth disease caused by human enterovirus (HEV) 71. In 91 severe or mild HEV 71-associated hand, foot, and mouth disease children, serum was collected between days 2 and 10 or day >10. Serum cytokines including Type 1 T helper (Th1) cytokines: interleukin (IL)-2, interferon-gamma (IFN-γ), IL-12, and IL-18, Type 1 T helper (Th2) cytokines: IL-4, IL-10, IL-13, proinflammatory cytokines: IL-1α, IL-1β, IL-6, IL-8, IL-17, and tumor necrosis factor alpha (TNF-α), were assessed during the early stage and recovery. In the patients with mild illness, the peaks of IL-8 and IL-10 were observed on day 6 and that of IL-18 was on day 4. In the patients with severe illness, all cytokines spiked on day 3 and peaked on day 11. All cytokines except IL-6, IL-8, IL-18, and TNF-α were significantly correlated with immunoglobulin M levels by the end of the disease course. Cytokine profile variations between the patients with mild and severe illness may indicate prognosis and strain virulence, useful in clinical treatment of patients.

  10. Graphene quantum dot based "switch-on" nanosensors for intracellular cytokine monitoring.

    PubMed

    Liu, Guozhen; Zhang, Kai; Ma, Ke; Care, Andrew; Hutchinson, Mark R; Goldys, Ewa M

    2017-04-03

    The detection of cytokines in body fluids, cells, tissues and organisms continues to attract considerable attention due to the importance of these key cell signalling molecules in biology and medicine. We report a graphene quantum dot (GQD) based aptasensor able to specifically detect ultra-small amounts of cytokine molecules intracellularly. Graphene quantum dots modified with cytokine aptamers (Ap-GQDs) and epitope modified GQDs (Ep-GQDs) were prepared; both are normally fluorescent at sufficient dilution. However, the fluorescence of the conjugates of Ap-GQDs and Ep-GQDs is quenched due to aggregation between Ap-GQDs and Ep-GQDs. After incubation of the cytokine-secreting cells with the conjugates of Ap-GQDs and Ep-GQDs, the cytokines secreted in cells compete for binding with the epitope which is then displaced. The ensuing binding of cytokines with the aptamers results in the disaggregation of Ap-GQDs and Ep-GQDs, and the recovery of fluorescence. The conjugates of Ap-GQDs and Ep-GQDs were used as nanosensors for monitoring intracellular cytokine IFN-γ secretion with very high sensitivity (2 pg mL(-1)). The disaggregation based sensing strategy in this nanosensor design is simple and universal; similar nanosensors can be used for the detection of a broad spectrum of cell-secreted molecules. Such nanosensors will serve as potential biomaterials for in vivo devices to monitor a variety of biological phenomena, in particular to understand cytokine secretion pathways in live cells.

  11. St. John's wort extract and hyperforin protect rat and human pancreatic islets against cytokine toxicity.

    PubMed

    Novelli, Michela; Beffy, Pascale; Menegazzi, Marta; De Tata, Vincenzo; Martino, Luisa; Sgarbossa, Anna; Porozov, Svetlana; Pippa, Anna; Masini, Matilde; Marchetti, Piero; Masiello, Pellegrino

    2014-02-01

    The extract of Hypericum perforatum (St. John's wort, SJW) and its component hyperforin (HPF) were previously shown to inhibit cytokine-induced activation of signal transducer and activator of transcription-1 and nuclear factor κB and prevent apoptosis in a cultured β-cell line. Objective of this study was to assess the protection exerted by SJW and HPF on isolated rat and human islets exposed to cytokines in vitro. Functional, ultrastructural, biomolecular and cell death evaluation studies were performed. In both rat and human islets, SJW and HPF counteracted cytokine-induced functional impairment and down-regulated mRNA expression of pro-inflammatory target genes, such as iNOS, CXCL9, CXCL10, COX2. Cytokine-induced NO production from cultured islets, evaluated by nitrites measurement in the medium, was significantly reduced in the presence of the vegetal compounds. Noteworthy, the increase in apoptosis and necrosis following 48-h exposure to cytokines was fully prevented by SJW and partially by HPF. Ultrastructural morphometric analysis in human islets exposed to cytokines for 20 h showed that SJW or HPF avoided early β-cell damage (e.g., mitochondrial alterations and loss of insulin granules). In conclusion, SJW compounds protect rat and human islets against cytokine effects by counteracting key mechanisms of cytokine-mediated β-cell injury and represent promising pharmacological tools for prevention or limitation of β-cell dysfunction and loss in type 1 diabetes.

  12. Novel cancer vaccines prepared by anchoring cytokines to tumor cells avoiding gene transfection

    NASA Astrophysics Data System (ADS)

    Nizard, Philippe; Gross, David-Alexandre; Chenal, Alexandre; Beaumelle, Bruno; Kosmatopoulos, Konstadinos; Gillet, Daniel

    2002-06-01

    Cytokines have a strong potential for triggering anticancer immunity if released in the tumor microenvironment. Successful vaccines have been engineered using tumor cells genetically modified to secrete the cytokines. Unfortunately, this approach remains difficult and hazardous to perform in the clinic. We describe a new way of combining cytokines with tumor cells to prepare anticancer vaccines. This consists in anchoring recombinant cytokines to the membrane of killed tumor cells. Attachment is mediated by a fragment of diphtheria toxin (T) genetically connected to the cytokine. It is triggered by an acid pH pulse. The method was applied to IL-2, a potent anti-tumor cytokine. IL-2 anchored to the surface of tumor cells by the T anchor retained its IL-2 activity and remained exposed several days. Interestingly, vaccination of mice with these modified tumor cells induced a protective anti-tumor immunity mediated by tumor-specific cytotoxic T lymphocytes. This procedure presents several advantages as compared to the conventional approaches based on the transfection of tumor cells with cytokine genes. It does not require the culture of tumor cells from the patients and eliminates the safety problems connected with viral vectors while allowing the control of the amount of cytokines delivered with the vaccine.

  13. Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest

    PubMed Central

    Mondet, Julie; Hussein, Kais; Mossuz, Pascal

    2015-01-01

    Cytokines are well known mediators of numerous physiological and pathological processes. They contribute to the regulation of normal hematopoiesis but increasing data suggest that they also have a clinical impact in some hematopoietic malignancies. In particular, there is evidence that cytokines are implicated in the functional symptoms of Philadelphia negative myeloproliferative neoplasms (Ph− MPNs), suggesting that evaluation of circulating levels of cytokines could be of clinical interest for the characterization of patients at the time of diagnosis and for disease prognosis. In this review, we present the current knowledge on alteration of circulating cytokine profiles in MPNs and their role in myelofibrosis pathogenesis. Phenotypic correlation, prognostic value of cytokines, and impact of JAK inhibitors are also discussed. PMID:26525644

  14. Proteomic-Based Approaches for the Study of Cytokines in Lung Cancer.

    PubMed

    Marrugal, Ángela; Ojeda, Laura; Paz-Ares, Luis; Molina-Pinelo, Sonia; Ferrer, Irene

    2016-01-01

    Proteomic techniques are currently used to understand the biology of different human diseases, including studies of the cell signaling pathways implicated in cancer progression, which is important in knowing the roles of different proteins in tumor development. Due to its poor prognosis, proteomic approaches are focused on the identification of new biomarkers for the early diagnosis, prognosis, and targeted treatment of lung cancer. Cytokines are proteins involved in inflammatory processes and have been proposed as lung cancer biomarkers and therapeutic targets because it has been reported that some cytokines play important roles in tumor development, invasion, and metastasis. In this review, we aim to summarize the different proteomic techniques used to discover new lung cancer biomarkers and therapeutic targets. Several cytokines have been identified as important players in lung cancer using these techniques. We underline the most important cytokines that are useful as biomarkers and therapeutic targets. We also summarize some of the therapeutic strategies targeted for these cytokines in lung cancer.

  15. Kinetic and organ-specific patterns of cytokine expression in acute graft-versus-host disease.

    PubMed

    Baker, K S; Allen, R D; Roths, J B; Sidman, C L

    1995-04-01

    Although many cytokines have been previously implicated in graft-versus-host disease (GVHD), no study to date has comprehensively evaluated their expression over time or in different tissues affected by GVHD. Using a semi-quantitative reverse transcriptase-PCR technique and a murine model of acute GVHD, we have evaluated the expression levels of mRNA for a wide range of cytokines in spleen, gut and liver tissues at weekly intervals after bone marrow transfer. The earliest cytokine responses seen were increases in IL-2, IL-10, IFN-gamma, MIP-1 alpha and TNF-alpha in the spleen, suggesting a primarily Th1 pathway. Other cytokines (IL-1 alpha, IL-10 and MIP-1 alpha) were persistently elevated in GVHD mice, but were variable depending on the tissue. These data demonstrate that a wide range of cytokines are involved in the GVHD response and that their kinetic pattern of expression is different in various affected tissues.

  16. Regulation of cytokine signaling by the SOCS and Spred family proteins.

    PubMed

    Yoshimura, Akihiko

    2009-06-01

    Various cytokines are involved in the regulation of the immune system and of hematopoiesis. Most cytokines utilize the so-called JAK-STAT pathway, but others activate the Ras-ERK pathway, which is more important than the STAT pathway for the proliferation of hematopoietic cells. Dysregulation of cytokine signaling can cause a variety of diseases, including allergy, inflammation, and cancer. We have identified two important regulator families involved in cytokine signaling: the SOCS proteins and the Spred proteins. Suppressors of cytokine signaling (SOCS) proteins bind to JAK and to certain receptors, thereby suppressing further signaling events. Spred family proteins interact with Ras and Raf, thereby suppressing ERK activation. Studies have shown that SOCS and Spred proteins are key physiological regulators of immunity, hematopoiesis, and angiogenesis. Evidence is also emerging for the involvement of these proteins in human diseases.

  17. Gallium arsenide selectively up-regulates inflammatory cytokine expression at exposure site.

    PubMed

    Becker, Stephen M; McCoy, Kathleen L

    2003-12-01

    Gallium arsenide (GaAs), a technologically and economically important semiconductor, is widely utilized in both military and commercial applications. This chemical is a potential health hazard as a carcinogen and immunotoxicant. We previously reported that macrophages at the exposure site exhibit characteristics of activation. In vitro culture of macrophages with GaAs fails to recapitulate the in vivo phenotype, suggesting that complete GaAs-mediated activation in vivo may require other cells or components found in the body's microenvironment. Our present study examined the role of cytokines upon GaAs-mediated macrophage activation. Intraperitoneal administration of GaAs elicited rapid specific recruitment of blood monocytes to the exposure site. This recruitment occurred concomitant with up-regulation of 17 chemokine and inflammatory cytokine mRNAs, while transcripts of three inhibitory cytokines diminished. Administration of latex beads caused less cytokine induction than GaAs, indicating that changes in mRNA levels could not be attributed to phagocytosis. Four representative chemokines and cytokines were selected for further analysis. Increased cytokine mRNA expression was paralleled by similar increases in cytokine protein levels, and secreted protein products were detected in peritoneal fluid. Cytokine protein expression was constrained to myeloid cells, and to a lesser extent to B cells. Alterations in patterns of cytokine gene expression elucidate mechanisms for increased cellular activation and antigen processing, and modulation of the inflammatory response. Our findings indicate that in vivo GaAs exposure alters cytokine gene expression, which may lead to an inflammatory reaction and contribute to pathological tissue damage.

  18. Cancer Cytokines and the Relevance of 3D Cultures for Studying those Implicated in Human Cancers.

    PubMed

    Maddaly, Ravi; Subramaniyan, Aishwarya; Balasubramanian, Harini

    2017-03-06

    Cancers are complex conditions and involving several factors for oncogenesis and progression. Of the various factors influencing the physiology of cancers, cytokines are known to play significant roles as mediators of functions. Intricate cytokine networks have been identified in cancers and interest in cytokines associated with cancers has been gaining ground. Of late, some of these cytokines are even identified as potential targets for cancer therapy apart from a few others such as IL-6 being identified as markers for disease prognosis. Of the major contributors to cancer research, cancer cell lines occupy the top slot as the most widely used material in vitro. In vitro cell cultures have seen significant evolution by the introduction of 3 dimensional (3D) culture systems. 3D cell cultures are now widely accepted as excellent material for cancer research which surpasses the traditional monolayer cultures. Cancer research has benefitted from 3D cell cultures for understanding the various hallmarks of cancers. However, the potential of these culture systems are still unexploited for cancer cytokine research compared to the other aspects of cancers such as gene expression changes, drug-induced toxicity, morphology, angiogenesis and invasion. Considering the importance of cancer cytokines, 3D cell cultures can be better utilized in understanding their roles and functions. Some of the possibilities where 3D cell cultures can contribute to cancer cytokine research arise from the distinct morphology of the tumor spheroids, the extracellular matrix (ECM), and the spontaneous occurrence of nutrient and oxygen gradients. Also, the 3D culture models enable one to co-culture different types of cells as a simulation of in vivo conditions, enhancing their utility to study cancer cytokines. We review here the cancer associated cytokines the contributions of 3D cancer cell cultures for studying cancer cytokines. This article is protected by copyright. All rights reserved.

  19. Effects of mesenchymal stem cell-derived cytokines on the functional properties of endothelial progenitor cells.

    PubMed

    Kamprom, Witchayaporn; Kheolamai, Pakpoom; U-Pratya, Yaowalak; Supokawej, Aungkura; Wattanapanitch, Methichit; Laowtammathron, Chuti; Issaragrisil, Surapol

    2016-01-01

    Human mesenchymal stem cell (hMSC) is a potential source for cell therapy due to its property to promote tissue repair. Although, it has been known that hMSCs promote tissue repair via angiogenic cytokines, the interaction between hMSC-derived cytokines and the endothelial progenitor cells (EPCs), which play an important role in tissue neovascularization, is poorly characterized. We investigate the effect of cytokine released from different sources of hMSCs including bone marrow and gestational tissues on the EPC functions in vitro. The migration, extracellular matrix invasion and vessel formation of EPCs were studied in the presence or absence of cytokines released from various sources of hMSCs using transwell culture system. The migration of EPCs was highest when co-culture with secretory factors from placenta-derived hMSCs (PL-hMSCs) compared to those co-culture with other sources of hMSCs. For invasion and vessel formation, secretory factors from bone marrow-derived hMSCs (BM-hMSCs) could produce the maximal enhancement compared to other sources. We further identified the secreted cytokines and found that the migratory-enhancing cytokine from PL-hMSCs was PDGF-BB while the enhancing cytokine from BM-hMSCs on invasion was IGF-1. For vessel formation, the cytokines released from BM-hMSCs were IGF1 and SDF-1. In conclusion, hMSCs can release angiogenic cytokines which increase the migration, invasion and vessel forming capacity of EPCs. We can then use hMSCs as a source of angiogenic cytokines to induce neovascularization in injured/ischemic tissues.

  20. Cytokine-induced neutrophil-derived interleukin-8.

    PubMed Central

    Strieter, R. M.; Kasahara, K.; Allen, R. M.; Standiford, T. J.; Rolfe, M. W.; Becker, F. S.; Chensue, S. W.; Kunkel, S. L.

    1992-01-01

    During acute inflammation, the first line of cellular response for host defense is the neutrophil. In addition to the historic role of the neutrophil as a phagocyte, recent studies have identified this cell as an important source of a number of cytokines. In this study, we provide evidence that the neutrophil is a significant source of interleukin-8 (IL-8). Neutrophils freshly isolated from whole blood were not found to constitutively express IL-8 mRNA. In contrast, when these leukocytes were cultured on plastic they were activated, leading to the significant expression of de novo steady-state levels of IL-8 mRNA. In addition, when neutrophils were treated with cycloheximide, there was evidence for "superinduction" of steady-state levels of IL-8 mRNA and inhibition of antigenic IL-8 production. Neutrophils were subsequently stimulated with lipopolysaccharide (LPS), tumor necrosis factor-alpha, or interleukin-1-beta and were found to express IL-8 mRNA and antigen in both a time- and dose-dependent manner. Furthermore, neutrophils stimulated with traditional chemotactic/activating factors, such as the split product of the fifth component of complement (C5a), formylmethionyleucylphenylalanine (fMLP), and leukotriene B4 (LTB4) in a dose-dependent manner did not produce significant antigenic IL-8, as compared with unstimulated controls. In contrast, when neutrophils were exposed to either of these neutrophil agonists in the presence of LPS, the production of antigenic IL-8 was significantly elevated, as compared with either of the stimuli alone, suggesting a synergistic response. These data would suggest that the neutrophil can no longer be viewed as only a phagocyte or warehouse for proteolytic enzymes, but is a pivotal effector cell that is able to respond to mediators in its environment and generate cytokines. This latter neutrophil response may be important for either the elicitation of additional neutrophils or to orchestrate the conventional immune response at

  1. Cross-Regulation of Proinflammatory Cytokines by Interleukin-10 and miR-155 in Orientia tsutsugamushi-Infected Human Macrophages Prevents Cytokine Storm.

