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1

Macrophage immunomodulatory activity of polysaccharides isolated from Opuntia polyacantha  

PubMed Central

Opuntia polyacantha (prickly pear cactus) has been used extensively for its nutritional properties; however, less is known regarding medicinal properties of Opuntia tissues. In the present study, we extracted polysaccharides from O. polyacantha and used size-exclusion chromatography to fractionate the crude polysaccharides into four polysaccharide fractions (designated as Opuntia polysaccharides C-I to C-IV). The average Mr of fractions C-I through C-IV was estimated to be 733, 550, 310, and 168 kDa, respectively, and sugar composition analysis revealed that Opuntia polysaccharides consisted primarily of galactose, galacturonic acid, xylose, arabinose, and rhamnose. Analysis of the effects of Opuntia polysaccharides on human and murine macrophages demonstrated that all four fractions had potent immunomodulatory activity, inducing production of reactive oxygen species, nitric oxide, tumor necrosis factor ?, and interleukin 6. Furthermore, modulation of macrophage function by Opuntia polysaccharides was mediated, at least in part, through activation of nuclear factor ?B. Together, our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of extracts from O. polyacantha and support the concept of using Opuntia polysaccharides as an immunotherapeutic adjuvant. PMID:18597716

Schepetkin, Igor A.; Xie, Gang; Kirpotina, Liliya N.; Klein, Robyn A.; Jutila, Mark A.; Quinn, Mark T.

2008-01-01

2

Macrophage immunomodulatory activity of polysaccharides isolated from Opuntia polyacantha.  

PubMed

Opuntia polyacantha (prickly pear cactus) has been used extensively for its nutritional properties; however, less is known regarding medicinal properties of Opuntia tissues. In the present study, we extracted polysaccharides from O. polyacantha and used size-exclusion chromatography to fractionate the crude polysaccharides into four polysaccharide fractions (designated as Opuntia polysaccharides C-I to C-IV). The average M(r) of fractions C-I through C-IV was estimated to be 733, 550, 310, and 168 kDa, respectively, and sugar composition analysis revealed that Opuntia polysaccharides consisted primarily of galactose, galacturonic acid, xylose, arabinose, and rhamnose. Analysis of the effects of Opuntia polysaccharides on human and murine macrophages demonstrated that all four fractions had potent immunomodulatory activity, inducing production of reactive oxygen species, nitric oxide, tumor necrosis factor alpha, and interleukin 6. Furthermore, modulation of macrophage function by Opuntia polysaccharides was mediated, at least in part, through activation of nuclear factor kappaB. Together, our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of extracts from O. polyacantha and support the concept of using Opuntia polysaccharides as an immunotherapeutic adjuvant. PMID:18597716

Schepetkin, Igor A; Xie, Gang; Kirpotina, Liliya N; Klein, Robyn A; Jutila, Mark A; Quinn, Mark T

2008-10-01

3

Musca domestica Pupae Lectin Improves the Immunomodulatory Activity of Macrophages by Activating Nuclear Factor-?B  

PubMed Central

Abstract In this study, Musca domestica pupae lectin (MPL) was screened for its immunomodulatory effect on macrophages. The phagocytosis of macrophages was improved significantly when they were treated with MPL: remarkable changes were observed in the morphology of the cells, the metabolic abilities of DNA and RNA were enhanced, and the production of hepatin was increased. Meanwhile, compared with the control group, not only the mRNA expressions of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), and interferon-? (IFN-?) in macrophages, but also the productions of proteins, were strongly induced by MPL; these effects were inhibited by pyrrolidine dithiocarbamate. Further study suggested that MPL could increase the nuclear factor-?B (NF-?B) p65 level in the nucleus. Overall, these results indicate that the improving immunomodulatory activity induced by MPL is mainly due to the increasing productions of TNF-?, IL-6, and IFN-? and that the activation of macrophage by MPL is partly mediated via the NF-?B pathway. PMID:22191632

Cao, Xiaohong; Zhou, Minghui; Hou, Lihua; Li, Yuanyuan; Chen, Linye

2012-01-01

4

Musca domestica pupae lectin improves the immunomodulatory activity of macrophages by activating nuclear factor-?B.  

PubMed

In this study, Musca domestica pupae lectin (MPL) was screened for its immunomodulatory effect on macrophages. The phagocytosis of macrophages was improved significantly when they were treated with MPL: remarkable changes were observed in the morphology of the cells, the metabolic abilities of DNA and RNA were enhanced, and the production of hepatin was increased. Meanwhile, compared with the control group, not only the mRNA expressions of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), and interferon-? (IFN-?) in macrophages, but also the productions of proteins, were strongly induced by MPL; these effects were inhibited by pyrrolidine dithiocarbamate. Further study suggested that MPL could increase the nuclear factor-?B (NF-?B) p65 level in the nucleus. Overall, these results indicate that the improving immunomodulatory activity induced by MPL is mainly due to the increasing productions of TNF-?, IL-6, and IFN-? and that the activation of macrophage by MPL is partly mediated via the NF-?B pathway. PMID:22191632

Cao, Xiaohong; Zhou, Minghui; Wang, Chunling; Hou, Lihua; Li, Yuanyuan; Chen, Linye

2012-02-01

5

Macrophage immunomodulatory activity of polysaccharides isolated from Juniperus scopolorum  

Microsoft Academic Search

Extracts of cones and leaves of different species of the genus Juniperus have been used for centuries to treat a variety of medical problems; however, little is known about the active components conferring therapeutic properties to these extracts. To address this issue, we extracted water-soluble polysaccharides from Juniperus scopolorum cones and used ion exchange and size exclusion chromatography to separate

Igor A. Schepetkin; Craig L. Faulkner; Laura K. Nelson-Overton; James A. Wiley; Mark T. Quinn

2005-01-01

6

Immunomodulatory Activity of a Novel, Synthetic Beta-glucan (?-glu6) in Murine Macrophages and Human Peripheral Blood Mononuclear Cells  

PubMed Central

Natural ?-glucans extracted from plants and fungi have been used in clinical therapies since the late 20th century. However, the heterogeneity of natural ?-glucans limits their clinical applicability. We have synthesized ?-glu6, which is an analog of the lentinan basic unit, ?-(1?6)-branched ?-(1?3) glucohexaose, that contains an ?-(1?3)-linked bond. We have demonstrated the stimulatory effect of this molecule on the immune response, but the mechanisms by which ?-glu6 activates innate immunity have not been elucidated. In this study, murine macrophages and human PBMCs were used to evaluate the immunomodulatory effects of ?-glu6. We showed that ?-glu6 activated ERK and c-Raf phosphorylation but suppressed the AKT signaling pathway in murine macrophages. Additionally, ?-glu6 enhanced the secretion of large levels of cytokines and chemokines, including CD54, IL-1?, IL-1?, IL-16, IL-17, IL-23, IFN-?, CCL1, CCL3, CCL4, CCL12, CXCL10, tissue inhibitor of metalloproteinase-1 (TIMP-1) and G-CSF in murine macrophages as well as IL-6, CCL2, CCL3, CCL5, CXCL1 and macrophage migration inhibitory factor (MIF) in human PBMCs. In summary, it demonstrates the immunomodulatory activity of ?-glu6 in innate immunity. PMID:24223225

Liu, Chunhong; Sun, Shuhui; Gu, Jianxin; Wang, Xun; Boraschi, Diana; Huang, Yuxian; Qu, Di

2013-01-01

7

Structure characterization of a novel polysaccharide from Dictyophora indusiata and its macrophage immunomodulatory activities.  

PubMed

A novel polysaccharide, here named DP1, was isolated from the fruiting body of Dictyophora indusiata using a water extraction method. Structure characterization revealed that DP1 had an average molecular weight of 1132 kDa and consisted of glucose (56.2%), galactose (14.1%), and mannose (29.7%). The main linkage type of DP1 were proven to be (1 ? 3)-linked ?-l-Man, (1 ? 2,6)-linked ?-d-Glc, (1 ? 6)-linked ?-d-Glc, (1 ? 6)-linked ?-d-Gal, and (1 ? 6)-linked ?-d-Man by periodate oxidation-Smith degradation and nuclear magnetic resonance analysis. The immunostimulating assay indicated that DP1 could significantly promote macrophage NO, TNF-?, and IL-6 secretion in murine RAW 264.7 cells involving complement receptor 3 (CR3). The immune activities of DP1 were quite stable under thermal processing (100, 121, and 145 °C). Besides, DP1 retained stability after acidic/alkline treatment (pH 4.0-10.0), which enabled it to be an ideal complementary medicine or functional food for therapeutics of hypoimmunity and immunodeficiency diseases. PMID:25525995

Liao, Wenzhen; Luo, Zhen; Liu, Dan; Ning, Zhengxiang; Yang, Jiguo; Ren, Jiaoyan

2015-01-21

8

Assessment of Immunomodulatory Activity of Euphorbia hirta L.  

PubMed

Immune system is the major target for development of treatment strategies to improve the management of infections. Many species of Indian medicinal plants have been reported to possess active principles with immunomodulating properties. Euphorbia hirta, a pantropic herb has been reported to be pharmacologically active. This study reports one another not widely reported property of the plant, immunomodulatory activity, which has been proved using simple techniques like the macrophage activity testing, carbon clearance test and mast cell de-granulation assay. PMID:21694995

Ramesh, K Vijaya; Padmavathi, K

2010-09-01

9

Effects of Pouteria cambodiana extracts on in vitro immunomodulatory activity of mouse immune system.  

PubMed

Immunomodulatory activity of water and acetone extracts of stem bark of Pouteria cambodiana was examined on murine macrophage phagocytosis [nitroblue tetrazolium (NBT) dye reduction and lysosomal enzyme activity] and proliferation of splenocytes and bone marrow cells by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with and without lipopolysaccharide (LPS) or pokeweed mitogen (PWM). Both aqueous and acetone extracts presented immunomodulatory activity without clear dose response relationship. PMID:16546328