    PubMed

    Tsai, Ming-Hsien; Chang, Chung-Hsing; Tsai, Rong-Kung; Hong, Yi-Ren; Chuang, Tsung-Hsien; Fan, Kan-Tang; Peng, Chi-Wen; Wu, Ching-Ying; Hsu, Wen-Li; Wang, Lih-Shinn; Chen, Li-Kuang; Yu, Hsin-Su

    2016-07-01

    Scrub typhus is caused by the obligate intracellular bacterium Orientia tsutsugamushi. Macrophages are host cells for its replication and clearance. Severe complications in patients are mainly caused by a cytokine storm resulting from overproduction of proinflammatory cytokines; nevertheless, the molecular mechanism for the occurrence remains obscure. Herein, we investigate the interactive regulation of cytokines and micro-RNA (miR) in human macrophages infected with low and high doses of O. tsutsugamushi. During low dose infection, macrophages produce high levels of IL-10 through extracellular signal-regulated kinase activation, which inhibits proinflammatory cytokine production and facilitates pathogen replication. Increasing levels of pathogen results in reduced levels of IL-10, and macrophages begin to generate high levels of proinflammatory cytokines through NF-κB activation. However, during a high dose infection, macrophages produce high levels of miR-155 to slow the proinflammatory response. The extracellular signal-regulated kinase/IL-10 axis suppresses the NF-κB/tumor necrosis factor alpha axis via activation of signal transducer and activator of transcription 3. Both IL-10 and miR-155 inhibit the NF-κB signaling pathway. Furthermore, IL-10 is a potent inhibitor of miR-155. Patients susceptible to a cytokine storm, peripheral blood mononuclear cells showed significantly lower IL-10 and miR-155 responses to O. tsutsugamushi challenge. Thus, IL-10 and miR-155 operate inhibitory mechanisms to achieve a proper defense mechanism and prevent a cytokine storm.

  2. Chemokine-cytokine cross-talk. The ELR+ CXC chemokine LIX (CXCL5) amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway.

    PubMed

    Chandrasekar, Bysani; Melby, Peter C; Sarau, Henry M; Raveendran, Muthuswamy; Perla, Rao P; Marelli-Berg, Federica M; Dulin, Nickolai O; Singh, Ishwar S

    2003-02-14

    It is well established that cytokines can induce the production of chemokines, but the role of chemokines in the regulation of cytokine expression has not been fully investigated. Exposure of rat cardiac-derived endothelial cells (CDEC) to lipopolysaccharide-induced CXC chemokine (LIX), and to a lesser extent to KC and MIP-2, activated NF-kappaB and induced kappaB-driven promoter activity. LIX did not activate Oct-1. LIX-induced interleukin-1beta and tumor necrosis factor-alpha promoter activity, and up-regulated mRNA expression. Increased transcription and mRNA stability both contributed to cytokine expression. LIX-mediated cytokine gene transcription was inhibited by interleukin-10. Transient overexpression of kinase-deficient NF-kappaB-inducing kinase (NIK) and IkappaB kinase (IKK), and dominant negative IkappaB significantly inhibited LIX-mediated NF-kappaB activation in rat CDEC. Inhibition of G(i) protein-coupled signal transduction, poly(ADP-ribose) polymerase, phosphatidylinositol 3-kinase, and the 26 S proteasome significantly inhibited LIX-mediated NF-kappaB activation and cytokine gene transcription. Blocking CXCR2 attenuated LIX-mediated kappaB activation and kappaB-driven promoter activity in rat CDEC that express both CXCR1 and -2, and abrogated its activation in mouse CDEC that express only CXCR2. These results indicate that LIX activates NF-kappaB and induces kappaB-responsive proinflammatory cytokines via either CXCR1 or CXCR2, and involved phosphatidylinositol 3-kinase, NIK, IKK, and IkappaB. Thus, in addition to attracting and activating neutrophils, the ELR(+) CXC chemokines amplify the inflammatory cascade, stimulating local production of cytokines that have negative inotropic and proapoptotic effects.

  3. Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

    PubMed Central

    Hasegawa, Hideaki; Mizoguchi, Izuru; Chiba, Yukino; Ohashi, Mio; Xu, Mingli; Yoshimoto, Takayuki

    2016-01-01

    The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein–Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus

  4. Ex vivo PBMC cytokine profile in familial Mediterranean fever patients: Involvement of IL-1β, IL-1α and Th17-associated cytokines and decrease of Th1 and Th2 cytokines.

    PubMed

    Ibrahim, José-Noel; Jounblat, Rania; Delwail, Adriana; Abou-Ghoch, Joelle; Salem, Nabiha; Chouery, Eliane; Megarbane, André; Medlej-Hashim, Myrna; Lecron, Jean-Claude

    2014-10-01

    In order to clarify the inflammatory mechanism underlying familial Mediterranean fever (FMF), we aimed to evaluate the ex vivo cytokine profile of FMF patients during acute attacks and attack-free periods, and compare it with that of healthy controls. The study included 34 FMF patients, of whom 9 were studied during attack and remission and 24 healthy controls. Cytokine levels were evaluated by Luminex technology in serum and supernatants of PBMC (Peripheral Blood Mononuclear Cells) cultures with and without 24h stimulation of monocytes by LPS and T lymphocytes by anti-CD3/CD28 beads. Levels of IL-6 and TNF-α were higher in unstimulated and LPS-stimulated PBMC supernatants of FMF patients in crises compared to controls. In response to LPS stimulation, higher levels of IL-1β and IL-1α were found in PBMC supernatants of patients during crises compared to those in remission and to controls. IFN-γ and IL-4 levels were the lowest in unstimulated and anti-CD3/CD28 stimulated PBMCs supernatants of patients during crises compared to remission and controls. The Th17 cytokines IL-17 and IL-22 were respectively higher in anti-CD3/CD28 stimulated PBMC supernatants of FMF patients during and between crises compared to controls. Amongst cytokines tested in serum, only IL-6 and TNFα were enhanced in FMF patients. The ex vivo study represents an interesting approach to evaluate cytokines' involvement in FMF. Our results suggest an ongoing subclinical inflammation and define an elevated inflammatory cytokine signature, distinctly for M694V homozygous patients. The absence of spontaneous IL-1β release by PBMCs reflects no constitutive activation of the inflammasome in FMF physiopathology.

  5. IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology

    PubMed Central

    Croce, Michela; Rigo, Valentina; Ferrini, Silvano

    2015-01-01

    Interleukin- (IL-) 21 is a pleiotropic cytokine that regulates the activity of both innate and specific immunity. Indeed, it costimulates T and natural killer (NK) cell proliferation and function and regulates B cell survival and differentiation and the function of dendritic cells. In addition, IL-21 exerts divergent effects on different lymphoid cell leukemia and lymphomas, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the neoplastic lymphoid cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanism involving the activation of NK and T or B cell responses. Moreover, IL-21's antitumor activity can be potentiated by its combination with other immune-enhancing molecules, monoclonal antibodies recognizing tumor antigens, chemotherapy, or molecular targeted agents. Clinical phase I-II studies of IL-21 in cancer patients showed immune stimulatory properties, acceptable toxicity profile, and antitumor effects in a fraction of patients. In view of its tolerability, IL-21 is also suitable for combinational therapeutic regimens with other agents. This review will summarize the biological functions of IL-21, and address its role in lymphoid malignancies and preclinical and clinical studies of cancer immunotherapy. PMID:25961061

  6. Gut commensalism, cytokines, and central nervous system demyelination.

    PubMed

    Telesford, Kiel; Ochoa-Repáraz, Javier; Kasper, Lloyd H

    2014-08-01

    There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to the development of autoimmune diseases, including human multiple sclerosis (MS). Perhaps the greatest environmental risk factor associated with the development of immune-mediated conditions is the gut microbiome. Microbial and helminthic agents are active participants in shaping the immune systems of their hosts. This concept is continually reinforced by studies in the burgeoning area of commensal-mediated immunomodulation. The clinical importance of these findings for MS is suggested by both their participation in disease and, perhaps of greater clinical importance, attenuation of disease severity. Observations made in murine models of central nervous system demyelinating disease and a limited number of small studies in human MS suggest that immune homeostasis within the gut microbiome may be of paramount importance in maintaining a disease-free state. This review describes three immunological factors associated with the gut microbiome that are central to cytokine network activities in MS pathogenesis: T helper cell polarization, T regulatory cell function, and B cell activity. Comparisons are drawn between the regulatory mechanisms attributed to first-line therapies and those described in commensal-mediated amelioration of central nervous system demyelination.

  7. Cytokines and macrophage function in humans - role of stress

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald (Principal Investigator)

    1996-01-01

    We have begun this study to commence the determination of the role of mild chronic stress in the effects of space flight on macrophage/monocyte function, a component of the immune response. Medical students undergoing regular periods of stress and relaxation have been shown to be an excellent model for determining the effects of stress on immune responses. We have begun using this model using the macrophage/monocyte as model leukocyte. The monocyte/macrophage plays a central role in immunoregulation. The studies to be included in this three year project are the effects of stress on: (1) interactions of monocytes with microbes, (2) monocyte production of cytokines, (3) monocyte phagocytosis and activity, and (4) monocyte expression of cell surface antigens important in immune responses. Stress hormone levels will also be carried out to determine if there is a correlation between stress effects on immune responses and hormonal levels. Psychological testing to insure subjects are actually stressed or relaxed at the time of testing will also be carried out. The results obtained from the proposed studies should be comparable with space flight studies with whole animals and isolated cell cultures. When complete this study should allow the commencement of the establishment of the role of stress as one compartment of the induction of immune alterations by space flight.

  8. Gut Commensalism, Cytokines, and Central Nervous System Demyelination

    PubMed Central

    Ochoa-Repáraz, Javier; Kasper, Lloyd H.

    2014-01-01

    There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to the development of autoimmune diseases, including human multiple sclerosis (MS). Perhaps the greatest environmental risk factor associated with the development of immune-mediated conditions is the gut microbiome. Microbial and helminthic agents are active participants in shaping the immune systems of their hosts. This concept is continually reinforced by studies in the burgeoning area of commensal-mediated immunomodulation. The clinical importance of these findings for MS is suggested by both their participation in disease and, perhaps of greater clinical importance, attenuation of disease severity. Observations made in murine models of central nervous system demyelinating disease and a limited number of small studies in human MS suggest that immune homeostasis within the gut microbiome may be of paramount importance in maintaining a disease-free state. This review describes three immunological factors associated with the gut microbiome that are central to cytokine network activities in MS pathogenesis: T helper cell polarization, T regulatory cell function, and B cell activity. Comparisons are drawn between the regulatory mechanisms attributed to first-line therapies and those described in commensal-mediated amelioration of central nervous system demyelination. PMID:25084177

  9. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling

    PubMed Central

    Jahani-Asl, Arezu; Yin, Hang; Soleimani, Vahab D; Haque, Takrima; Luchman, H Artee; Chang, Natasha C; Sincennes, Marie-Claude; Puram, Sidharth V; Scott, Andrew M; Lorimer, Ian A J; Perkins, Theodore J; Ligon, Keith L; Weiss, Samuel; Rudnicki, Michael A; Bonni, Azad

    2016-01-01

    EGFRvIII-STAT3 signaling is important in glioblastoma pathogenesis. Here, we identified the cytokine receptor OSMR as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells (BTSCs). We found that OSMR functioned as an essential co-receptor for EGFRvIII. OSMR formed a physical complex with EGFRvIII, and depletion of OSMR impaired EGFRvIII-STAT3 signaling. Conversely, pharmacological inhibition of EGFRvIII phosphorylation inhibited the EGFRvIII-OSMR interaction and activation of STAT3. EGFRvIII-OSMR signaling in tumors operated constitutively, whereas EGFR-OSMR signaling in nontumor cells was synergistically activated by the ligands EGF and OSM. Finally, knockdown of OSMR strongly suppressed cell proliferation and tumor growth of mouse glioblastoma cells and human BTSC xenografts in mice, and prolonged the lifespan of those mice. Our findings identify OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed-forward signaling mechanism with EGFRvIII and STAT3 to drive tumorigenesis. PMID:27110918

  10. Molecular epidemiology, cancer-related symptoms, and cytokines pathway

    PubMed Central

    Reyes-Gibby, Cielito C; Wu, Xifeng; Spitz, Margaret; Kurzrock, Razelle; Fisch, Michael; Bruera, Eduardo; Shete, Sanjay

    2012-01-01

    The Human Genome Project and HapMap have led to a better appreciation of the importance of common genetic variation in determining cancer risk, created potential for predicting response to therapy, and made possible the development of targeted prevention and therapeutic interventions. Advances in molecular epidemiology can be used to explore the role of genetic variation in modulating the risk for severe and persistent symptoms, such as pain, depression, and fatigue, in patients with cancer. The same genes that are implicated in cancer risk might also be involved in the modulation of therapeutic outcomes. For example, polymorphisms in several cytokine genes are potential markers for genetic susceptibility both for cancer risk and for cancer-related symptoms. These genetic polymorphisms are stable markers and easily and reliably assayed to explore the extent to which genetic variation might prove useful in identifying patients with cancer at high-risk of symptom development. Likewise, they could identify subgroups who might benefit most from symptom intervention, and contribute to developing personalised and more effective therapies for persistent symptoms. PMID:18672213

  11. Measuring Cytokine Concentrations Using Magnetic Spectroscopy of Nanoparticle Brownian Relaxation

    NASA Astrophysics Data System (ADS)

    Khurshid, Hafsa; Shi, Yipeng; Weaver, John

    The magnetic particle spectroscopy is a newly developed non-invasive technique for obtaining information about the nanoparticles' micro environment. In this technique the nanoparticles' magnetization, induced by an alternating magnetic field at various applied frequencies, is processed to analyze rotational freedom of nanoparticles. By analyzing average rotational freedom, it is possible to measure the nanoparticle's relaxation time, and hence get an estimate of the temperature and viscosity of the medium. In molecular concentration sensing, the rotational freedom indicates the number of nanoparticles that are bound by a selected analyte. We have developed microscopic nanoparticles probes to measure the concentration of selected molecules. The nanoparticles are targeted to bind the selected molecule and the resulting reduction in rotational freedom can be quantified remotely. Previously, sensitivity measurements has been reported to be of the factor of 200. However, with our newer perpendicular field setup (US Patent Application Serial No 61/721,378), it possible to sense cytokine concentrations as low as 5 Pico-Molar in-vitro. The excellent sensitivity of this apparatus is due to isolation of the drive field from the signal so the output can be amplified to a higher level. Dartmouth College.

  12. Effect of Cytokine Signaling 3 Gene Polymorphisms in Childhood Obesity

    PubMed Central

    Boyraz, Mehmet; Yeşilkaya, Ediz; Ezgü, Fatih; Bideci, Aysun; Doğan, Haldun; Ulucan, Korkut; Cinaz, Peyami

    2016-01-01

    Objective: Although polymorphisms in suppressor of cytokine signaling 3 (SOCS3) was reported to be related to obesity, Metabolic syndrome (MS), and type 2 diabetes mellitus in various adult studies, there is a lack of data in children. In this study, we examined eight reported polymorphisms of SOCS3 in obese Turkish children and adolescent with and without MS and compared the results with that of controls. Methods: One hundred and forty eight obese and 63 age- and sex-matched control subjects were enrolled in the study. Obesity classification was carried out according to body mass index. World Health Organization and National Cholesterol Education Program criteria were used for the diagnosis of MS. Genotyping procedure was carried out by polymerase chain reaction and Sanger sequencing protocol. Results: The frequency of rs2280148 polymorphism was significantly higher in obese subjects with MS than in the control group, whereas the frequency of rs8064821 polymorphism was significantly higher in obese subjects with MS than in obese children without MS. Conclusion: The significant associations of certain SOCS3 polymorphisms with obesity parameters in both MS and MS -related insulin resistance, hypertension, and fatty liver suggest that polymorphisms in this gene may play a role in the pathogenesis of MS and also that they can be potentially used as a marker for attenuated or aggressive disease. PMID:27611604

  13. Translational implications of inflammatory biomarkers and cytokine networks in psychoneuroimmunology.

    PubMed

    Yan, Qing

    2012-01-01

    Developments in psychoneuroimmunology (PNI) need to be translated into personalized medicine to achieve better clinical outcomes. One of the most critical steps in this translational process is to identify systemic biomarkers for better diagnosis and treatment. Applications of systems biology approaches in PNI would enable the insights into the correlations among various systems and different levels for the identification of the basic elements of the psychophysiological framework. Among the potential PNI biomarkers, inflammatory markers deserve special attention as they play a pivotal role linking various health conditions and disorders. The elucidation of inflammatory markers, cytokine networks, and immune-brain-behavior interactions may help establish PNI profiles for the identification of potential targets for personalized interventions in at risk populations. The understanding of the general systemic pathways among different disorders may contribute to the transition from the disease-centered medicine to patient-centered medicine. Integrative strategies targeting these factors and pathways would be useful for the prevention and treatment of a spectrum of diseases that share the common links. Examples of the translational implications of potential PNI biomarkers and networks in diseases including depression, Alzheimer's disease, obesity, cardiovascular disease, stroke, and HIV are discussed in details.