Manosroi, Aranya; Saraphanchotiwitthaya, Aurasorn; Manosroi, Jiradej

2006-04-01

10

Immunomodulatory activity of polysaccharides isolated from Alchornea cordifolia  

PubMed Central

Ethnopharmacological relevance Extracts of leaves from different species of the genus Alchornea have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. Objective The aim of this study was to evaluate the immunomodulatory activity of polysaccharides isolated from the leaves of Alchornea cordifolia. Materials and methods Water-soluble polysaccharides from leaves of A. cordifolia were extracted and fractionated by DEAE-cellulose, Diaion HP-20, and size-exclusion chromatography. Molecular weight, sugar analysis, and other physical and chemical characterization of the fractions were performed. Immunomodulatory activity of the polysaccharide fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO) and cytokine production. Activation of mitogen activated protein kinases (MAPK) was also assessed using a phospho-MAPK array. Activation of nuclear factor ?B (NF-?B) was measured using an alkaline phosphatase reporter gene assay in THP1-Blue monocytic cells. Results Six polysaccharide fractions from A. cordifolia were isolated. Fractions containing type II arabinogalactan had potent immunomodulatory activity. Particularly, the parent fraction AP-AU and its high-molecular weight sub-fraction AP-AU1 (average Mr was estimated to be 39.5 kDa) induced production of NO and cytokines [interleukin (IL)-1?, -6, -10, tumor necrosis factor (TNF)-?, and granulocyte macrophage-colony stimulating factor (GM-CSF)] in human peripheral blood mononuclear cells and human and murine monocyte/macrophages cell lines in vitro. Furthermore, treatment with AP-AU1 induced phosphorylation of Akt2, p38?/p38?, p70S6K1, RSK2, and mTOR, as well as stimulation of NF-?B transcriptional activity. Conclusion Our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of water extracts from A. cordifolia leaves in traditional folk medicine of Africa. PMID:23291534

Kouakou, Koffi; Schepetkin, Igor A.; Yapi, Ahoua; Kirpotina, Liliya N.; Jutila, Mark A.; Quinn, Mark T.

2013-01-01

11

Permanent culture of macrophages at physiological oxygen attenuates the antioxidant and immunomodulatory properties of dimethyl fumarate.  

PubMed

We hypothesized that O2 tension influences the redox state and the immunomodulatory responses of inflammatory cells to dimethyl fumarate (DMF), an activator of the nuclear factor Nrf2 that controls antioxidant genes expression. This concept was investigated in macrophages permanently cultured at either physiological (5% O2) or atmospheric (20% O2) oxygen levels and then treated with DMF or challenged with lipopolysaccharide (LPS) to induce inflammation. RAW 264.7 macrophages cultured at 20% O2 exhibited a pro-oxidant phenotype, reflected by a lower content of reduced glutathione, higher oxidized glutathione and increased production of reactive oxygen species when compared to macrophages continuously grown at 5% O2. At 20% O2, DMF induced a stronger antioxidant response compared to 5% O2 as evidenced by a higher expression of heme oxygenase-1, NAD(P)H:quinone oxydoreductase-1 and superoxide dismutase-2. After challenge of macrophages with LPS, several pro-inflammatory (iNOS, TNF-?, MMP-2, MMP-9), anti-inflammatory (arginase-1, IL-10) and pro-angiogenic (VEGF-A) mediators were evaluated in the presence or absence of DMF. All markers, with few interesting exceptions, were significantly reduced at 5% O2. This study brings new insights on the effects of O2 in the cellular adaptation to oxidative and inflammatory stimuli and highlights the importance of characterizing the effects of chemicals and drugs at physiologically relevant O2 tension. Our results demonstrate that the common practice of culturing cells at atmospheric O2 drives the endogenous cellular environment towards an oxidative stress phenotype, affecting inflammation and the expression of antioxidant pathways by exogenous modulators. PMID:25303683

Haas, Benjamin; Chrusciel, Sandra; Fayad-Kobeissi, Sarah; Dubois-Randé, Jean-Luc; Azuaje, Francisco; Boczkowski, Jorge; Motterlini, Roberto; Foresti, Roberta

2015-05-01

12

Characterization and immunomodulatory activity of rice hull polysaccharides.  

PubMed

Rice hulls (Oryza sativa) are high in carbohydrate content and have been utilized as dietary fiber. The immunomodulatory bioactivity of rice hull polysaccharides (RHPS) has rarely been reported. This study demonstrated the structural characteristics and immunomodulating of RHPS. The RHPS were fractioned using DEAE-650M column, producing one neutral and 3 acidic polysaccharide fractions. RHPS were examined using HPAEC-PAD, HP-SEC, NMR and GC-MS for structural characteristics. The results showed that RHPS consisted of arabinose, galactose, glucose, mannose, and xylose in ratios of 10:44.8:29.8:9.3:6.1 and comprised (1?3)-Gal as backbone, and its average molecular weight was 77kDa. The presence of type II arabinogalactan (AGII) was confirmed through LM2-ELISA and Yariv gel diffusion showed the RHPS had AGII features. This study examined the immunomodulatory effects of orally administering RHPS in vivo. The RHPS increased the cytotoxicity of splenic natural killer cells, macrophage phagocytosis, and cytokine inductions. This is the first study to demonstrate the structural characteristics of an active polysaccharide from rice hulls and its immunopharmacological effects in vivo. PMID:25839805

Yang, Li-Chan; Hsieh, Chang-Chi; Lin, Wen-Chuan

2015-06-25

13

Immunomodulatory Activity of Chlorophytum borivilianum Sant. F  

PubMed Central

Chlorophytum borivilianum Santapau & Fernandes (Liliaceae) is a very popular herb in traditional Indian medicine and constitute a group of herbs used as ‘Rasayan’ or adaptogen. Ethanolic extract of the roots and its sapogenin were evaluated for their immunomodulatory activity. Effect of azathioprine-induced myelosuppresion and administration of extracts on hematological and serological parameters was determined. Administration of extracts greatly improved survival against Candida albicans infection. An increase in delayed-type hypersensitivity response (DTH), % neutrophil adhesion and in vivo phagocytosis by carbon clearance method was observed after treatment with extracts. Immunostimulant activity of ethanolic extract was more pronounced as compared to sapogenins. The results, thus justifies the traditional use of C. borivilianum as a rasayana drug. PMID:18227908