  14. Proinflammatory cytokines induce amelotin transcription in human gingival fibroblasts.

    PubMed

    Nakayama, Yohei; Takai, Hideki; Matsui, Sari; Matsumura, Hiroyoshi; Zhou, Liming; Kato, Ayako; Ganss, Bernhard; Ogata, Yorimasa

    2014-12-01

    Amelotin (AMTN) is a secreted protein transcribed predominantly during the maturation stage of enamel formation and localized in the junctional epithelium. We investigated differences in the levels of AMTN gene expression between non-inflamed gingiva and inflamed gingiva from patients with chronic periodontitis. Total RNAs were isolated from these tissues and their gene expression profiles were monitored by DNA microarray. The observed induction of AMTN mRNA in inflamed gingiva and cultured human gingival fibroblasts (HGF) was confirmed by real-time PCR. Transient transfection assays were performed using chimeric constructs of mouse AMTN gene promoter fragments linked to a luciferase reporter gene. Immunohistochemical localization of AMTN in inflamed and non-inflamed gingiva was assessed by immunohistochemistry. Among many differentially expressed genes, the level of AMTN mRNA was significantly increased in inflamed gingiva. Treatment of HGF with interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) induced the expression of AMTN mRNA, and increased the luciferase activities of the AMTN promoter constructs. AMTN protein was detected in inflamed gingival connective tissue and junctional epithelium. These findings demonstrate that proinflammatory cytokines induce AMTN gene expression in human gingival fibroblasts and suggest a role for AMTN in gingival inflammation.

  15. IL-18; a cytokine translates a stress into medical science.

    PubMed

    Sekiyama, Atsuo; Ueda, Haruyasu; Kashiwamura, Shin-ichiro; Nishida, Kensei; Kawai, Kaori; Teshima-kondo, Shigetada; Rokutan, Kazuhito; Okamura, Haruki

    2005-11-01

    Psychological/physical stresses have been reported to exacerbate auto-immune and inflammatory diseases. To clarify a mechanism by which non-inflammatory stresses disrupt host defenses, responses to immobilization stress in mice were investigated, focusing on the role of a multifunctional cytokine, interleukin-18 (IL-18). In the adrenal cortex, the stress induced IL-18 precursor proteins (pro-IL-18) via ACTH and a superoxide-mediated caspase-1 activation pathway, resulting in conversion of pro-IL-18 to the mature form which was released into plasma. Inhibitors of caspase-1, reactive oxygen species and P38 MAPK prevented stress-induced accumulation of plasma IL-18. These inhibitors also blocked stress-induced IL-6 expression. This, together with the observation that IL-6 was not induced in stressed-IL-18 deficient mice, showed that IL-6 induction by stress is dependent on IL-18. In stressed organisms, IL-18 may influence pathological and physiological processes. Controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses.

  16. Plasmodium genetic loci linked to host cytokine and chemokine responses

    PubMed Central

    Pattaradilokrat, Sittiporn; Li, Jian; Wu, Jian; Qi, Yanwei; Eastman, Richard T.; Zilversmit, Martine; Nair, Sethu C.; Huaman, Maria Cecilia; Quinones, Mariam; Jiang, Hongying; Li, Na; Zhu, Jun; Zhao, Keji; Kaneko, Osamu; Long, Carole A.; Su, Xin-zhuan

    2014-01-01

    Both host and parasite factors contribute to disease severity of malaria infection; however, the molecular mechanisms responsible for the disease and the host-parasite interactions involved remain largely unresolved. To investigate effects of parasite factors on host immune responses and pathogenesis, we measured levels of plasma cytokines/chemokines (CC) and growth rates in mice infected with two Plasmodium yoelii strains having different virulence phenotypes and in progeny from a genetic cross of the two parasites. Quantitative trait loci (QTL) analysis linked levels of many CCs, particularly IL-1β, IP-10, IFN-γ, MCP-1, and MIG, and early parasite growth rate to loci on multiple parasite chromosomes, including chromosomes 7, 9, 10, 12, and 13. Comparison of the genome sequences spanning the mapped loci revealed various candidate genes. The loci on chromosome 7 and 13 had significant (p < 0.005) additive effects on IL-1β, IL-5, and IP-10 responses, and the chromosome 9 and 12 loci had significant (p = 0.017) interaction. Infection of knockout mice showed critical roles of MCP-1 and IL-10 in parasitemia control and host mortality. These results provide important information for better understanding of malaria pathogenesis and can be used to examine the role of these factors in human malaria infection. PMID:24452266

  17. Plasmodium genetic loci linked to host cytokine and chemokine responses.

    PubMed

    Pattaradilokrat, S; Li, J; Wu, J; Qi, Y; Eastman, R T; Zilversmit, M; Nair, S C; Huaman, M C; Quinones, M; Jiang, H; Li, N; Zhu, J; Zhao, K; Kaneko, O; Long, C A; Su, X-z

    2014-01-01

    Both host and parasite factors contribute to disease severity of malaria infection; however, the molecular mechanisms responsible for the disease and the host-parasite interactions involved remain largely unresolved. To investigate the effects of parasite factors on host immune responses and pathogenesis, we measured levels of plasma cytokines/chemokines (CCs) and growth rates in mice infected with two Plasmodium yoelii strains having different virulence phenotypes and in progeny from a genetic cross of the two parasites. Quantitative trait loci (QTL) analysis linked levels of many CCs, particularly IL-1β, IP-10, IFN-γ, MCP-1 and MIG, and early parasite growth rate to loci on multiple parasite chromosomes, including chromosomes 7, 9, 10, 12 and 13. Comparison of the genome sequences spanning the mapped loci revealed various candidate genes. The loci on chromosomes 7 and 13 had significant (P<0.005) additive effects on IL-1β, IL-5 and IP-10 responses, and the chromosome 9 and 12 loci had significant (P=0.017) interaction. Infection of knockout mice showed critical roles of MCP-1 and IL-10 in parasitemia control and host mortality. These results provide important information for a better understanding of malaria pathogenesis and can be used to examine the role of these factors in human malaria infection.

  18. Aspergillus fumigatus challenge increases cytokine levels in nasal lavage fluid.

    PubMed

    Stark, H; Roponen, M; Purokivi, M; Randell, J; Tukiainen, H; Hirvonen, M-R

    2006-12-01

    Several studies have shown an association between exposure in moisture-damaged buildings and adverse health effects. There are several indicator microbes of moisture damage, but Aspergillus fumigatus is one of the best-documented molds provoking health problems in different occupational conditions. We assessed whether inhalation of a commercial A. fumigatus solution would affect cytokine levels (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-4, IL-6, interferon [IFN]-gamma) in nasal lavage fluid (NAL) compared with that evoked by placebo challenge. Twenty-seven subjects were studied: 13 had occupational exposure in a moisture-damaged building, 4 were atopic, and 10 were considered as controls. In all the subjects, the IL-1beta levels were increased significantly both at 6 (p = 0.013) and 24 h (p = .005) after the A. fumigatus challenge compared to placebo. In subjects with previous occupational exposure in a moisture-damaged building, IL-4 concentrations were increased significantly both at 6 (p =.046) and 24 h (p =.008) after the A. fumigatus challenge compared with placebo. Furthermore, in the control group, TNF-alpha levels were significantly increased at 6 h after the A. fumigatus challenge compared to placebo (p = .028). Thus, these data show a link between markers of inflammation in NAL and experimental A. fumigatus challenge.

  19. Plasma Cytokine Levels During Long-Duration Spaceflight

    NASA Technical Reports Server (NTRS)

    Crucian, Brian E.; Zwart, Sara R.; Quiriarte, Heather A.; Smith, Scott M.; Sams, Clarence F.

    2012-01-01

    Determine the in-flight status of immunity, physiological stress, viral immunity/reactivation. Specific measurements include leukocyte distribution, T cell function, cytokine production profiles (mRNA, intracellular, secreted, plasma), virus-specific T cell number/function, latent herpesvirus reactivation, stress hormone levels. Determine the clinical risk related to immune dysregulation for exploration class spaceflight, as well as an appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures. Specific Study Objectives: Determine the nutritional status of astronauts before, during, and after spaceflight ensure adequate intake of energy, protein, and vitamins during missions. The Clinical Nutritional Status Assessment measures dietary intake, body composition, protein, bone, iron, mineral, vitamin, and antioxidant status (60 total analytes). Currently, it is a medical requirement for U.S. crewmembers on-board the ISS. The results of data analysis are used both to understand the connections between nutrition and human health during space flight, and to develop effective dietary strategies to reduce adverse health impacts (including bone loss, loss of important vitamins and minerals, and increased genetic damage from radiation).

  20. Enhancing cytokine-induced killer cell therapy of multiple myeloma.

    PubMed

    Liu, Chunsheng; Suksanpaisan, Lukkana; Chen, Yun-Wen; Russell, Stephen J; Peng, Kah-Whye

    2013-06-01

    Cytokine-induced killer (CIK) cells are in clinical testing against various tumor types, including multiple myeloma. In this study, we show that CIK cells have activity against subcutaneous and disseminated models of human myeloma (KAS-6/1), which can be enhanced by infecting the CIK cells with an oncolytic measles virus (MV) or by pretreating the myeloma cells with ionizing radiation (XRT). KAS-6/1 cells were killed by coculture with CIK or MV-infected CIK (CIK/MV) cells, and the addition of an anti-NKG2D antibody inhibited cytolysis by 50%. However, human bone marrow stromal cells can reduce CIK and CIK/MV mediated killing of myeloma cells (RPMI 8226, JJN-3 and MM1). In vivo, CIK and CIK/MV prolonged the survival of mice with systemic myeloma, although CIK/MV showed enhanced antitumor activity compared with CIK. Irradiation of the KAS-6/1 cells induced mRNA and protein expression of NKG2D ligands, MICA, and MICB in a dose-dependent manner and enhanced delivery of CIK/MV to the irradiated tumors. In both subcutaneous and disseminated myeloma models, XRT at 2 Gy resulted in superior prolongation of the survival of mice given CIK/MV therapy compared with CIK/MV with no XRT. This study demonstrates the potential of CIK against myeloma and that the combination of virotherapy with radiation could be used to further enhance therapeutic outcome using CIK cells.

  1. Cytokines induce nitric oxide production in mouse osteoblasts.

    PubMed

    Damoulis, P D; Hauschka, P V

    1994-06-15

    MC3T3-E1 mouse clonal osteogenic cells were incubated with interferon-gamma, interleukin-1 beta, tumor necrosis factor-alpha, and E. coli lipopolysaccharide. TNF alpha, IL-1 beta, and LPS caused a dose- and time-dependent increase of nitrite (NO2-), the stable metabolite of nitric oxide (NO), in conditioned media over 48 hours, while IFN gamma had a minimal effect. Different combinations of the same factors caused a synergistic enhancement of NO2- accumulation, except for IL-1 beta with LPS. The earliest detectable NO2- production was at 6-9 hours, with continued accumulation over 48 hours. NO2- production was inhibited dose-dependently by three arginine analogs known to be specific inhibitors of NO synthase, as well as by actinomycin D, cycloheximide, and dexamethasone; EGTA or indomethacin had a small inhibitory effect. It is concluded that osteoblast-like cells can be induced by proinflammatory cytokines and bacterial endotoxin to produce NO, which can play an important role in bone pathophysiology.

  2. Viral infection induces cytokine release by beta islet cells.

    PubMed Central

    Cavallo, M G; Baroni, M G; Toto, A; Gearing, A J; Forsey, T; Andreani, D; Thorpe, R; Pozzilli, P

    1992-01-01

    Viral infection has been suggested to play a triggering role in the pancreatic beta cell destruction which occurs in insulin-dependent diabetes (IDDM). However, the underlying mechanism of this phenomenon is unknown. In this study a human insulinoma cell line has been infected with measles, mumps and rubella viruses since a temporal association is reported between the clinical onset of IDDM and diseases caused by these viruses. The infection with measles and mumps viruses induced the release of interleukin-1 (IL-1) and interleukin-6 (IL-6) by the cell line as assessed by a bioassay and up-regulated the expression of human leucocyte antigen (HLA) class I and class II antigens as evaluated by cytofluorimetric analysis. Stimulation with rubella virus induced the release of IL-6 only and had no effect on HLA antigen expression. These data show for the first time that IL-1 and IL-6 secretion by an insulinoma cell line may occur after viral infection and suggest that cytokine release and increased expression of HLA molecules by beta cells may act to induce the immune response towards beta cells in IDDM. PMID:1592439

  3. Role of IRS-2 in insulin and cytokine signalling.

    PubMed

    Sun, X J; Wang, L M; Zhang, Y; Yenush, L; Myers, M G; Glasheen, E; Lane, W S; Pierce, J H; White, M F

    1995-09-14

    The protein IRS-1 acts as an interface between signalling proteins with Src-homology-2 domains (SH2 proteins) and the receptors for insulin, IGF-1, growth hormone, several interleukins (IL-4, IL-9, IL-13) and other cytokines. It regulates gene expression and stimulates mitogenesis, and appears to mediate insulin/IGF-1-stimulated glucose transport. Thus, survival of the IRS-1-/- mouse with only mild resistance to insulin was surprising. This dilemma is provisionally resolved with our discovery of a second IRS-signalling protein. We purified and cloned a likely candidate called 4PS from myeloid progenitor cells and, because of its resemblance to IRS-1, we designate it IRS-2. Alignment of the sequences of IRS-2 and IRS-1 revealed a highly conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, and a poorly conserved carboxy terminus containing several tyrosine phosphorylation motifs. IRS-2 is expressed in many cells, including tissues from IRS-1-/- mice, and may be essential for signalling by several receptor systems.

  4. Application of photonic crystal enhanced fluorescence to a cytokine immunoassay.

    PubMed

    Mathias, Patrick C; Ganesh, Nikhil; Cunningham, Brian T

    2008-12-01

    Photonic crystal surfaces are demonstrated as a means for enhancing the detection sensitivity and resolution for assays that use a fluorescent tag to quantify the concentration of an analyte protein molecule in a liquid test sample. Computer modeling of the spatial distribution of resonantly coupled electromagnetic fields on the photonic crystal surface are used to estimate the magnitude of enhancement factor compared to performing the same fluorescent assay on a plain glass surface, and the photonic crystal structure is fabricated and tested to experimentally verify the performance using a sandwich immunoassay for the protein tumor necrosis factor-alpha (TNFalpha). The demonstrated photonic crystal fabrication method utilizes a nanoreplica molding technique that allows for large-area inexpensive fabrication of the structure in a format that is compatible with confocal microarray laser scanners. The signal-to-noise ratio for fluorescent spots on the photonic crystal is increased by at least 5-fold relative to the glass slide, allowing a TNF-alpha concentration of 1.6 pg/mL to be distinguished from noise on a photonic crystal surface. In addition, the minimum quantitative limit of detection on the photonic crystal surface is one-third the limit on the glass slide--a decrease from 18 to 6 pg/mL. The increased performance of the immunoassay allows for more accurate quantitation of physiologically relevant concentrations of TNF-alpha in a protein microarray format that can be expanded to multiple cytokines.