Thakur, Mayank; Bhargava, Shilpi

2007-01-01

14

Antimicrobial and Immunomodulatory Activities of PR-39 Derived Peptides  

PubMed Central

The porcine cathelicidin PR-39 is a host defence peptide that plays a pivotal role in the innate immune defence of the pig against infections. Besides direct antimicrobial activity, it is involved in immunomodulation, wound healing and several other biological processes. In this study, the antimicrobial- and immunomodulatory activity of PR-39, and N- and C-terminal derivatives of PR-39 were tested. PR-39 exhibited an unexpected broad antimicrobial spectrum including several Gram positive strains such as Bacillus globigii and Enterococcus faecalis. Of organisms tested, only Staphylococcus aureus was insensitive to PR-39. Truncation of PR-39 down to 15 (N-terminal) amino acids did not lead to major loss of activity, while peptides corresponding to the C-terminal part of PR-39 were hampered in their antimicrobial activity. However, shorter peptides were all much more sensitive to inhibition by salt. Active peptides induced ATP leakage and loss of membrane potential in Bacillus globigii and Escherichia coli, indicating a lytic mechanism of action for these peptides. Finally, only the mature peptide was able to induce IL-8 production in porcine macrophages, but some shorter peptides also had an effect on TNF-? production showing differential regulation of cytokine induction by PR-39 derived peptides. None of the active peptides showed high cytotoxicity highlighting the potential of these peptides for use as an alternative to antibiotics. PMID:24755622

Veldhuizen, Edwin J. A.; Schneider, Viktoria A. F.; Agustiandari, Herfita; van Dijk, Albert; Tjeerdsma-van Bokhoven, Johanna L. M.; Bikker, Floris J.; Haagsman, Henk P.

2014-01-01

15

Immunomodulatory activity of Mollugo verticillata L.  

PubMed

This article describes the evaluation of immunomodulatory activity of Mollugo verticillata L. (Molluginaceae), a weed plant common in warm and/or wet regions of the American continent. Nitric oxide (NO) release was evaluated in mice peritoneal cell cultures treated in vivo using the ethanolic extract of M. verticillata with and without BCG. The plant extract showed immunostimulatory activity when peritoneal cells were stimulated in vitro with BCG antigen only. However, mice peritoneal cells treated with M. verticillata plus BCG showed a drastic reduction in NO production when they received the additional stimulus in vitro with BCG. Ethanolic extracts of M. verticillata could directly increase NO release by peritoneal cells, but suppress the immune response of these cells when treated with BCG antigen and Mycobacterium tuberculosis whole antigen (TB). Preliminary phytochemical tests allowed the detection of quercetin and triterpenoid glycosides in the ethanolic extract of M. verticillata, and those compounds are probably responsible for the effect of this plant material on the immune system. PMID:12725569

Ferreira, A P; Soares, G L G; Salgado, C A; Gonçalves, L S; Teixeira, F M; Teixeira, H C; Kaplan, M A C

2003-03-01

16

Immunomodulatory activity of triphala on neutrophil functions.  

PubMed

Immune activation is an effective as well as protective approach against emerging infectious diseases. The immunomodulatory activities of Triphala (Terminalia chebula, Terminalia belerica and Emblica officinalis) were assessed by testing the various neutrophil functions like adherence, phagocytosis (phagocytic index (P.I) and avidity index (A.I)) and nitro blue tetrazolium (NBT) reduction in albino rats. In recent years much attention is being focused on the immunological changes occur during stress. Noise (100 dB) stress for 4 h/d for 15 d, was employed to alter the neutrophil functions. The neutrophil function tests and corticosterone levels were carried out in eight different groups of animals, namely control, Triphala, noise-stress, Triphala noise-stress, and corresponding immunized groups were used. Sheep red blood cells (SRBC 5 x 10(9) cells per ml) were used for immunizing the animals that belongs to immunized groups. In Triphala administration (1 g/kg/d for 48 d), A.I was found to be significantly enhanced in the Triphala group, while the remaining neutrophil functions and steroid levels were not altered significantly. However the neutrophil functions were significantly enhanced in the Triphala immunized group with a significant decrease in corticosterone level was observed. Upon exposure to the noise-stress, the neutrophil functions were significantly suppressed and followed by a significant increase in the corticosterone levels were observed in both the noise-stress and the noise-stress immunized groups. These noise-stress-induced changes were significantly prevented by Triphala administration in both the Triphala noise-stress and the Triphala noise-stress immunized groups. Hence our study has divulged that oral administration of Triphala appears to stimulate the neutrophil functions in the immunized rats and stress induced suppression in the neutrophil functions were significantly prevented by Triphala. PMID:16079482

Srikumar, Ramasundaram; Jeya Parthasarathy, Narayanaperumal; Sheela Devi, Rathinasamy

2005-08-01

17

A comparative study on immunomodulatory activity of polysaccharides from two official species of Ganoderma (Lingzhi).  

PubMed

Two Ganoderma species, G. lucidum and G. sinense, are listed as Lingzhi in Chinese Pharmacopoeia and they are considered to have the same therapeutic effects. Polysaccharides were the main immunomodulatory and anticancer components in Ganoderma. In this study, the chemical characters and the effects of polysaccharides from G. lucidum (GLPS) and G. sinense (GSPS) on macrophage functions were investigated and compared. Chemical studies showed that GLPS and GSPS were different, displaying various molecular weight distribution and ratio of monosaccharide components. In vitro pharmacological studies showed that both GLPS and GSPS had potent effects on macrophage functions, such as promoting macrophage phagocytosis, increasing their release of nitric oxide and cytokines interleukin (IL)-1?, IL-6, IL-10, and tumor necrosis factor-?. Generally, GLPS was more powerful than GSPS. This study is helpful to elucidate the active components and pharmacological variation between the 2 Ganoderma species. The structure-activity relationship of polysaccharides from Ganoderma needs further study. PMID:25204488

Meng, Lan-Zhen; Xie, Jing; Lv, Guang-Ping; Hu, De-Jun; Zhao, Jing; Duan, Jin-Ao; Li, Shao-Ping

2014-01-01

18

Immunomodulatory activity of fruits of Randia dumetorum Lamk  

Microsoft Academic Search

Randia dumetorum Lamk., a plant widely used in the traditional medicinal systems of India, has been reported to possess antiviral, antibacterial and anti-inflammatory activities. In present study, the attempt was made to screen immunomodulatory activity of methanol extract and its petroleum ether, chloroform, ethyl acetate and methanol fraction of fruits of R. dumetorum. The effects of R. dumetorum on cell

K. L. Satpute; M. M. Jadhav; R. S. Karodi; Y. S. Katare; M. J. Patil; Rukhsana Rub; A. R. Bafna

19

Immunomodulatory activity of ?malaki Ras?yana: An experimental evaluation  

PubMed Central

Background: Ayurvedic system of medicine holds a number of drugs that improves the immunity. ?malaki (Emblica officinalis) is one such drug. Researches with crude extracts of ?malaki have proven the antioxidant and immunomodulatory activities. But, works on ?malaki Ras?yana are not found reported. Aims: Considering this, two samples of ?malaki Ras?yana (AR7 and AR21) were studied to evaluate comparative immunomodulatory activity against the cyclophosphamide immunosuppression in rats. Materials and Methods: Test drugs were prepared by following classical guidelines. Wistar strain albino rats of either sex were used in the study. Statistical Analysis: For comparison of data from cyclophosphamide control group with remaining cyclophosphamide plus test drug administered groups one way ANOVA with Dunnett's multiple t-test (DMTT) was employed. Results and Conclusions: ?malaki Ras?yana possesses significant immunostimulant activity and moderate cytoprotective activity. AR21 was found to have better activity profile in terms of both immunostimulant as well as cytoprotective activity. PMID:24167334

Rajani, Jignesh; Ashok, B.K.; Galib; Patgiri, B.J.; Prajapati, P.K.; Ravishankar, B.

2012-01-01

20

In vivo evidence of the immunomodulatory activity of orally administered Aloe vera gel  

Microsoft Academic Search

The gels of Aloe species contain immunomodulatory components such as aloctin A and acemannan. Most studies on these gels were performed in\\u000a in vitro cell culture systems. Although several studies examined their immunomodulatory activity in vivo, the route of administration was intraperitoneal or intramuscular. Here, we evaluated the in vivo immunomodulatory activity of processed Aloe vera gel (PAG) in mice.

Sun-A. Im; Young-Ran Lee; Young-Hee Lee; Myung-Koo Lee; Young In Park; Sungwon Lee; Kyungjae Kim; Chong-Kil Lee

2010-01-01

21

Development of QSAR model for immunomodulatory activity of natural coumarinolignoids  

PubMed Central

Immunomodulation is the process of alteration in immune response due to foreign intrusion of molecules inside the body. Along with the available drugs, a large number of herbal drugs are promoted in traditional Indian treatments, for their immunomodulating activity. Natural coumarinolignoids isolated from the seeds of Cleome viscose have been recognized as having hepatoprotective action and have recently been tested preclinically for their immunomodulatory activity affecting both cell-mediated and humoral immune response. To explore the immunomodulatory compound from derivatives of coumarinolignoids, a quantitative structure activity relationship (QSAR) and molecular docking studies were performed. Theoretical results are in accord with the in vivo experimental data studied on Swiss albino mice. Immunostimulatory activity was predicted through QSAR model, developed by forward feed multiple linear regression method with leave-one-out approach. Relationship correlating measure of QSAR model was 99% (R2 = 0.99) and predictive accuracy was 96% (RCV2 = 0.96). QSAR studies indicate that dipole moment, steric energy, amide group count, lambda max (UV-visible), and molar refractivity correlates well with biological activity, while decrease in dipole moment, steric energy, and molar refractivity has negative correlation. Docking studies also showed strong binding affinity to immunomodulatory receptors. PMID:20856844

Yadav, Dharmendra K; Meena, Abha; Srivastava, Ankit; Chanda, D; Khan, Feroz; Chattopadhyay, SK

2010-01-01

22

Isolation and characterization of exopolysaccharide with immunomodulatory activity from fermentation broth of Morchella conica  