  5. Active immunization by a dengue virus-induced cytokine.

    PubMed Central

    Chaturvedi, U C; Mukerjee, R; Dhawan, R

    1994-01-01

    Dengue type 2 virus (DV)-induced cytotoxic factor (CF) is capable of reproducing various pathological lesions in mice that are seen in human dengue. The present study was undertaken to investigate the protective effect of active immunization of mice with CF. Mice were immunized with 5 microgram of CF and prevention of CF-induced increase in capillary permeability and damage to the blood-brain barrier were studied at weekly intervals, up to 48 weeks, by challenging with 3 microgram of CF. Maximum protection against increase in capillary permeability and damage to the blood-brain barrier was observed in week 4 after immunization. A breakthrough in the protection occurred with higher doses of CF in a dose-dependent manner. Challenge with a lethal intracerebral (i.c.) dose of DV showed significantly prolonged mean survival time and delayed onset of symptoms of sickness in the immunized mice compared with the normal mice, but the titre of the virus in the brain was similar in the two groups. On i.p. challenge with the virus the protection against damage to the blood-brain barrier was 86 +/- 7% at week 4 and 17 +/- 4% at week 26 after immunization. Sera obtained from the immunized mice showed the presence of CF-specific antibodies by ELISA, Western blot, and by neutralization of the cytotoxic activity of CF in vitro. The present study describes successful prevention of a cytokine-induced pathology by specific active immunization. PMID:8187327

  6. Preterm birth and single nucleotide polymorphisms in cytokine genes

    PubMed Central

    Zhu, Qin; Sun, Jian

    2014-01-01

    Preterm birth (PTB) is an important issue in neonates because of its complications as well as high morbidity and mortality. The prevalence of PTB is approximately 12-13% in USA and 5-9% in many other developed countries. China represents 7.8% (approximately one million) of 14.9 million babies born prematurely annually worldwide. The rate of PTB is still increasing. Both genetic susceptibility and environmental factors are the major causes of PTB. Inflammation is regarded as an enabling characteristic factor of PTB. The aim of this review is to summarize the current literatures to illustrate the role of single nucleotide polymorphisms (SNPs) of cytokine genes in PTB. These polymorphisms are different among different geographic regions and different races, thus different populations may have different risk factors of PTB. SNPs affect the ability to metabolize poisonous substances and determine inflammation susceptibility, which in turn has an influence on reproduction-related risks and on delivery outcomes after exposure to environmental toxicants and pathogenic organisms. PMID:26835330

  7. Cryptococcus gattii induces a cytokine pattern that is distinct from other cryptococcal species.

    PubMed

    Schoffelen, Teske; Illnait-Zaragozi, Maria-Teresa; Joosten, Leo A B; Netea, Mihai G; Boekhout, Teun; Meis, Jacques F; Sprong, Tom

    2013-01-01

    Understanding more about the host's immune response to different Cryptococcus spp. will provide additional insight into the pathogenesis of cryptocococcis. We hypothesized that the ability of C. gattii to cause disease in immunocompetent humans depends on a distinct innate cytokine response of the host to this emerging pathogen. In the current study we assessed the cytokine profile of human peripheral blood mononuclear cells (PBMCs) of healthy individuals, after in vitro stimulation with 40 different well-defined heat-killed isolates of C. gattii, C. neoformans and several hybrid strains. In addition, we investigated the involvement of TLR2, TLR4 and TLR9 in the pro-inflammatory cytokine response to C. gattii. Isolates of C. gattii induced higher concentrations of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6 and the Th17/22 cytokine IL-17 and IL-22 compared to C. neoformans var neoformans and C. neoformans var grubii. In addition, clinical C. gattii isolates induced higher amounts of cytokines than environmental isolates. This difference was not observed in C. neoformans var. grubii isolates. Furthermore, we demonstrated a likely contribution of TLR4 and TLR9, but no role for TLR2, in the host's cytokine response to C. gattii. In conclusion, clinical heat-killed C. gattii isolates induced a more pronounced inflammatory response compared to other Cryptococcus species and non-clinical C. gattii. This is dependent on TLR4 and TLR9 as cellular receptors.

  8. Mast cells in the cytokine network: the what, where from and what for.

    PubMed

    Czarnetzki, B M; Grabbe, J; Kolde, G; Krüger-Krasagakes, S; Welker, P; Zuberbier, T

    1995-08-01

    The basic understanding of mast cell ontogeny and function has been fundamentally changed in recent years with observations that the cells produce and respond to a broad range of cytokines. These rapidly accruing data and their potential significance were discussed at the recent symposium "Mast Cells in the Cytokine Network", and the overview lectures of most speakers are summarized in this special journal issue. In the present introductory manuscript, the organizers of the meeting discuss data fundamental to an understanding of the topic and highlight aspects of special interest. They consider mast cells to be defined most reliably by their unique ultrastructure since the cells are highly heterogeneous in dependence of the species studied, their tissue location, their stage of development and probably also in relation to cytokines. Most other characteristics of mast cells are shared with diverse other cell types. Murine mast cell development is induced by several cytokines. These factors are mostly ineffective in human cells except for stem cell factor which causes mast cell development from CD34+/c-kit+ progenitors. There is however recent evidence that fibroblasts and keratinocytes produce additional growth factors for human mast cells. Regarding cytokine secretion, most molecules known so far are produced by both murine and human mast cells. The cells furthermore bear receptors for several cytokines, enabling them to respond in an autocrine and paracrine fashion. Mast cells may thus function within a complex cytokine network, affecting physiological as well as immunological and inflammatory processes.

  9. Serum Cytokine Levels in Major Depressive Disorder and Its Role in Antidepressant Response

    PubMed Central

    Myung, Woojae; Lim, Shinn-Won; Woo, Hye In; Park, Jin Hong; Shim, Sanghong

    2016-01-01

    Objective Cytokines have been reported to have key roles in major depressive disorder (MDD). However, much less is known about cytokines in MDD and antidepressant treatment due to the diversity of cytokines and the heterogeneity of depression. We investigated the levels of cytokines in patients with MDD compared with healthy subjects and their associations with antidepressant response. Methods We investigated the changes of several cytokines (eotaxin, sCD40L, IL-8, MCP-1alpha, TNF-alpha, INF-gamma and MIP-1alpha) by Luminex assay in 66 patients with MDD and 22 healthy controls. The antidepressant response was assessed by 17-item Hamilton Rating Scale for Depression. Results We found the levels of sCD40L (p=0.001), IL-8 (p=0.004) and MCP-1 (p=0.03) of healthy controls were significantly higher than those of depressive patients. However, the level of eotaxin and TNF-alpha were not associated with MDD. In addition, we found the level of MCP-1 was significantly changed after antidepressant treatment (p=0.01). Conclusion These findings suggest the roles of cytokines in MDD are complex, and could vary according to the individual characteristics of each patient. Further studies regarding the relationship between cytokines and MDD will be required. PMID:27909456

  10. Cytokine levels in rat blood and brain structures after administration of lipopolysaccharide.

    PubMed

    Abramova, A Yu; Pertsov, S S; Kozlov, A Yu; Nikenina, E V; Kalinichenko, L S; Dudnik, E N; Alekseeva, I V

    2013-08-01

    We compared cytokine profile of rat serum and brain structures after immune status modulation by LPS (30 μg/kg intraperitoneally). The content of inflammatory (IL-1α, IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) and anti-inflammatory (IL-4 and IL-10) cytokines in biological samples of animals was measured on days 1 and 7 after antigenic stimulation. LPS administration reduced the levels of both inflammatory and anti-inflammatory cytokines in the peripheral blood of the rats, especially on the 1st day. LPS administration was also accompanied by specific changes in cytokine content in the dorsal hippocampus and anterior cingulate cortex. Antigenic stimulation increased the level of anti-inflammatory cytokines IL-4 and IL-10 in the examined brain tissues, the changes were most pronounced on day 1 after LPS injection. No significant changes in the levels of proinflammatory cytokines in the brain tissue of animals were found at the above terms after LPS injection. Thus, peripheral LPS administration to rats shifts the balance between the inflammatory and anti-inflammatory cytokines in the CNS structures towards the latter.

  11. Abdominal visceral adiposity influences CD4+ T cell cytokine production in pregnancy.

    PubMed

    Ozias, Marlies K; Li, Shengqi; Hull, Holly R; Brooks, William M; Petroff, Margaret G; Carlson, Susan E

    2015-02-01

    Women with pre-gravid obesity are at risk for pregnancy complications. While the macrophage response of obese pregnant women categorized by body mass index (BMI) has been documented, the relationship between the peripheral CD4(+) T cell cytokine profile and body fat compartments during pregnancy is unknown. In this study, third trimester peripheral CD4(+) T cell cytokine profiles were measured in healthy pregnant women [n=35; pre-pregnancy BMI: 18.5-40]. CD4(+) T cells were isolated from peripheral blood mononuclear cells and stimulated to examine their capacity to generate cytokines. Between 1 and 3weeks postpartum, total body fat was determined by dual-energy X-ray absorptiometry and abdominal subcutaneous and visceral fat masses were determined by magnetic resonance imaging. Pearson's correlation was performed to assess relationships between cytokines and fat mass. Results showed that greater abdominal visceral fat mass was associated with a decrease in stimulated CD4(+) T cell cytokine expression. IFN-gamma, TNF-alpha, IL-12p70, IL-10 and IL-17A were inversely related to visceral fat mass. Chemokines CCL3 and IL-8 and growth factors G-CSF and FLT-3L were also inversely correlated. Additionally, total body fat mass was inversely correlated with FGF-2 while abdominal subcutaneous fat mass and BMI were unrelated to any CD4(+) T cell cytokine. In conclusion, lower responsiveness of CD4(+) T cell cytokines associated with abdominal visceral fat mass is a novel finding late in gestation.

  12. Inflammatory cytokine expression in the quadriceps of rats with posttraumatic knee stiffness: A preliminary study.

    PubMed

    Liu, Kemin; Wang, Fei; Cui, Zhigang; Liu, Sihai; Han, Xinzuo

    2015-06-01

    The primary purpose of this study was to investigate cytokine expression in the quadriceps of rats with posttraumatic knee stiffness (PTKS) and to determine the effect of exercise training on these cytokines at different follow-up time points. The PTKS rats were randomly assigned into two even groups. The treatment group received exercise training, while the control group received no treatment. Quadriceps specimens were harvested randomly from each group at 8, 12, 16, and 20 weeks. RT-qPCR and immunohistochemical analyses were used to assess the protein and mRNA expression levels of the cytokines IL-1, IL-2, TNF-α, COX-1, and COX-2. TNF-α immunostaining did not differ between the treated and control group tissues, whereas weak immunostaining was observed for all other cytokines in the specimens from the treatment group compared with those from the control group at approximately 12 and 20 weeks. The cytokine levels decreased at approximately 8 weeks in the treatment group, whereas these levels remained elevated or plateaued in the control group. These differences were statistically significant (p<0.05). This study demonstrated that the expression of cytokines IL-1, IL-2, COX-1, and COX-2 increased in the quadriceps of rats with PTKS and that exercise training affected the observed profile trends of these cytokines.

  13. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review.

    PubMed

    Kothur, Kavitha; Wienholt, Louise; Brilot, Fabienne; Dale, Russell C

    2016-01-01

    Despite improved understanding of the pathogenesis of neuroinflammatory disorders of the brain and development of new diagnostic markers, our biomarker repertoire to demonstrate and monitor inflammation remains limited. Using PubMed database, we reviewed 83 studies on CSF cytokines and chemokines and describe the pattern of elevation and possible role of cytokines/chemokines as biomarkers in viral and autoimmune inflammatory neurological disorders of the CNS. Despite inconsistencies and overlap of cytokines and chemokines in different neuroinflammation syndromes, there are some trends regarding the pattern of cytokines/chemokine elevation. Namely B cell markers, such as CXCL13 and BAFF are predominantly investigated and found to be elevated in autoantibody-associated disorders, whereas interferon gamma (IFN-γ) is elevated mainly in viral encephalitis. Th2 and Th17 cytokines are frequently elevated in acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO), whereas Th1 and Th17 cytokines are more commonly elevated in multiple sclerosis (MS). Cytokine/chemokine profiling might provide new insights into disease pathogenesis, and improve our ability to monitor inflammation and response to treatment.

  14. Role of inflammatory cytokines in the response of solid cancers to photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Sun, Jinghai; Cecic, Ivana; Dougherty, Graeme J.

    2001-04-01

    Photodynamic therapy (PDT) elicits a strong acute inflammatory response that has both local and systemic (acute phase response) attributes. The insult mediated by PDT-induced oxidative stress at the targeted site triggers a complex multifactorial response engaging host defence mechanisms associated with the inflammatory process to participate in the eradication of the treated tumor. Inflammatory cytokines are important mediators of critical events in this process as they regulate the activity of inflammatory, endothelial and other cells. The initial stimulus for enhanced production and release of cytokines likely originates from several types of events, such as activated transcription factors and complement deposition. The PDT-induced complement activation appears to be directly linked to the enhanced expression of various cytokines, including chemokines such as KC (in mouse models), and classic inflammatory cytokines such as IL-1β, TNF-α , IL-6 and IL-10. A variety of interventions that modulate the activity of particular cytokines performed in conjunction with PDT were shown to influence the therapy outcome. The treatments such as using blocking antibodies and local or systemic cytokine delivery may either reduce or dramatically improve the curative effect of PDT. The inflammatory and related cytokines that at present appear particularly interesting and merit further investigation for use as adjuvants to PDT are IL-3, IL-8, IL-15, TNF-α, IFN-γ, G-CSF and GM-CSF.

  15. Principles of interleukin (IL)-6-type cytokine signalling and its regulation.

    PubMed Central

    Heinrich, Peter C; Behrmann, Iris; Haan, Serge; Hermanns, Heike M; Müller-Newen, Gerhard; Schaper, Fred

    2003-01-01

    The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed. PMID:12773095

  16. Modulating Effect of Cytokines on Mechanisms of Synaptic Plasticity in the Brain.

    PubMed

    Levin, S G; Godukhin, O V

    2017-03-01

    After accumulation of data showing that resident brain cells (neurons, astrocytes, and microglia) produce mediators of the immune system, such as cytokines and their receptors under normal physiological conditions, a critical need emerged for investigating the role of these mediators in cognitive processes. The major problem for understanding the functional role of cytokines in the mechanisms of synaptic plasticity, de novo neurogenesis, and learning and memory is the small number of investigated cytokines. Existing concepts are based on data from just three proinflammatory cytokines: interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. The amount of information in the literature on the functional role of antiinflammatory cytokines in the mechanisms of synaptic plasticity and cognitive functions of mature mammalian brain is dismally low. However, they are of principle importance for understanding the mechanisms of local information processing in the brain, since they modulate the activity of individual cells and local neural networks, being able to reconstruct the processes of synaptic plasticity and intercellular communication, in general, depending on the local ratio of the levels of different cytokines in certain areas of the brain. Understanding the functional role of cytokines in cellular mechanisms of information processing and storage in the brain would allow developing preventive and therapeutic means for the treatment of neuropathologies related to impairment of these mechanisms.

  17. Polyfunctional responses by human T cells result from sequential release of cytokines

    PubMed Central

    Han, Qing; Bagheri, Neda; Bradshaw, Elizabeth M.; Hafler, David A.; Lauffenburger, Douglas A.; Love, J. Christopher

    2012-01-01

    The release of cytokines by T cells defines a significant part of their functional activity in vivo, and their ability to produce multiple cytokines has been associated with beneficial immune responses. To date, time-integrated end-point measurements have obscured whether these polyfunctional states arise from the simultaneous or successive release of cytokines. Here, we used serial, time-dependent, single-cell analysis of primary human T cells to resolve the temporal dynamics of cytokine secretion from individual cells after activation ex vivo. We show that multifunctional, Th1-skewed cytokine responses (IFN-γ, IL-2, TNFα) are initiated asynchronously, but the ensuing dynamic trajectories of these responses evolve programmatically in a sequential manner. That is, cells predominantly release one of these cytokines at a time rather than maintain active secretion of multiple cytokines simultaneously. Furthermore, these dynamic trajectories are strongly associated with the various states of cell differentiation suggesting that transient programmatic activities of many individual T cells contribute to sustained, population-level responses. The trajectories of responses by single cells may also provide unique, time-dependent signatures for immune monitoring that are less compromised by the timing and duration of integrated measures. PMID:22160692

  18. Efficient killing of radioresistant breast cancer cells by cytokine-induced killer cells.

    PubMed

    Guo, Qingming; Zhu, Danni; Bu, Xiaocui; Wei, Xiaofang; Li, Changyou; Gao, Daiqing; Wei, Xiaoqiang; Ma, Xuezhen; Zhao, Peng

    2017-03-01

    Recurrence of breast cancer after radiotherapy may be partly explained by the presence of radioresistant cells. Thus, it would be desirable to develop an effective therapy against radioresistant cells. In this study, we demonstrated the intense antitumor activity of cytokine-induced killer cells against MCF-7 and radioresistant MCF-7 cells, as revealed by cytokine-induced killer-mediated cytotoxicity, tumor cell proliferation, and tumor invasion. Radioresistant MCF-7 cells were more susceptible to cytokine-induced killer cell killing. The stronger cytotoxicity of cytokine-induced killer cells against radioresistant MCF-7 cells was dependent on the expression of major histocompatibility complex class I polypeptide-related sequence A/B on radioresistant MCF-7 cells after exposure of cytokine-induced killer cells to sensitized targets. In addition, we demonstrated that cytokine-induced killer cell treatment sensitized breast cancer cells to chemotherapy via the downregulation of TK1, TYMS, and MDR1. These results indicate that cytokine-induced killer cell treatment in combination with radiotherapy and/or chemotherapy may induce synergistic antitumor activities and represent a novel strategy for breast cancer.

  19. Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model.

    PubMed

    Liu, Yu-Ching; Ho, Heng-Chien; Lee, Miau-Rong; Lai, Kuang-Chi; Yeh, Chung-Min; Lin, Yueh-Min; Ho, Tin-Yun; Hsiang, Chien-Yun; Chung, Jing-Gung

    2012-07-15

    The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9-18 fold) of induction in the microarray data, and its early induction was observed in a 2h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

  20. Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model

    SciTech Connect

    Liu, Yu-Ching; Ho, Heng-Chien; Lee, Miau-Rong; Lai, Kuang-Chi; Yeh, Chung-Min; Lin, Yueh-Min; Ho, Tin-Yun; Hsiang, Chien-Yun; Chung, Jing-Gung

    2012-07-15

    The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9–18 fold) of induction in the microarray data, and its early induction was observed in a 2 h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

  1. Cytokine Production in the Serum and Spleen of Mice from Day 6 to 14 of Gestation: Cytokines/Placenta/ Spleen/Serum

    PubMed Central

    Iconomidou, Bessy

    1995-01-01

    Pregnancy, like most biologic phenomena, involves the action of cytokines. These proteins have a short half-life and are believed to exert their effect close to their site of production, where diagnostic tests cannot be easily performed. Here we show that the cytokine content in the maternal serum reflects cytokine production and secretion from maternal spleen cells, which also correlates with production from decidual cells. We show that GM-CSF, IL- 3, and IL-10 are present in the serum at specific time intervals during the first half of murine pregnancy, which correlates with their production from maternal spleen cells. Purified GM-CSF and IL-3 from spleen-cell-culture supernatants are biologically active molecules, able to stimulate placental-cell proliferation. Furthermore, TNF-0, which has been identified in many cases of fetal rejection as well as in labor, is shown to be naturally produced during the second half of pregnancy. Additionally, within the limits of the sensitivity of the technique we have used, the detection of IL-4 and the absence of detectable levels of IL- 2 in the maternal serum strongly comforts the hypothesis that pregnancy is a Th2-dependent phenomenon. The results presented in this paper show that the cytokine profile during pregnancy can be monitored by simple blood tests, which may be of relevance both in the followup of a physiological human pregnancy and to the diagnosis of recurrent abortions due to cytokine imbalance. PMID:8924760

  2. Emerging Cytokine Biosensors with Optical Detection Modalities and Nanomaterial-Enabled Signal Enhancement.

    PubMed

    Singh, Manpreet; Truong, Johnson; Reeves, W Brian; Hahm, Jong-In

    2017-02-22

    Protein biomarkers, especially cytokines, play a pivotal role in the diagnosis and treatment of a wide spectrum of diseases. Therefore, a critical need for advanced cytokine sensors has been rapidly growing and will continue to expand to promote clinical testing, new biomarker development, and disease studies. In particular, sensors employing transduction principles of various optical modalities have emerged as the most common means of detection. In typical cytokine assays which are based on the binding affinities between the analytes of cytokines and their specific antibodies, optical schemes represent the most widely used mechanisms, with some serving as the gold standard against which all existing and new sensors are benchmarked. With recent advancements in nanoscience and nanotechnology, many of the recently emerging technologies for cytokine detection exploit various forms of nanomaterials for improved sensing capabilities. Nanomaterials have been demonstrated to exhibit exceptional optical properties unique to their reduced dimensionality. Novel sensing approaches based on the newly identified properties of nanomaterials have shown drastically improved performances in both the qualitative and quantitative analyses of cytokines. This article brings together the fundamentals in the literature that are central to different optical modalities developed for cytokine detection. Recent advancements in the applications of novel technologies are also discussed in terms of those that enable highly sensitive and multiplexed cytokine quantification spanning a wide dynamic range. For each highlighted optical technique, its current detection capabilities as well as associated challenges are discussed. Lastly, an outlook for nanomaterial-based cytokine sensors is provided from the perspective of optimizing the technologies for sensitivity and multiplexity as well as promoting widespread adaptations of the emerging optical techniques by lowering high thresholds currently

  3. Effects of Risperidone on Cytokine Profile in Drug-Naïve First-Episode Psychosis

    PubMed Central

    Noto, Cristiano; Ota, Vanessa Kiyomi; Gouvea, Eduardo S.; Rizzo, Lucas B.; Spindola, Leticia M. N.; Honda, Pedro H. S.; Cordeiro, Quirino; Belangero, Sintia Iole; Bressan, Rodrigo Affonseca; Gadelha, Ary; Maes, Michael

    2015-01-01

    Background: There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. Methods: The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. Results: We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone-induced changes in IL-10 and the negative symptoms. Conclusions: In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T-regulatory functions. PMID:25522386

  4. Emerging Cytokine Biosensors with Optical Detection Modalities and Nanomaterial-Enabled Signal Enhancement

    PubMed Central

    Singh, Manpreet; Truong, Johnson; Reeves, W. Brian; Hahm, Jong-in

    2017-01-01

    Protein biomarkers, especially cytokines, play a pivotal role in the diagnosis and treatment of a wide spectrum of diseases. Therefore, a critical need for advanced cytokine sensors has been rapidly growing and will continue to expand to promote clinical testing, new biomarker development, and disease studies. In particular, sensors employing transduction principles of various optical modalities have emerged as the most common means of detection. In typical cytokine assays which are based on the binding affinities between the analytes of cytokines and their specific antibodies, optical schemes represent the most widely used mechanisms, with some serving as the gold standard against which all existing and new sensors are benchmarked. With recent advancements in nanoscience and nanotechnology, many of the recently emerging technologies for cytokine detection exploit various forms of nanomaterials for improved sensing capabilities. Nanomaterials have been demonstrated to exhibit exceptional optical properties unique to their reduced dimensionality. Novel sensing approaches based on the newly identified properties of nanomaterials have shown drastically improved performances in both the qualitative and quantitative analyses of cytokines. This article brings together the fundamentals in the literature that are central to different optical modalities developed for cytokine detection. Recent advancements in the applications of novel technologies are also discussed in terms of those that enable highly sensitive and multiplexed cytokine quantification spanning a wide dynamic range. For each highlighted optical technique, its current detection capabilities as well as associated challenges are discussed. Lastly, an outlook for nanomaterial-based cytokine sensors is provided from the perspective of optimizing the technologies for sensitivity and multiplexity as well as promoting widespread adaptations of the emerging optical techniques by lowering high thresholds currently

  5. Multiple Serum Cytokine Profiling to Identify Combinational Diagnostic Biomarkers in Attacks of Familial Mediterranean Fever

    PubMed Central

    Koga, Tomohiro; Migita, Kiyoshi; Sato, Shuntaro; Umeda, Masataka; Nonaka, Fumiaki; Kawashiri, Shin-Ya; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Nakamura, Hideki; Origuchi, Tomoki; Ueki, Yukitaka; Masumoto, Junya; Agematsu, Kazunaga; Yachie, Akihiro; Yoshiura, Koh-Ichiro; Eguchi, Katsumi; Kawakami, Atsushi

    2016-01-01

    Abstract The precise cytokine networks in the serum of individuals with familial Mediterranean fever (FMF) that are associated with its pathogenesis have been unknown. Here, we attempted to identify specific biomarkers to diagnose or assess disease activity in FMF patients. We measured serum levels of 45 cytokines in 75 FMF patients and 40 age-matched controls by multisuspension cytokine array. FMF in “attack” or “remission” was classified by Japan College of Rheumatology-certified rheumatologists according to the Tel Hashomer criteria. Cytokines were ranked by their importance by a multivariate classification algorithm. We performed a logistic regression analysis to determine specific biomarkers for discriminating FMF patients in attack. To identify specific molecular networks, we performed a cluster analysis of each cytokine. Twenty-nine of the 45 cytokines were available for further analyses. Eight cytokines’ serum levels were significantly elevated in the FMF attack versus healthy control group. Nine cytokines were increased in FMF attack compared to FMF remission. Multivariate classification algorithms followed by a logistic regression analysis revealed that the combined measurement of IL-6, IL-18, and IL-17 distinguished FMF patients in attack from the controls with the highest accuracy (sensitivity 89.2%, specificity 100%, and accuracy 95.5%). Among the FMF patients, the combined measurement of IL-6, G-CSF, IL-10, and IL-12p40 discriminated febrile attack periods from remission periods with the highest accuracy (sensitivity 75.0%, specificity 87.9%, and accuracy 84.0%). Our data identified combinational diagnostic biomarkers in FMF patients based on the measurement of multiple cytokines. These findings help to improve the diagnostic performance of FMF in daily practice and extend our understanding of the activation of the inflammasome leading to enhanced cytokine networks. PMID:27100444

  6. Relationship between Pesticide Metabolites, Cytokine Patterns, and Asthma-Related Outcomes in Rural Women Workers

    PubMed Central

    Mwanga, Hussein H.; Dalvie, Mohamed Aqiel; Singh, Tanusha S.; Channa, Kalavati; Jeebhay, Mohamed F.

    2016-01-01

    The objective of this study was to investigate the relationship between exposure to organophosphate (OP) and pyrethroid (PYR) pesticides with serum cytokine patterns and asthma-related outcomes among rural women workers. A cross-sectional study was conducted among rural women (n = 211), including those working and living on farms and nearby town dwellers. Pesticide exposure was assessed using urinary metabolite concentrations of OP and PYR pesticides. Health outcome assessment was ascertained through the European Community Respiratory Health Survey (ECRHS) questionnaire, fractional exhaled nitric oxide (FeNO), and serum cytokines associated with asthma. The prevalence of doctor-diagnosed asthma was 11%, adult-onset asthma 9%, and current asthma 6%. In this population, the proportion of T helper type 2 (Th2) cytokines (interleukin (IL)-4, IL-5, and IL-13) detectable in subjects was between 18% and 40%, while the proportion of non-Th2 cytokines (IL-6, IL-8, IL-10, IL-17, and interferon gamma) was between 35% and 71%. Most Th2 and non-Th2 cytokines were positively associated with either OP or PYR metabolites. Non-Th2 cytokines showed much stronger associations with OP metabolites (Dimethyl phosphate OR = 4.23; 95% CI: 1.54–11.65) than Th2 cytokines (Dimethyl phosphate OR = 1.69; 95% CI: 0.83–3.46). This study suggests that exposure to most OP and some PYR pesticides may be associated with asthma-related cytokines, with non-Th2 cytokines demonstrating consistently stronger relationships. PMID:27690066

  7. Pro- and anti-inflammatory cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome.

    PubMed

    Breen, Elizabeth Crabb

    2002-09-01

    In persons with human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS), the immune system becomes dysfunctional in many ways. There is both immunodeficiency due to the loss of CD4-positive T helper cells and hyperactivity as a result of B-cell activation. Likewise, both decreases and increases are seen in the production and/or activity of cytokines. Cytokine changes in HIV infection have been assessed by a variety of techniques, ranging from determination of cytokine gene expression at the mRNA level to secretion of cytokine proteins in vivo and in vitro. Changes in cytokine levels in HIV-infected persons can affect the function of the immune system, and have the potential to directly impact the course of HIV disease by enhancing or suppressing HIV replication. In particular, the balance between the pro-inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha, which up-regulate HIV expression, and IL-10, which can act both as an anti-inflammatory cytokine and a B-cell stimulatory factor, may play an important role in the progression to AIDS. In light of its ability to suppress the production of pro-inflammatory cytokines and, under some conditions, suppress HIV replication, increased IL-10 may be viewed as beneficial in slowing HIV disease progression. However, an association between increased IL-10 and the development of AIDS-associated B-cell lymphoma highlights the bifunctional nature of IL-10 as both an anti-inflammatory and B-cell-stimulatory cytokine that could have beneficial and detrimental effects on the course of HIV infection and AIDS.

  8. Differential binding of cytokines to environmentally relevant particles: a possible source for misinterpretation of in vitro results?

    PubMed

    Kocbach, A; Totlandsdal, A I; Låg, M; Refsnes, M; Schwarze, P E

    2008-01-30

    Inflammation is considered as a key event in adverse health effects associated with exposure to ambient particulate matter. The inflammatory potential of particles is often compared using in vitro cell systems, where the particle-induced release of pro-inflammatory cytokines is measured. A major concern in these assays is the potential of particles to bind cytokines, which may lead to an underestimation of the inflammatory potential. We therefore investigated the cytokine binding to a selection of particle samples, including particles collected from outdoor sources (wood combustion, traffic) and particles commonly used to model environmental sources (ultrafine carbon black, diesel, quartz), for a range of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IL-8). Furthermore, the influence of serum proteins and particle- and cytokine concentrations on the cytokine binding was studied. Cytokines primarily bound to carbonaceous particles (up to 85%), not to mineral particles. Furthermore, depending on the type of cytokine, the cytokine binding could be reduced partly or completely by adding serum proteins to the cell growth medium or particle suspensions. Based on these observations we recommend either to adjust culturing and exposure conditions to prevent cytokine binding, or to adjust the measured cytokine release by application of correction factors obtained from cytokine binding experiments.

  9. Serum cytokine and chemokine profiles in patients with chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Beppu, Minako; Sawai, Setsu; Misawa, Sonoko; Sogawa, Kazuyuki; Mori, Masahiro; Ishige, Takayuki; Satoh, Mamoru; Nomura, Fumio; Kuwabara, Satoshi

    2015-02-15

    To identify serum cytokine networks specific to chronic inflammatory demyelinating polyneuropathy (CIDP), serum samples of two subgroups (18 patients with typical CIDP and 12 patients with multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]) were analyzed with multiplex magnetic bead-based cytokine assay. TNF-α, HGF, MIP-1β and IL-1β levels were significantly higher in total CIDP patients than in normal controls. Of these, HGF levels were elevated in typical CIDP patients, but not in MADSAM patients. Patients with high HGF levels showed good responses to steroid treatment. Different cytokine profiles among the CIDP subtypes presumably reflect differences in pathophysiology.

  10. IL-17 family member cytokines: regulation, and function in innate immunity

    PubMed Central

    Reynolds, Joseph M.; Angkasekwinai, Pornpimon; Dong, Chen

    2010-01-01

    Recently, the IL-17 family member cytokines have become prominent subjects of investigation. IL-17 (IL-17A) is the best-described member of this family where its production has been mainly attributed to a specialized T helper subset of the adaptive immune response termed Th17. However, recent research on this and other Th17 cytokines has revealed new sources and functions of IL-17 family members in the innate immune response. This review will highlight recent advances in the field of IL-17 family member cytokines and will predominately focus on the innate regulation and function of IL-17, IL-17F, and IL-25. PMID:21074482

  11. A new platform for constructing antibody-cytokine fusion proteins (immunocytokines) with improved biological properties and adaptable cytokine activity.

    PubMed

    Gillies, Stephen D

    2013-10-01

    A novel method for constructing immunocytokines has been developed that utilizes fusion of cytokines to the C-terminus of the Ig light chain, rather than fusing to the heavy chain. Such molecules are expressed well in transfected cells, are very stable in normal buffers and have biological properties that are superior to immunocytokines made by fusion to the heavy chain. These properties include longer circulating half-life, increased uptake following subcutaneous dosing and similar or improved antibody effector activities of antibody-dependent cytotoxic activity and complement-dependent cytotoxicity, respectively. Furthermore, the sequestering effect of this fusion junction allows one to adjust intermediate affinity (βγ) interleukin 2 receptor (IL2R) binding and activation by shortening the N-terminus of IL2 at the fusion point. This appears to limit access of the critical contact residue Asp20 of IL2 to the β-chain of βγ IL2R, while maintaining binding and activation of high-affinity (αβγ) IL2R-expressing cells. Several immunocytokine forms with varying degrees of IL2R specificity have been constructed, and some appear to regain their activity for the βγ IL2R when bound to antigen-coated beads. Such molecules may have reduced toxicity in the circulation and enhanced anti-tumor activity.

  12. Role of the cytokine environment and cytokine receptor expression on the generation of functionally distinct dendritic cells from human monocytes.

    PubMed

    Conti, Lucia; Cardone, Marco; Varano, Barbara; Puddu, Patrizia; Belardelli, Filippo; Gessani, Sandra

    2008-03-01

    Myeloid dendritic cells (DC) and macrophages evolve from a common precursor. However, factors controlling monocyte differentiation toward DC or macrophages are poorly defined. We report that the surface density of the GM-CSF receptor (GM-CSFR) alpha subunit in human peripheral blood monocytes varies among donors. Although no correlation was found between the extent of GM-CSFR and monocyte differentiation into DC driven by GM-CSF and IL-4, GM-CSFR expression strongly influenced the generation of CD1a(+) dendritic-like cells in the absence of IL-4. CD1a(+) cells generated in the presence of GM-CSF express CD40, CD80, MHC class I and II, DC-SIGN, MR, CCR5, and partially retain CD14 expression. Interestingly, they spontaneously induce the expansion of CD4(+) and CD8(+) allogeneic T lymphocytes producing IFN-gamma, and migrate toward CCL4 and CCL19. Upon stimulation with TLR ligands, they acquire the phenotypic features of mature DC. In contrast, the allostimulatory capacity is not further increased upon LPS activation. However, by blocking LPS-induced IL-10, a higher T cell proliferative response and IL-12 production were observed. Interestingly, IL-23 secretion was not affected by endogenous IL-10. These results highlight the importance of GM-CSFR expression in monocytes for cytokine-induced DC generation and point to GM-CSF as a direct player in the generation of functionally distinct DC.

  13. Regulatory T-cell cytokines in patients with nonsegmental vitiligo.

    PubMed

    Kidir, Mehtap; Karabulut, Ayse A; Ercin, Mustafa E; Atasoy, Pınar

    2017-05-01

    In the etiopathogenesis of vitiligo, the role of suppressor cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), associated with regulatory T-cells (Treg) is not completely known. In this study, the role of Treg-cell functions in the skin of patients with nonsegmental vitiligo was investigated. Lesional and nonlesional skin samples from 30 adult volunteers ranging in age from 18 to 36 years with nonsegmental vitiligo were compared with normal skin area excision specimens of 30 benign melanocytic nevus cases as controls. All samples were evaluated staining for forkhead box P3 (Foxp3), TGF-β, and IL-10 using the standardized streptavidin-biotin immunoperoxidase immunohistochemistry method. Foxp3 expression was lower in lesional vitiligo skin specimens compared to controls; it was also lower in lesional vitiligo specimens than nonlesional vitiligo specimens. IL-10 levels were lower in lesional vitiligo specimens compared to the controls, whereas IL-10 expression was significantly lower in lesional specimens compared with nonlesional specimens. TGF-β expression was higher in both lesional and nonlesional skin specimens of patients with vitiligo compared to controls. TGF-β expression was lower in lesional skin specimens than nonlesional skin specimens. In addition, there was no significant correlation between Foxp3 expression with TGF-β and IL-10 expressions in lesional skin specimens in the vitiligo group. In this study, results supporting the contribution of Treg cells and IL-10 deficiency to the autoimmune process were obtained. Therefore, future studies are necessary to demonstrate the definitive role of Treg-cell functions in the etiopathogenesis of vitiligo.