PubMed Central

Background and the purpose of this study Mushroom polysaccharides have traditionally been used for the prevention and treatment of a multitude of disorders like infectious illnesses, cancers and various autoimmune diseases. In vitro and in vivo studies suggest that certain polysaccharides affect immune system function. Morchella conica (M. conica) is a species of rare edible mushroom whose multiple medicinal functions have been proven. Thus, the objective of this study is to isolate and characterize of exopolysaccharide from submerged mycelial culture of M. conica, and to evaluate its immunomodulatory activity. Methods A water-soluble Morchella conica Polysaccharides (MCP) were extracted and isolated from the fermentation broth of M. conica through a combination of DEAE-cellulose and Sephacryl S-300 HR chromatograph. NMR and IR spectroscopy has played a developing role in identification of polysaccharide with different structure and composition from fungal and plant sources, as well as complex glycosaminoglycans of animal origin. Thus, NMR and IR spectroscopy were used to analyze the chemical structure and composition of the isolated polysaccharide. Moreover, the polysaccharide was tested for its immunomodulatory activity at different concentrations using in vitro model. Results The results showed that MCP may significantly modulate nitric oxide production in macrophages, and promote splenocytes proliferation. Analysis from HPLC, infrared spectra and nuclear magnetic resonance spectroscopy showed that MCP was a homogeneous mannan with an average molecular weight of approximately 81.2 kDa. The glycosidic bond links is ?6)-?-D-Man p-(1?. Conclusion The results suggested that the extracted MCP may modulate nitric oxide production in macrophages and promote splenocytes proliferation, and it may act as a potent immunomodulatory agent. PMID:23351529

2013-01-01

23

Recognition of TLR2 N-Glycans: Critical Role in ArtinM Immunomodulatory Activity  

PubMed Central

TLR2 plays a critical role in the protection against Paracoccidioides brasiliensis conferred by ArtinM administration. ArtinM, a D-mannose-binding lectin from Artocarpus heterophyllus, induces IL-12 production in macrophages and dendritic cells, which accounts for the T helper1 immunity that results from ArtinM administration. We examined the direct interaction of ArtinM with TLR2using HEK293A cells transfected with TLR2, alone or in combination with TLR1 or TLR6, together with accessory proteins. Stimulation with ArtinM induced NF-?B activation and interleukin (IL)-8 production in cells transfected with TLR2, TLR2/1, or TLR2/6. Murine macrophages that were stimulated with ArtinM had augmented TLR2 mRNA expression. Furthermore, pre-incubation of unstimulated macrophages with an anti-TLR2 antibody reduced the cell labeling with ArtinM. In addition, a microplate assay revealed that ArtinM bound to TLR2 molecules that had been captured by specific antibodies from a macrophages lysate. Notably,ArtinM binding to TLR2 was selectively inhibited when the lectin was pre-incubated with mannotriose. The biological relevance of the direct interaction of ArtinM with TLR2 glycans was assessed using macrophages from TLR2-KOmice, which produced significantly lower levels of IL-12 and IL-10 in response to ArtinM than macrophages from wild-type mice. Pre-treatment of murine macrophages with pharmacological inhibitors of signaling molecules demonstrated the involvement of p38 MAPK and JNK in the IL-12 production induced by ArtinM and the involvement ofPI3K in IL-10 production. Thus, ArtinM interacts directly with TLR2 or TLR2 heterodimers in a carbohydrate recognition-dependent manner and functions as a TLR2 agonist with immunomodulatory properties. PMID:24892697

da Silva, Thiago Aparecido; Ruas, Luciana Pereira; Nohara, Lilian L.; de Almeida, Igor Correia; Roque-Barreira, Maria Cristina

2014-01-01

24

In vivo and in vitro antileishmanial activity of Bungarus caeruleus snake venom through alteration of immunomodulatory activity.  

PubMed

Leishmaniasis threatens more than 350 million people worldwide specially in tropical and subtropical region. Antileishmanial drugs that are currently available have various limitations. The search of new drugs from natural products (plants, animals) possessing antileishmanial activity is ventured throughout the world. The present study deals with the antileishmanial activity of Bungarus caeruleus snake venom (BCV) on in vitro promastigotes and amastigotes of Leishmania donovani parasite and leishmania infected BALB/c mice. The effect of BCV on peritoneal macrophage, release of cytokines from the activated macrophages, production of nitric oxide, reactive oxygen species and cytokines were studied in vivo and in vitro. IC50 value of BCV on L. donovani promastigote was 14.5 ?g/ml and intracellular amastigote was 11.2 ?g/ml. It activated peritoneal macrophages, significantly increased cytokines and interleukin production. BCV (20 ?g/kg and 40 ?g/kg body weight of mice) decreased parasite count by 54.9% and 74.2% in spleen and 41.4% and 60.4% in liver of infected BALB/c mice. BCV treatment significantly increased production of TNF-?, IFN-?, ROS, NO in infected mice. Histological studies showed decreased granuloma formation in treated liver as compared with control. Liver and spleen structure was partially restored due to BCV treatment in infected mice. The present study revealed that BCV possessed antileishmanial activity against L. donovani parasite in vivo and in vitro and this activity was partly mediated through immunomodulatory activity involving macrophages. PMID:23830987

Bhattacharya, Shamik; Ghosh, Prasanta; De, Tripti; Gomes, Antony; Gomes, Aparna; Dungdung, Sandhya Rekha

2013-09-01

25

Immunomodulatory activity of Vachadhatryadi Avaleha in albino rats  

PubMed Central

The present study is carried out to evaluate the immuno-modulatory activity of Vacha Dhatryadi Avaleha in albino rats. Vacha Dhatryadi Avaleha was prepared by classical method and evaluated for humoral antibody formation and cell-medicated immunity in established experimental models. Test formulation was administered at the dose of 900 mg/kg and parameters like hemagglutination titer, ponderal changes, histopathology of immunological organs and immunological paw edema were recorded. Vacha Dhatryadi Avaleha significantly enhanced antibody formation and moderately suppressed the immunological edema. The present study concludes that Vachadhatryadi Avaleha has immunopotentiating activity. PMID:22408316

Rajagopala, S.; Ashok, B.K.; Ravishankar, B.