  14. Selected serum cytokines in systemic lupus erythematosus treated with quinagolide.

    PubMed

    Hrycek, A; Cieślik, P; Tustanowski, J; Nowak, S; Jedynak, P

    2001-01-01

    The objective of this study was to determine the effect of quinagolide (Norprolac) on serum level of cytokines in systemic lupus erythematosus (SLE) patients. In 20 SLE patients treated with a low dose of quinagolide, and in 17 healthy persons who constituted the control group, concentration of serum prolactin (PRL), interleukins (ILs), soluble tumor necrosis factor receptors (sTNF Rs) preceded by calculation of disease activity index (SLEDAI) were tested at entry and then after 3 months in 16 patients and after 6 months in 11 patients who completed the study. Serum PRL level was higher (though insignificantly) in the SLE group than in the controls and decreased significantly after 6 months of therapy. A raised SLEDAI score at entry was significantly reduced during therapy but a weak correlation with PRL level was revealed. A significant increase in IL-6 level in SLE group as compared to controls was observed (respectively 14.57 +/- 13.25 and 5.04 +/- 3.35 microg/ml) as well as a significantly decreased level after 6 months of treatment (4.30 +/- 2.51 pg/ml). There was a significant difference between sTNF RI concentration before and after 3 months of quinagolide treatment (respectively 1140.83 +/- 312.08 and 1454.58 +/- 465.54 pg/ml). After 6 months of treatment a statistically significant correlation between concentration of PRL and level of IL-6 and a negative correlation between PRL and sTNF RI was revealed. Quinagolide treatment may have a role in the management of SLE patients.

  15. Cytokine-induced macrophage differentiation: a tale of 2 genes.

    PubMed

    Winston, B W; Krein, P M; Mowat, C; Huang, Y

    1999-12-01

    Macrophages are versatile cells found in every tissue in the body. They must perform a number of diverse cellular functions that allow them to kill invading micro-organisms and neoplastic cells as well as produce growth factors involved in wound healing. Macrophages that develop these diverse functions arise from a common precursor. By a process of selective adaptation, the common precursor monocyte/macrophage differentiates into a distinctive macrophage with a different and specific phenotype, characterized by the expression of a specific set of gene products. The local environment plays a critical role in shaping or directing the pattern or pathway of macrophage differentiation. The authors have focused on 2 specific macrophage differentiation pathways in a murine bone marrow-derived macrophage model. One pathway is believed to play a role in wound repair and is characterized by the induction of insulin-like growth factor-1 (IGF-I). The second pathway is involved in macrophage cytocidal activation and is characterized by the induction of the inducible form of nitric oxide synthase (iNOS). The pleotropic cytokine tumour necrosis factor-alpha (TNF-alpha) appears to mediate macrophage differentiation along both of these pathways. Interferon-gamma (IFN-gamma), however, appears to act as a molecular switch. In the presence of IFN-gamma, stimulation of macrophages with TNF-alpha results in macrophage differentiation along a pathway in which iNOS is expressed, whereas, in the absence of IFN-gamma, stimulation of macrophages with TNF-alpha results in differentiation along a pathway in which IGF-I is expressed. The authors focus on some of the molecular events involved in TNF-alpha and IFN-gamma signal transduction and the regulation of iNOS and IGF-I genes in macrophages.

  16. Carbohydrate Supplementation Influences Serum Cytokines after Exercise under Hypoxic Conditions

    PubMed Central

    Caris, Aline Venticinque; Da Silva, Edgar Tavares; Dos Santos, Samile Amorim; Lira, Fabio Santos; Oyama, Lila Missae; Tufik, Sergio; Dos Santos, Ronaldo Vagner Thomatieli

    2016-01-01

    Introduction: Exercise performed at the hypoxia equivalent of an altitude of 4200 m is associated with elevated inflammatory mediators and changes in the Th1/Th2 response. By contrast, supplementation with carbohydrates has an anti-inflammatory effect when exercise is performed under normoxic conditions. The objective of this study was to evaluate the effect of carbohydrate supplementation on cytokines and cellular damage markers after exercise under hypoxic conditions at a simulated altitude of 4200 m. Methods: Seven adult male volunteers who exercised for 60 min at an intensity of 50% VO2Peak were randomly evaluated under three distinct conditions; normoxia, hypoxia and hypoxia + carbohydrate supplementation. Blood samples were collected at rest, at the end of exercise and after 60 min of recovery. To evaluate hypoxia + carbohydrate supplementation, volunteers received a solution of 6% carbohydrate (maltodextrin) or a placebo (strawberry-flavored Crystal Light®; Kraft Foods, Northfield, IL, USA) every 20 min during exercise and recovery. Statistical analyses comprised analysis of variance, with a one-way ANOVA followed by the Tukey post hoc test with a significance level of p < 0.05. Results: Under normoxic and hypoxic conditions, there was a significant increase in the concentration of IL-6 after exercise and after recovery compared to at rest (p < 0.05), while in the hypoxia + carbohydrate group, there was a significant increase in the concentration of IL-6 and TNF-α after exercise compared to at rest (p < 0.05). Furthermore, under this condition, TNF-α, IL-2 and the balance of IL-2/IL-4 were increased after recovery compared to at rest (p < 0.05). Conclusion: We conclude that carbohydrate supplementation modified the IL-6 and TNF-α serum concentrations and shifted the IL-2/IL-4 balance towards Th1 in response without glycemic, glutaminemia and cell damage effects. PMID:27827949

  17. Noncoding RNAs, cytokines, and inflammation-related diseases.

    PubMed

    Marques-Rocha, José Luiz; Samblas, Mirian; Milagro, Fermin I; Bressan, Josefina; Martínez, J Alfredo; Marti, Amelia

    2015-09-01

    Chronic inflammation is involved in the onset and development of many diseases, including obesity, atherosclerosis, type 2 diabetes, osteoarthritis, autoimmune and degenerative diseases, asthma, periodontitis, and cirrhosis. The inflammation process is mediated by chemokines, cytokines, and different inflammatory cells. Although the molecules and mechanisms that regulate this primary defense mechanism are not fully understood, recent findings offer a putative role of noncoding RNAs, especially microRNAs (miRNAs), in the progression and management of the inflammatory response. These noncoding RNAs are crucial for the stability and maintenance of gene expression patterns that characterize some cell types, tissues, and biologic responses. Several miRNAs, such as miR-126, miR-132, miR-146, miR-155, and miR-221, have emerged as important transcriptional regulators of some inflammation-related mediators. Additionally, little is known about the involvement of long noncoding RNAs, long intergenic noncoding RNAs, and circular RNAs in inflammation-mediated processes and the homeostatic imbalance associated with metabolic disorders. These noncoding RNAs are emerging as biomarkers with diagnosis value, in prognosis protocols, or in the personalized treatment of inflammation-related alterations. In this context, this review summarizes findings in the field, highlighting those noncoding RNAs that regulate inflammation, with emphasis on recognized mediators such as TNF-α, IL-1, IL-6, IL-18, intercellular adhesion molecule 1, VCAM-1, and plasminogen activator inhibitor 1. The down-regulation or antagonism of the noncoding RNAs and the administration of exogenous miRNAs could be, in the near future, a promising therapeutic strategy in the treatment of inflammation-related diseases.

  18. Cytokine response after severe RSV bronchiolitis in early life

    PubMed Central

    Castro, Mario; Schweiger, Toni; Yin-DeClue, Huiquing; Ramkumar, Thiruvamoor P; Christie, Chandrika; Zheng, Jie; Cohen, Rebecca; Schechtman, Kenneth B; Strunk, Robert; Bacharier, Leonard B.

    2008-01-01

    Background Immune response following viral infection usually involves Th1-mediated response; however, severe respiratory syncytial virus (RSV) infection appears to be associated with the development of asthma, a Th2-predominant phenotype. Objective To understand the early and subsequent immunologic response to a serious RSV infection in children over time. Methods 206 previously healthy infants hospitalized with severe RSV bronchiolitis were enrolled in a prospective cohort called the RSV Bronchiolitis in Early Life (RBEL) study. Peripheral blood T cells were obtained immediately following RSV infection and at 2, 4 and 6 years of age, stimulated with PMA and ionomycin, and analyzed for interleukin (IL)-2, -4, and - 13 and interferon-γ (IFN-γ) by flow cytometry and real time PCR. Results 48% (n=97) of the children developed asthma (physician-diagnosed) and 48% (n=97) had eczema by age 6. 32% (n=48 of 150) developed allergic sensitization by 3 yrs of age. Children with asthma had lower IL-13 expression at 6 yrs of age than those without (p=0.001). IFN-γ, IL-2 and -4 levels did not differ by asthma or eczema status during follow-up (all p>0.05). Allergic sensitization was not associated with differences in cytokine levels during follow-up (all p>0.05). Conclusion Severe RSV infection early in life is associated with a high incidence of asthma and eczema. Contrary to expectations, subsequent immunologic development in those who developed asthma, eczema or allergic sensitization was not associated with a Th2 phenotype in the peripheral blood. PMID:18760461

  19. A cytokine-inducing hemagglutinin from small taros.

    PubMed

    Chan, Yau Sang; Wong, Jack Ho; Ng, Tzi Bun

    2010-07-01

    A 22.4-kDa dimeric hemagglutinin was isolated from tubers of Colocasia esculenta cv. 'Small Taro' by employing a purification protocol that involved ion exchange chromatography on Q-Sepharose, fast protein liquid chromatography (FPLC)-ion exchange chromatography on Mono Q, and FPLC-gel filtration on Superdex 75. The hemagglutinin was isolated from the fraction of the taro extract adsorbed on Q-Sepharose and subsequently adsorbed on Mono Q. The major absorbance peak from the Superdex 75 column constituted purified hemagglutinin. Its hemagglutinating activity could not be inhibited by simple sugars, and was stable after exposure for 30 minutes to temperatures up to 40 degrees C and to ambient pH in the range of pH 2 to pH 13. The activity decreased progressively when the ambient temperature was raised from 40 degrees C to 100 degrees C. Negligible activity was detected at 100 degrees C. The activity plummeted, with about 40% and 10% remaining, 4 minutes and 20 minutes after exposure to 100 degrees C, respectively. About half of the activity remained at pH 0 and pH 1 whereas the activity was completely abolished at pH 14. The hemagglutinin exhibited slight anti-tumor activity toward hepatoma HepG2 cells, and weak mitogenic activity toward murine splenocytes. It induced expression of the cytokines interleukin-1 beta, interleukin-2, interferon-gamma and tumor necrosis factor-alpha. However, it was devoid of anti-fungal activity toward a number of fungal species.

  20. Liver cyst cytokines promote endothelial cell proliferation and development.

    PubMed

    Brodsky, Kelley S; McWilliams, Ryan R; Amura, Claudia R; Barry, Nicholas P; Doctor, R Brian

    2009-10-01

    Autosomal dominant polycystic kidney (ADPKD) is highly prevalent genetic disease. Liver cyst disease is the most common extrarenal manifestation in ADPKD and accounts for up to 10% of ADPKD morbidity and mortality. The clinical features of ADPKD liver disease arise from dramatic increases in liver cyst volumes. To identify mechanisms that promote liver cyst growth, the present study characterized the degree of vascularization of liver cyst walls and determined that cyst-specific cytokines and growth factors can drive endothelial cell proliferation and development. Microscopic techniques demonstrated liver cyst walls are well vascularized. A comparative analysis found the vascular density in free liver cyst walls was greater in mice than in humans. Treatment of human micro-vascular endothelial cells (HMEC-1) with human liver cyst fluid (huLCF) induced a rapid increase in vascular endothelium growth factor receptor 2 (VEGFR2) phosphorylation that persisted for 45-60 min and was blocked by 20 microM SU5416, a VEGFR tyrosine kinase inhibitor. Similarly, huLCF treatment of HMEC-1 cells induced an increase in the cell proliferation rate (131 +/- 6% of control levels; P > 0.05) and the degree of vascular development ('tube' diameter assay: 92 +/- 14 microm for huLCF vs. 12 +/- 7 microm for vehicle); P > 0.05). Both cell proliferation and vascular development were sensitive to SU5416. These studies indicate that factors secreted by liver cyst epithelia can activate VEGF signaling pathways and induce endothelial cell proliferation and differentiation. The present studies suggest that targeting VEGFR2-dependent angiogenesis may be an effective therapeutic strategy in blocking ADPKD liver cyst vascularization and growth.

  1. Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair.

    PubMed

    Chu, C Q; Field, M; Allard, S; Abney, E; Feldmann, M; Maini, R N

    1992-10-01

    Cytokine release at the cartilage/pannus junction (CPJ) may be involved in cartilage destruction and tissue repair in rheumatoid arthritis (RA). Tissue samples of CPJ from 12 RA patients were examined for the presence of cytokines using immunohistochemical techniques with immunoaffinity purified F(ab')2 antibodies raised against recombinant human cytokines. Twenty-four areas of distinct CPJ at which a discrete junction between cartilage and overlying pannus exists were observed. In all specimens, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha. IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor (TGF)-beta 1 were detected in cells in pannus particularly along the surface of cartilage and at the site of cartilage erosion. Double immunofluorescence staining showed that most cytokine containing cells also labelled with a macrophage marker (CD68). About 50% of blood vessel endothelial cells stained for GM-CSF. Twelve areas of diffuse fibroblastic CPJ, at which an indistinct margin is seen between cartilage and pannus were examined. At this site, TGF-beta 1 was the only cytokine detected in fibroblast-like cells. None of these cytokines were detected in synovial tissue at the normal synovium/cartilage junction. Chondrocytes from all 11 normal specimens as well as those from RA patients stained for IL-1 alpha, TNF-alpha, IL-6, GM-CSF and TGF-beta 1, especially those close to subchondral bone. However, IL-1 beta, interferon-gamma and lymphotoxin were not detected in either the normal synovium/cartilage junction or rheumatoid CPJ.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Neutral buoyancy and sleep-deprived serum factors alter expression of cytokines regulating osteogenesis

    NASA Astrophysics Data System (ADS)

    Gorczynski, Reginald M.; Gorczynski, Christopher P.; Gorczynski, Laura Y.; Hu, Jiang; Lu, Jin; Manuel, Justin; Lee, Lydia

    2005-05-01

    We examined expression of genes associated with cytokine production, and genes implicated in regulating bone metabolism, in bone stromal and osteoblast cells incubated under standard ground conditions and under conditions of neutral buoyancy, and in the presence/absence of serum from normal or sleep-deprived mice. We observed a clear interaction between these two conditions (exposure to neutral buoyancy and serum stimulation) in promoting enhanced osteoclastogenesis. Both conditions independently altered expression of a number of cytokines implicated in the regulation of bone metabolism. However, using stromal cells from IL-1 and TNF α cytokine r KO mice, we concluded that the increased bone loss under microgravity conditions was not primarily cytokine mediated.

  3. Benzimidazole derivatives protect against cytokine-induced apoptosis in pancreatic β-Cells.

    PubMed

    Zawawi, Nik Khairunissa Nik Abdullah; Rajput, Sajid Ali; Taha, Muhammad; Ahmat, Norizan; Ismail, Nor Hadiani; Abdullah, Noraishah; Khan, Khalid Mohammed; Choudhary, M Iqbal

    2015-10-15

    Apoptotic cell death is the cause of the loss of insulin-producing β-cells in all forms of diabetes mellitus. The identification of small molecules capable of protecting cytokine-induced apoptosis could form the basis of useful therapeutic interventions. Here in, we present the discovery and synthesis of new benzimidazole derivatives, capable of rescuing pancreatic β-cells from cytokine-induced apoptosis. Three hydrazone derivatives of benzimidazole significantly increased the cellular ATP levels, reduced caspase-3 activity, reduced nitrite production and increased glucose-stimulated insulin secretion in the presence of proinflammatory cytokines. These findings suggest that these compounds may protect β-cells from the harmful effects of cytokines and may serve as candidates for therapeutic intervention for diabetes.