2011-01-01

26

Immunomodulatory effects of Hedysarum polybotrys extract in mice macrophages, splenocytes and leucopenia.  

PubMed

Astragali Radix (Huang-Qi) is a popular herbal medicine commonly used as a constituent in tonic herbal preparations. Hedysarum polybotrys Handel-Mazzetti is one species used of Astragali Radix. In this study, the immunomodulatory properties of H. polybotrys were explored by LPS-activated and SNP-treated RAW 264.7 cells and splenocytes and, daunoblastina-induced leucopenia BALB/c mice. Formononetin was used as the bioactive marker to monitor the quality of the H. polybotrys extracts. H. polybotrys was extracted with hot-water and methanol, and MeOH extract partitioned with H2O (M-H) and ethyl acetate (M-EA) to yield four different fractions. M-EA had the highest formononetin and total proanthocyanidin content and showed stronger inhibitory effects on the production and expression of NO, PGE2, iNOS and COX-2 in LPS-activated RAW 264.7 cells and splenocytes than the other fractions. In addition, M-EA significantly stimulated the proliferation of LPS-activated RAW 264.7 cells and splenocytes, enhanced NO radicals scavenging and attenuated NO-induced cytotoxicity.  Furthermore, M-EA also significantly increased the rate of recovery of white blood cells level in daunoblastina-induced leucopenia mice. These evidences suggest that this traditional Qi-tonifying herb has potential effects in clinical conditions when immune-enhancing and anti-inflammatory effect is desired. PMID:24300120

Huang, Guan-Cheng; Lee, Chia-Jung; Wang, Kun-Teng; Weng, Bor-Chun; Chien, Ting-Yi; Tseng, Sung-Hui; Wang, Ching-Chiung

2013-01-01

27

Immunomodulatory activity of polysaccharides isolated from Clerodendrum splendens: Beneficial effects in experimental autoimmune encephalomyelitis  

PubMed Central

Background Extracts of leaves from Clerodendrum have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. Methods Polysaccharides from the leaves of Clerodendrum splendens were extracted and fractionated by ion exchange and size-exclusion chromatography. Molecular weight determination, sugar analysis, degree of methyl esterification, and other chemical characterization of the fractions were performed. Immunomodulatory activity of the fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO), cytokine production, and mitogen-activated protein kinase (MAPK) phosphorylation. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice, and severity of EAE was monitored in mice treated with intraperitoneal (i.p.) injections of the most active polysaccharide fraction. Lymph nodes (LN) and spleen were harvested, and levels of cytokines in supernatants from LN cells and splenocytes challenged with myelin oligodendrocyte glycoprotein peptide were determined. Results Fractions containing type II arabinogalactan had potent immunomodulatory activity. Specifically, the high-molecular weight sub-fraction CSP-AU1 (average of 38.5 kDa) induced NO and cytokine [interleukin (IL)-1?, -1?, -6, -10, tumor necrosis factor (TNF; designated previously as TNF-?), and granulocyte macrophage-colony stimulating factor (GM-CSF)] production by human peripheral blood mononuclear cells (PBMCs) and monocyte/macrophages. CSP-AU1-induced secretion of TNF was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS, indicating a role for TLR4 signaling. Treatment with CSP-AU1 also induced phosphorylation of a number of MAPKs in human PBMC and activated AP-1/NF-?B. In vivo treatment of mice with CSP-AU1 and CSP-NU1 resulted in increased serum IL-6, IL-10, TNF, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1?/CCL3, and MIP-1?/CCL4. CSP-AU1 treatment of mice with EAE (50 mg/kg, i.p., daily, 13 days) resulted in significantly reduced disease severity in this experimental model of multiple sclerosis. Levels of IL-13, TNF, interferon (IFN)-?, IL-17, and GM-CSF were also significantly decreased, whereas transforming growth factor (TGF)-? was increased in LN cells from CSP-AU1-treated EAE mice. Conclusions Polysaccharide CSP-AU1 is a potent natural innate immunomodulator with a broad spectrum of agonist activity in vitro and immunosupressive properties after chronic administration in vivo. PMID:23806004

2013-01-01

28

Anti-tumour and immunomodulatory activities of oligosaccharides isolated from Panax ginseng C.A. Meyer.  

PubMed

Water-soluble ginseng oligosaccharides (WGOS) composed of D-glucose with a degree of polymerisation ranging from 2 to 14 were obtained from Panax ginseng C.A. Meyer. In this study, the anti-tumour and immunoregulatory effects of WGOS were evaluated in Hepatoma-22 (H22)-bearing mice. Treatment with WGOS inhibited tumour growth in vivo and significantly increased relative spleen and thymus weight, serum tumour necrosis factor-? level, spleen lymphocyte proliferation, natural killer cell activity, phagocytic function and nitric oxide production secreted by macrophage in H22-bearing mice. However, no direct cytotoxicity was detected. Therefore, the anti-tumour activity of WGOS may be related to their immunomodulatory effects. PMID:24468047

Jiao, Lili; Zhang, Xiaoyu; Li, Bo; Liu, Zhen; Wang, Mingzhu; Liu, Shuying

2014-04-01

29

Characterization, antioxidant and immunomodulatory activities of polysaccharides from Prunella vulgaris Linn.  