  4. Dataset of aqueous humor cytokine profile in HIV patients with Cytomegalovirus (CMV) retinitis.

    PubMed

    Iyer, Jayant Venkatramani; Agrawal, Rupesh; Yeo, Tun Kuan; Gunasekeran, Dinesh V; Balne, Praveen Kumar; Lee, Bernett; Au, Veonice Bijin; Connolly, John; Teoh, Stephen C B

    2016-09-01

    The data shows the aqueous humor cytokine profiling results acquired in a small cohort of 17 HIV patients clinically diagnosed with Cytomegalovirus retinitis using the FlexMAP 3D (Luminex®) platform using the Milliplex Human Cytokine® kit. Aqueous humor samples were collected from these patients at different time points (pre-treatment and at 4-weekly intervals through the 12-week course of intravitreal ganciclovir treatment) and 41 cytokine levels were analyzed at each time point. CMV DNA viral load was assessed in 8 patients at different time points throughout the course of ganciclovir treatment. The data described herein is related to the research article entitled "Aqueous humor immune factors and cytomegalovirus (CMV) levels in CMV retinitis through treatment - The CRIGSS study" (Iyer et al., 2016) [1]. Cytokine levels against the different time points which indicate the response to the given treatment and against the CMV viral load were analyzed.

  5. Cytokine receptor expression in human lymphoid tissue: analysis by fluorescence microscopy.

    PubMed

    Zola, H; Ridings, J; Weedon, H; Fusco, M; Byard, R W; Macardle, P J

    1995-08-01

    A highly-sensitive flourescence method, capable of detecting cytokine receptors present at low concentrations (around 100 molecules per cell) by flow cytometry, was adapted for use on tissue sections. This method was used to examine the expression of several cytokine receptors in lymphoid tissues. IL-2 receptors were distributed broadly, with higher concentrations in T cell areas. IL-1 receptor Type 1 was detected in T cell areas and in the follicular mantle, and was strongly expressed on vascular endothelium. IL-6 receptor was found at very low concentration, both within and outside germinal centres. The gp 130 molecule, which is involved in the functional receptor complex for IL-6 and several other cytokines, was present at higher concentrations, particularly in the germinal centre. Analysis of receptor expression in secondary lymphoid tissue provides evidence bearing on the physiological roles of cytokines, as these tissues contain cells at various stages of physiological activation located in well-defined functional zones.

  6. EXTRINSIC COAGULATION BLOCKADE ATTENUATES LUNG INJURY AND PROINFLAMMATORY CYTOKINE RELEASE AFTER INTRATRACHEAL LIPOPOLYSACCHARIDE

    EPA Science Inventory

    Initiation of coagulation by tissue factor (TF) is a potentially powerful regulator of local inflammatory responses. We hypothesized that blockade of TF-factor VIIa (FVIIa) complex would decrease lung inflammation and proinflammatory cytokine release after tracheal instillation o...

  7. Proinflammatory cytokines and matrix metalloproteinases in CSF of patients with VZV vasculopathy

    PubMed Central

    Jones, Dallas; Alvarez, Enrique; Selva, Sean; Gilden, Don

    2016-01-01

    Objective: To determine the levels of proinflammatory cytokines and matrix metalloproteinases (MMPs) in the CSF of patients with virologically verified varicella zoster virus (VZV) vasculopathy. Methods: CSF from 30 patients with virologically verified VZV vasculopathy was analyzed for levels of proinflammatory cytokines and MMPs using the Meso Scale Discovery multiplex ELISA platform. Positive CNS inflammatory disease controls were provided by CSF from 30 patients with multiple sclerosis. Negative controls were provided by CSF from 20 healthy controls. Results: Compared to multiple sclerosis CSF and CSF from healthy controls, levels of interleukin (IL)-8, IL-6, and MMP-2 were significantly elevated in VZV vasculopathy CSF. Conclusions: CSF of patients with VZV vasculopathy revealed a unique profile of elevated proinflammatory cytokines, IL-8 and IL-6, along with elevated MMP-2. The relevance of these cytokines to the pathogenesis of VZV vasculopathy requires further study. PMID:27340684

  8. Immune Surveillance, Cytokines and Breast Cancer Risk: Genetic and Psychological Influences in African American Women

    DTIC Science & Technology

    2006-08-01

    cytokines, psychoneuroimmunology 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...hypotheses related to psychoneuroimmunology and using technology and paradigms from molecular epidemiology, this research may make important contributions

  9. Transcriptional profiling of inflammatory cytokine genes in African buffaloes (Syncerus caffer) infected with Theileria parva.

    PubMed

    Okagawa, Tomohiro; Konnai, Satoru; Mekata, Hirohisa; Githaka, Naftaly; Suzuki, Saori; Kariuki, Edward; Gakuya, Francis; Kanduma, Esther; Shirai, Tatsuya; Ikebuchi, Ryoyo; Ikenaka, Yoshinori; Ishizuka, Mayumi; Murata, Shiro; Ohashi, Kazuhiko

    2012-08-15

    Theileria parva (T. parva) causes East Coast fever (ECF), which is of huge economic importance to Eastern and Southern African countries. In a previous bovine model, inflammatory cytokines were closely associated with disease progression in animals experimentally infected with T. parva. The African Cape buffalo (Syncerus caffer), the natural reservoir for T. parva, is completely resistant to ECF despite a persistently high parasitaemia following infection with T. parva. Characterizing basic immunological interactions in the host is critical to understanding the mechanism underlying disease resistance in the African Cape buffalo. In this study, the expression level of several cytokines was analyzed in T. parva-infected buffaloes. There were no significant differences in the expression profiles of inflammatory cytokines between the infected and uninfected animals despite a remarkably high parasitaemia in the former. However, the expression level of IL-10 was significantly upregulated in the infected animals. These results indicate a correlation between diminished inflammatory cytokines response and disease resistance in the buffalo.

  10. Inflammatory Cytokines as Preclinical Markers of Adverse Responses to Chemical Stressors

    EPA Science Inventory

    Abstract: The in vivo cytokine response to chemical stressors is a promising mainstream tool used to assess potential systemic inflammation and immune function changes. Notably, new instrumentation and statistical analysis provide the selectivity and sensitivity to rapidly diff...

  11. Effects of poor hygiene on cytokine phenotypes in children in the tropics.

    PubMed

    Figueiredo, C A; Amorim, L D; Vaca, M; Chico, M E; Campos, A C; Barreto, M L; Cooper, P J

    2016-01-01

    We describe immune phenotypes (innate and adaptive cytokines) according to environmental exposure using latent class analysis. A total of 310 schoolchildren living in Ecuador were assayed for spontaneous cytokine production as well as mitogen (SEB)-stimulated cytokines in whole blood cultures. We collected data on environmental exposures by questionnaire and on intestinal parasites by examination of stool samples. Latent class analysis (LCA) was used to group children according to their innate (IL-6, IL-8, IL-10 and TNF-α) and adaptive (IL-5, IL-13, IL-17, IFN-γ and IL-10) cytokine profile. We also conducted multiple-group LCA and LCA with covariates to evaluate the effect of predictors on profile membership. We identified both hyporesponsive and Th2-modified immune phenotypes produced by peripheral blood leukocytes (PBLs) that were associated with intestinal worms and birth order, providing insights into how poor hygiene mediates immunologic effects on immune-mediated diseases.

  12. Targeting cytokines in inflammatory diseases: focus on interleukin-1-mediated autoinflammation

    PubMed Central

    Kalliolias, George D

    2009-01-01

    In this commentary, we summarize the most recent advances in the cytokine-targeting therapies. We focus on new aspects of interleukin-1 (IL-1)-mediated autoinflammation and novel strategies to target IL-1. PMID:20948617

  13. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease

    PubMed Central

    Patel, Nikunj S; Paris, Daniel; Mathura, Venkatarajan; Quadros, Amita N; Crawford, Fiona C; Mullan, Michael J

    2005-01-01

    Background Inflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of Aβ. Methods Organotypic brain slice cultures from 15-month-old mice (TgAPPsw, PS1/APPsw and control littermates) were established and multiple cytokine levels were analyzed using the Bio-plex multiple cytokine assay system. Soluble and insoluble forms of Aβ were quantified and Aβ-cytokine relationships were analyzed. Results Compared to control littermates, transgenic mice showed a significant increase in the following pro-inflammatory cytokines: TNF-α, IL-6, IL-12p40, IL-1β, IL-1α and GM-CSF. TNF-α, IL-6, IL-1α and GM-CSF showed a sequential increase from control to TgAPPsw to PS1/APPsw suggesting that the amplitude of this cytokine response is dependent on brain Aβ levels, since PS1/APPsw mouse brains accumulate more Aβ than TgAPPsw mouse brains. Quantification of Aβ levels in the same slices showed a wide range of Aβ soluble:insoluble ratio values across TgAPPsw and PS1/APPsw brain slices. Aβ-cytokine correlations revealed significant relationships between Aβ1–40, 1–42 (both soluble and insoluble) and all the above cytokines that changed in the brain slices. Conclusion Our data confirm that the brains of transgenic APPsw and PS1/APPsw mice are under an active inflammatory stress, and that the levels of particular cytokines may be directly related to the amount of soluble and insoluble Aβ present in the brain suggesting that pathological accumulation of Aβ is a key driver of the neuroinflammatory response. PMID:15762998

  14. The impact of weight loss on circulating cytokines in Beagle dogs.

    PubMed

    Bastien, Berenice C; Patil, Avinash; Satyaraj, Ebenezer

    2015-02-15

    Chronic low-grade inflammation in obesity is characterized by an increased production of pro-inflammatory and chemotactic cytokines that are contributing to insulin resistance and related co-morbidities. Cytokines act in networks and exhibit pleiotropic effects so we investigated the circulating levels of a wide array of cytokines (pro and anti-inflammatory, chemotactic and growth factors) in a canine model of weight loss. The dogs served as their own control in order to study the impact of weight loss independent of potential confounding factors, such as history of excess weight or gender. While low-grade inflammation had been previously investigated in obese dogs by measuring changes in adipokines, acute phase proteins and key pro-inflammatory cytokines, to the best of our knowledge this is the first study to evaluate how weight loss impacts a wide array of circulating cytokines. Eighteen overweight Beagle dogs were recruited (six spayed females and 12 neutered males), and none of them were grossly obese according to the body condition score (BCS). All the dogs reached an ideal weight by the end of the program. Parameters were assessed before (baseline), at mid-point (month 3) and at end-point (month 6). Plasma GM-CSF, IL-2, Il-4, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, IFNγ, IP-10, TNFα, monocyte chemotactic protein 1 (MCP-1), keratinocyte chemokine (KC) were measured with canine multiplex immunoassays. Fat mass was assessed by dual energy X-ray absorption (DEXA). Several cytokines decreased throughout the weight loss program (p<0.01) and were correlated with the percentage of fat measured by DEXA (p<0.05): chemotactic (MCP-1), growth factors (GM-CSF, IL-7 and IL-2), and pro-inflammatory (KC and IL-18). We could not show trends for several cytokines, possibly because their level may be lower than the assay sensitivity: anti-inflammatory (IL-4 and IL-10), and pro-inflammatory (IL-6 and TNFα). In conclusion, while our findings for several pro-inflammatory and

  15. Diverse Toll-like receptors mediate cytokine production by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in macrophages.

    PubMed

    Park, Se-Ra; Kim, Dong-Jae; Han, Seung-Hyun; Kang, Min-Jung; Lee, Jun-Young; Jeong, Yu-Jin; Lee, Sang-Jin; Kim, Tae-Hyoun; Ahn, Sang-Gun; Yoon, Jung-Hoon; Park, Jong-Hwan

    2014-05-01

    Toll-like receptors (TLRs) orchestrate a repertoire of immune responses in macrophages against various pathogens. Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans are two important periodontal pathogens. In the present study, we investigated TLR signaling regulating cytokine production of macrophages in response to F. nucleatum and A. actinomycetemcomitans. TLR2 and TLR4 are redundant in the production of cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF-α]) in F. nucleatum- and A. actinomycetemcomitans-infected macrophages. The production of cytokines by macrophages in response to F. nucleatum and A. actinomycetemcomitans infection was impaired in MyD88-deficient macrophages. Moreover, cytokine concentrations were lower in MyD88-deficient macrophages than in TLR2/TLR4 (TLR2/4) double-deficient cells. An endosomal TLR inhibitor, chloroquine, reduced cytokine production in TLR2/4-deficient macrophages in response to F. nucleatum and A. actinomycetemcomitans, and DNA from F. nucleatum or A. actinomycetemcomitans induced IL-6 production in bone marrow-derived macrophages (BMDMs), which was abolished by chloroquine. Western blot analysis revealed that TLR2/4 and MyD88 were required for optimal activation of NF-κB and mitogen-activated protein kinases (MAPKs) in macrophages in response to F. nucleatum and A. actinomycetemcomitans, with different kinetics. An inhibitor assay showed that NF-κB and all MAPKs (p38, extracellular signal-regulated kinase [ERK], and Jun N-terminal protein kinase [JNK]) mediate F. nucleatum-induced production of cytokines in macrophages, whereas NF-κB and p38, but not ERK and JNK, are involved in A. actinomycetemcomitans-mediated cytokine production. These findings suggest that multiple TLRs may participate in the cytokine production of macrophages against periodontal bacteria.

  16. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis.

    PubMed

    Hannestad, Jonas; DellaGioia, Nicole; Bloch, Michael

    2011-11-01

    Serum levels of inflammatory cytokines, for example, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1 beta (IL-1β), are elevated in subjects with major depressive disorder (MDD). The reason why this occurs is unclear. Elevated levels of inflammatory cytokines could be a result of brain dysfunction in MDD. It is also possible that inflammatory cytokines contribute to depressive symptoms in MDD. If the first assumption is correct, one would expect levels to normalize with resolution of the depressive episode after treatment. Several studies have measured changes in cytokine levels during antidepressant treatment; however, the results vary. The purpose of this study was to pool all available data on changes in serum levels of TNFα, IL-6, and IL-1β during antidepressant treatment to determine whether these levels change. Studies were included if they used an approved pharmacological treatment for depression, patients had a diagnosis of MDD, and serum levels of TNFα, IL-6, and/or IL-1β were measured before and after treatment. Twenty-two studies fulfilled these criteria. Meta-analysis of these studies showed that, overall, while pharmacological antidepressant treatment reduced depressive symptoms, it did not reduce serum levels of TNFα. On the other hand, antidepressant treatment did reduce levels of IL-1β and possibly those of IL-6. Stratified subgroup analysis by class of antidepressant indicated that serotonin reuptake inhibitors may reduce levels of IL-6 and TNFα. Other antidepressants, while efficacious for depressive symptoms, did not appear to reduce cytokine levels. These results argue against the notion that resolution of a depressive episode is associated with normalization of levels of circulating inflammatory cytokines; however, the results are consistent with the possibility that inflammatory cytokines contribute to depressive symptoms and that antidepressants block the effects of inflammatory cytokines on the brain.

  17. Rapid Detection of Neutrophil Oxidative Burst Capacity is Predictive of Whole Blood Cytokine Responses

    PubMed Central

    Vernon, Philip J.; Schaub, Leasha J.; Dallelucca, Jurandir J.; Pusateri, Anthony E.; Sheppard, Forest R.

    2015-01-01

    Background Maladaptive immune responses, particularly cytokine and chemokine-driven, are a significant contributor to the deleterious inflammation present in many types of injury and infection. Widely available applications to rapidly assess individual inflammatory capacity could permit identification of patients at risk for exacerbated immune responses and guide therapy. Here we evaluate neutrophil oxidative burst (NOX) capacity measured by plate reader to immuno-type Rhesus Macaques as an acute strategy to rapidly detect inflammatory capacity and predict maladaptive immune responses as assayed by cytokine array. Methods Whole blood was collected from anesthetized Rhesus Macaques (n = 25) and analyzed for plasma cytokine secretion (23-plex Luminex assay) and NOX capacity. For cytokine secretion, paired samples were either unstimulated or ex-vivo lipopolysaccharide (LPS)-stimulated (100μg/mL/24h). NOX capacity was measured in dihydrorhodamine-123 loaded samples following phorbol 12-myristate 13-acetate (PMA)/ionomycin treatment. Pearson’s test was utilized to correlate NOX capacity with cytokine secretion, p<0.05 considered significant. Results LPS stimulation induced secretion of the inflammatory molecules G-CSF, IL-1β, IL-1RA, IL-6, IL-10, IL-12/23(p40), IL-18, MIP-1α, MIP-1β, and TNFα. Although values were variable, several cytokines correlated with NOX capacity, p-values≤0.0001. Specifically, IL-1β (r = 0.66), IL-6 (r = 0.74), the Th1-polarizing cytokine IL-12/23(p40) (r = 0.78), and TNFα (r = 0.76) were strongly associated with NOX. Conclusion NOX capacity correlated with Th1-polarizing cytokine secretion, indicating its ability to rapidly predict inflammatory responses. These data suggest that NOX capacity may quickly identify patients at risk for maladaptive immune responses and who may benefit from immuno-modulatory therapies. Future studies will assess the in-vivo predictive value of NOX in animal models of immune-mediated pathologies. PMID

  18. Aspergillus flavus induces granulomatous cerebral aspergillosis in mice with display of distinct cytokine profile.

    PubMed

    Anand, R; Shankar, J; Tiwary, B N; Singh, A P

    2015-04-01

    Aspergillus flavus is one of the leading Aspergillus spp. resulting in invasive aspergillosis of central nervous system (CNS) in human beings. Immunological status in aspergillosis of central nervous system remains elusive in case of both immunocompetent and immunocompromised patients. Since cytokines are the major mediators of host response, evaluation of disease pathology along with cytokine profile in brain may provide snapshots of neuro-immunological response. An intravenous model of A. flavus infection was utilized to determine the pathogenicity of infection and cytokine profile in the brain of male BALB/c mice. Enumeration of colony forming units and histopathological analyses were performed on the brain tissue at distinct time periods. The kinetics of cytokines (TNF-α, IFN-γ, IL-12/IL-23p40, IL-6, IL-23, IL-17A and IL-4) was evaluated at 6, 12, 24, 48, 72 and 96h post infection (hPI) in brain homogenates using murine cytokine specific enzyme linked immunosorbent assay. Histological analysis exhibited the hyphae with leukocyte infiltrations leading to formation of granulomata along with ischemia and pyknosis of neurons in the brain of infected mice. Diseased mice displayed increased secretion of IFN-γ, IL-12p40 and IL-6 with a concomitant reduction in the secretion of Th2 cytokine IL-4, and Th17 promoting cytokine, IL-23 during the late phase of infection. A.flavus induced inflammatory granulomatous cerebral aspergillosis in mice, characterized by a marked increase in the Th1 cytokines and neurons undergoing necrosis. A marked increase in necrosis of neurons with concurrent inflammatory responses might have led to the host mortality during late phase of infection.

  19. Cytokine combinations on the potential for ex vivo expansion of murine hematopoietic stem cells.

    PubMed

    Lui, Wing Chi; Chan, Yuen Fan; Chan, Li Chong; Ng, Ray Kit

    2014-08-01

    Hematopoietic stem cell (HSC) is a rare cell population, which is capable of self-renewal and differentiation to all blood lineages. The clinical potential of HSCs for treating hematological disorders has led to the use of cytokine stimulation for ex vivo expansion. However, little is known about the molecular features of the HSC populations expanded under different cytokine combinations. We studied the expansion of murine HSCs cultured with six different cytokine combinations under serum-containing or serum-free conditions for 14days. We found that all the cytokine combinations promoted expansion of murine HSCs. Although SCF/IL-3/IL-6 induced the highest expansion of the immunophenotypic Lineage(-)Sca-1(+)c-Kit(+) (LSK) cells at day 14, over 90% of them were FcεRIα(+) mast cells. In contrast, the serum-free medium with SCF/Flt3-L/IL-11 effectively promoted the expansion of LSK/FcεRIα(-) HSCs by over 50-fold. HSCs expanded by SCF/Flt3-L/IL-11 combination formed compact hematopoietic colonies and demonstrated a higher degree of multipotency compared to the HSCs cultured with other cytokine combinations. Surprisingly, despite the same LSK/FcεRIα(-) immunophenotype, HSCs cultured with different cytokine combinations demonstrated differential patterns of hematopoietic gene expression. HSCs cultured with SCF/Flt3-L/IL-11 maintained a transcription profile resembling that of freshly isolated HSCs. We propose that serum-free medium supplemented with SCF/Flt3-L/IL-11 is the optimal culture condition to maintain the stemness of ex vivo expanded HSCs. This study used molecular characterization of cytokine-expanded murine HSCs to facilitate the selection of cytokine combinations that could induce fully competent HSC for clinical applications.

  20. Modulation of cytokines and chemokines expression by NAC in cadmium chloride treated human lung cells.

    PubMed

    Odewumi, Caroline O; Latinwo, Lekan M; Ruden, Michael L; Badisa, Veera L D; Fils-Aime, Sheila; Badisa, Ramesh B

    2016-11-01

    Cadmium (Cd), is one of the most hazardous metals found in the environment. Cd exposure through inhalation has been linked to various diseases in lungs. It was shown that Cd induces proinflammatory cytokines through oxidative stress mechanism. In this report, we studied the immunomodulatory effect of a well known antioxidant, N-acetylcysteine (NAC) on cadmium chloride (CdCl2 ) treated human lung A549 cells through human cytokine array 6. The lung cells were treated with 0 or 75 µM CdCl2 alone, 2.5 mM NAC alone, or co-treated with 2.5 mM NAC and 75 µM CdCl2 for 24 h. The viability of cells was measured by crystal violet dye. The array results were validated by human IL-1alpha enzyme- linked immunosorbent assay (ELISA) kit. The viability of the 75 µM CdCl2 alone treated cells was decreased to 44.5%, while the viability of the co-treated cells with 2.5 mM NAC was increased to 84.1% in comparison with untreated cells. In the cell lysate of CdCl2 alone treated cells, 19 and 8 cytokines were up and down-regulated, while in the medium 15 and 3 cytokines were up and downregulated in comparison with the untreated cells. In the co-treated cells, all these cytokines expression was modulated by the NAC treatment. The IL-1α ELISA result showed the same pattern of cytokine expression as the cytokine array. This study clearly showed the modulatory effect of NAC on cytokines and chemokines expression in CdCl2- treated cells and suggests the use of NAC as protective agent against cadmium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1612-1619, 2016.

  1. Liver X receptor is a key regulator of cytokine release in human monocytes.

    PubMed

    Myhre, Anders E; Agren, Joanna; Dahle, Maria K; Tamburstuen, Margareth V; Lyngstadaas, Ståle P; Collins, A Jon L; Foster, Simon J; Thiemermann, Christoph; Aasen, Ansgar O; Wang, Jacob E

    2008-04-01

    Aberrant regulation of innate immune responses and uncontrolled cytokine bursts are hallmarks of sepsis and endotoxemia. Activation of the nuclear liver X receptor (LXR) was recently demonstrated to suppress inflammatory genes. Our aim was to investigate the expression of LXR in human monocytes under normal and endotoxemic conditions and to study the influence of LXR activation on endotoxin-induced cytokine synthesis and release. Adherent human monocytes or whole blood were pretreated with a synthetic LXR agonist (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid) and subsequently challenged with LPS (from Escherichia coli) or peptidoglycan (from Staphylococcus aureus). Cytokine release was assessed by a Multiplex antibody bead kit, and cytokine mRNA levels were measured by real-time reverse-transcriptase-polymerase chain reaction. We found that LXRalpha mRNA was up-regulated in CD14+ monocytes in LPS-challenged blood, whereas LXRbeta mRNA was not altered. Addition of 3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid to monocytes suppressed the LPS-induced release of IL-1beta, IL-6, IL-8, IL-10, IL-12p40, TMF-alpha, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and monocyte chemoattractant protein 1 in a concentration-dependent manner. Surprisingly, an accompanying decrease in cytokine mRNA accumulation was not observed. The suppressed cytokine release could not be explained by a diminished transport of mRNA out of the nucleus or a decreased secretion of cytokines. We propose that LXR is a key regulator of cytokine release in LPS-challenged human monocytes, possibly by interfering with translational events.

  2. A striking local esophageal cytokine expression profile in eosinophilic esophagitis1

    PubMed Central

    Blanchard, Carine; Stucke, Emily M.; Rodriguez-Jimenez, Beatriz; Burwinkel, Karen; Collins, Margaret H.; Ahrens, Annette; Alexander, Eileen S.; Butz, Bridget K. Buckmeier; Jameson, Sean C.; Kaul, Ajay; Franciosi, James P.; Kushner, Jonathan P.; Putnam, Philip E.; Abonia, J. Pablo; Rothenberg, Marc E.

    2011-01-01

    Background Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease. Objective Early studies have suggested that esophageal eosinophilia occurs in association with T helper type 2 allergic responses, yet the local and systemic expression of relevant cytokines has not been well characterized. Methods A human inflammatory cytokine and receptor PCR array containing 84 genes followed by PCR validation and multiplex arrays were used to quantify cytokine mRNA in esophageal biopsies and blood levels. Results Esophageal transcripts of numerous chemokines [e.g. CCL1, CCL23, CCL26 (eotaxin-3), CXCL1, and CXCL2], cytokines (e.g. IL13 and ABCF1), and cytokine receptors (e.g. IL5RA) were induced at least 4-fold in individuals with EE. Analysis of esophageal biopsies (n=288) revealed that eotaxin-3 mRNA level alone had 89% sensitivity for distinguishing EE from non-EE individuals. The presence of allergy was associated with significantly increased esophageal expression of IL4 and IL5 mRNA in active EE patients. We identified 8 cytokines (IL-4, IL-13, IL-5, IL-6, IL-12p70, CD40L, IL-1α, and IL-17) whose blood levels retrospectively distinguished 12 non-EE from 13 EE patients with 100% specificity and 100% sensitivity. When applied to a blinded, prospectively recruited group of 36 patients, the cytokine panel scoring system had a 79% positive predictive value, 68% negative predictive value, 61% sensitivity, and 83% specificity for identifying EE. Conclusion Evidence is presented that IL13 and IL5 associate with eosinophil and eotaxin-3 levels, indicating the key role of adaptive Th2 immunity in regulating eotaxin-3-driven esophageal eosinophilia in the absence of a consistent systemic change in cytokines. PMID:21211656

  3. Tityus bahiensis scorpion venom injected to dams during pregnancy affects some cytokines of fetuses.

    PubMed

    Dorce, Ana L C; Frare, Eduardo O; Paulo, Maria E F V; Dorce, Valquiria A C; Nencioni, Ana L A

    2015-09-01

    Due to the high incidence of scorpion stings in Brazil, pregnant women are among the possible victims. Cytokines are important during the pregnancy, and scorpion venoms can change their release. We evaluated the levels of some cytokines in the fetuses after the treatment of pregnant rats with the Tityus bahiensis scorpion venom. The concentration of some of them is altered and can be responsible for the effects previously observed on innate reflexes, and the physical and behavioral development of the offspring.

  4. Modeling the Intra- and Extracellular Cytokine Signaling Pathway under Heat Stroke in the Liver

    PubMed Central

    Rodriguez-Fernandez, Maria; Grosman, Benyamin; Yuraszeck, Theresa M.; Helwig, Bryan G.; Leon, Lisa R.; Doyle III, Francis J.

    2013-01-01

    Heat stroke (HS) is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS). The observation that pro- (e.g., IL-1) and anti-inflammatory (e.g., IL-10) cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF) receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events) in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation) and proteomic (circulating cytokines and receptors) data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico). PMID:24039931

  5. Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: a case-control study.

    PubMed

    Dauvilliers, Yves; Jaussent, Isabelle; Lecendreux, Michel; Scholz, Sabine; Bayard, Sophie; Cristol, Jean Paul; Blain, Hubert; Dupuy, Anne-Marie

    2014-03-01

    Recent advances in the identification of susceptibility genes and environmental exposures provide strong support that narcolepsy-cataplexy is an immune-mediated disease. Only few serum cytokine studies with controversial results were performed in narcolepsy and none in the cerebrospinal fluid. We measured a panel of 12 cytokines by a proteomic approach in the serum of 35 patients with narcolepsy-cataplexy compared to 156 healthy controls, and in the cerebrospinal fluid of 34 patients with narcolepsy-cataplexy compared to 17 non-narcoleptic patients; and analyzed the effect of age, duration and severity of disease on the cytokine levels. After multiple adjustments we reported lower serum IL-2, IL-8, TNF-α, MCP-1 and EGF levels, and a tendency for higher IL-4 level in narcolepsy compared to controls. Significant differences were only found for IL-4 in cerebrospinal fluid, being higher in narcolepsy. Positive correlations were found in serum between IL-4, daytime sleepiness, and cataplexy frequency. The expression of some pro-inflammatory cytokines (MCP-1, VEGF, EGF, IL2, IL-1β, IFN-γ) in either serum or CSF was negatively correlated with disease severity and duration. No correlation was found for any specific cytokine in 18 of the patients with narcolepsy with peripheral and central samples collected the same day. Significant decreased pro/anti-inflammatory cytokine profiles were found at peripheral and central levels in narcolepsy, together with a T helper 2/Th1 serum cytokine secretion imbalance. To conclude, we showed some evidence for alterations in the cytokine profile in patients with narcolepsy-cataplexy compared to controls at peripheral and central levels, with the potential role of IL-4 and significant Th1/2 imbalance in the pathophysiology of narcolepsy.

  6. RNA-Seq Reveals Activation of Both Common and Cytokine-Specific Pathways following Neutrophil Priming

    PubMed Central

    Moots, Robert J.; Edwards, Steven W.

    2013-01-01

    Neutrophils are central to the pathology of inflammatory diseases, where they can damage host tissue through release of reactive oxygen metabolites and proteases, and drive inflammation via secretion of cytokines and chemokines. Many cytokines, such as those generated during inflammation, can induce a similar “primed” phenotype in neutrophils, but it is unknown if different cytokines utilise common or cytokine-specific pathways to induce these functional changes. Here, we describe the transcriptomic changes induced in control human neutrophils during priming in vitro with pro-inflammatory cytokines (TNF-α and GM-CSF) using RNA-seq. Priming led to the rapid expression of a common set of transcripts for cytokines, chemokines and cell surface receptors (CXCL1, CXCL2, IL1A, IL1B, IL1RA, ICAM1). However, 580 genes were differentially regulated by TNF-α and GM-CSF treatment, and of these 58 were directly implicated in the control of apoptosis. While these two cytokines both delayed apoptosis, they induced changes in expression of different pro- and anti-apoptotic genes. Bioinformatics analysis predicted that these genes were regulated via differential activation of transcription factors by TNF-α and GM-CSF and these predictions were confirmed using functional assays: inhibition of NF-κB signalling abrogated the protective effect of TNF-α (but not that of GM-CSF) on neutrophil apoptosis, whereas inhibition of JAK/STAT signalling abrogated the anti-apoptotic effect of GM-CSF, but not that of TNF-α (p<0.05). These data provide the first characterisation of the human neutrophil transcriptome following GM-CSF and TNF-α priming, and demonstrate the utility of this approach to define functional changes in neutrophils following cytokine exposure. This may provide an important, new approach to define the molecular properties of neutrophils after in vivo activation during inflammation. PMID:23554905

  7. Multisite Comparison of High-Sensitivity Multiplex Cytokine Assays▿†

    PubMed Central

    Breen, Elizabeth Crabb; Reynolds, Sandra M.; Cox, Christopher; Jacobson, Lisa P.; Magpantay, Larry; Mulder, Candice B.; Dibben, Oliver; Margolick, Joseph B.; Bream, Jay H.; Sambrano, Elise; Martínez-Maza, Otoniel; Sinclair, Elizabeth; Borrow, Persephone; Landay, Alan L.; Rinaldo, Charles R.; Norris, Philip J.

    2011-01-01

    The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1β was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important. PMID:21697338

  8. Fatigue in primary Sjögren's syndrome is associated with lower levels of proinflammatory cytokines

    PubMed Central

    Howard Tripp, Nadia; Tarn, Jessica; Natasari, Andini; Gillespie, Colin; Mitchell, Sheryl; Hackett, Katie L; Bowman, Simon J; Price, Elizabeth; Pease, Colin T; Emery, Paul; Lanyon, Peter; Hunter, John; Gupta, Monica; Bombardieri, Michele; Sutcliffe, Nurhan; Pitzalis, Costantino; McLaren, John; Cooper, Annie; Regan, Marian; Giles, Ian; Isenberg, David A; Saravanan, Vadivelu; Coady, David; Dasgupta, Bhaskar; McHugh, Neil; Young-Min, Steven; Moots, Robert; Gendi, Nagui; Akil, Mohammed; Griffiths, Bridget; Lendrem, Dennis W; Ng, Wan-Fai

    2016-01-01

    Objectives This article reports relationships between serum cytokine levels and patient-reported levels of fatigue, in the chronic immunological condition primary Sjögren's syndrome (pSS). Methods Blood levels of 24 cytokines were measured in 159 patients with pSS from the United Kingdom Primary Sjögren's Syndrome Registry and 28 healthy non-fatigued controls. Differences between cytokines in cases and controls were evaluated using Wilcoxon test. Patient-reported scores for fatigue were evaluated, classified according to severity and compared with cytokine levels using analysis of variance. Logistic regression was used to determine the most important predictors of fatigue levels. Results 14 cytokines were significantly higher in patients with pSS (n=159) compared to non-fatigued healthy controls (n=28). While serum levels were elevated in patients with pSS compared to healthy controls, unexpectedly, the levels of 4 proinflammatory cytokines—interferon-γ-induced protein-10 (IP-10) (p=0.019), tumour necrosis factor-α (p=0.046), lymphotoxin-α (p=0.034) and interferon-γ (IFN-γ) (p=0.022)—were inversely related to patient-reported levels of fatigue. A regression model predicting fatigue levels in pSS based on cytokine levels, disease-specific and clinical parameters, as well as anxiety, pain and depression, revealed IP-10, IFN-γ (both inversely), pain and depression (both positively) as the most important predictors of fatigue. This model correctly predicts fatigue levels with reasonable (67%) accuracy. Conclusions Cytokines, pain and depression appear to be the most powerful predictors of fatigue in pSS. Our data challenge the notion that proinflammatory cytokines directly mediate fatigue in chroni