PubMed

Water-soluble polysaccharides from Prunella vulgaris Linn (P. vulgaris) were fractionated using DEAE-Sepharose fast-flow column to obtain several eluents of water (PV-P1), 0.1M NaCl (PV-P2) and 0.2M NaCl (PV-P3). Structural analyses showed that PV-P1 had a higher molecular weight and degree of branching as compared to PV-P2 and PV-P3. Tertiary structure analyses indicated that PV-P1, PV-P2 and PV-P3 did not have triple-helical conformation. PV-P2 and PV-P3 showed stronger antioxidant activities than PV-P1, as measured radical scavenging capacities. PV-P1 showed stronger immunomodulatory activities than PV-P2 and PV-P3 in term of stimulation of the production of pro-inflammatory cytokines, including nitric oxide (NO), tumor necrosis factor-? (TNF-?), and interleukin-6 (IL-6) in murine macrophage RAW 264.7 cells. PV-P1, PV-P2 and PV-P3 did not exhibit cytotoxicities against RAW 264.7 at the concentrations tested. These results suggest that P. vulgaris polysaccharides could be explored as potential antioxidant and immunomodulatory agents for the complementary medicine or functional foods. PMID:25596012

Li, Chao; Huang, Qiang; Fu, Xiong; Yue, Xiu-Jie; Liu, Rui Hai; You, Li-Jun

2015-04-01

30

Alternative Macrophage Activation and Metabolism  

PubMed Central

Obesity and its attendant metabolic disorders represent the great public health challenge of our time. Recent evidence suggests that onset of inflammation in metabolic tissues pathogenically links obesity to insulin resistance and type 2 diabetes. In this review, we briefly summarize the extant literature with special attention to the central role of the tissue-associated macrophage in the initiation of metabolic inflammation. We argue that rather than simple inflammatory disease, obesity and metabolic syndrome represent derangements in macrophage activation with concomitant loss of metabolic coordination. As such, the sequelae of obesity are as much products of the loss of positive macrophage influences as the presence of deleterious inflammation. The therapeutic implications of this conclusion are profound because they suggest that pharmacologic targeting of macrophage activation, rather than purely inflammation, might be efficacious in treating this global epidemic. PMID:21034223

Odegaard, Justin I.; Chawla, Ajay

2012-01-01

31

In vitro and in vivo immunomodulatory activity of sulfated polysaccharides from red seaweed Nemalion helminthoides.  

PubMed

Water-soluble sulfated polysaccharides from the red seaweed Nemalion helminthoides: two xylomannan fractions (N3 and N4) and a mannan fraction (N6) were investigated to determine their in vitro and in vivo immunomodulatory activities. N3 and N4 induced in vitro proliferation of macrophages of the murine cell line RAW 264.7 and significantly stimulated the production of nitric oxide (NO) and cytokines (IL-6 and TNF-?) in the same cells, whereas this response was not observed with the mannan N6. The cytokine production was also stimulated by sulfated xylomannans in vivo in BALB/c mice inoculated intravenously with these polysaccharides. Remarkably, when mice were treated with N3 and N4 for 1 h before being infected with Herpes simplex virus type 2, they remained asymptomatic with no signs of disease. The in vitro and in vivo results suggest that sulfated xylomannans could be strong immunomodulators. PMID:24444887

Pérez-Recalde, Mercedes; Matulewicz, María C; Pujol, Carlos A; Carlucci, María J

2014-02-01

32

Tumor-inhibitory effect and immunomodulatory activity of fullerol C60(OH)x.  

PubMed

The tumor-inhibitory effect of C60(OH)x was tested on the murine H22 hepatocarcinoma model. Doses of 0.2 and 1.0 mg kg(-1) body weight both showed significant antitumor activity with tumor inhibition rates of 31.9 and 38.4%, respectively, when mice were treated for 17 consecutive days. The damnification of liver was prominently reduced. Furthermore, histological examination indicated that an envelope of fibroblasts and lymphocytes was formed surrounding tumor tissues in the C60(OH)x-treated group, which inhibited the infiltration of tumor to the neighboring normal skeleton muscle tissues. To understand the antitumor mechanism, the immunomodulatory activity of C60(OH)x was investigated. The results indicate that C60(OH)x enhances the phagocytosis of peritoneal macrophages and elevates the activity of arginase and acid phosphatase in vivo. The tumor necrosis factor alpha production of C60(OH)x-treated macrophages also increases in vitro. These results suggest that C60(OH)x can enhance the innate immunity of tumor-bearing mice, and therefore inhibits growth of the tumor. PMID:18574800

Zhu, Jiadan; Ji, Zhiqiang; Wang, Jing; Sun, Ronghua; Zhang, Xiang; Gao, Yang; Sun, Hongfang; Liu, Yuanfang; Wang, Zheng; Li, Aidong; Ma, Jie; Wang, Tiancheng; Jia, Guang; Gu, Yiqun

2008-08-01

33

Effect of ultrasonic extraction conditions on antioxidative and immunomodulatory activities of a Ganoderma lucidum polysaccharide originated from fermented soybean curd residue.  

PubMed

A crude Ganoderma lucidum polysaccharide (GLPL) was extracted from fermented soybean curd residue by ultrasonic assisted extraction. The optimal extraction conditions were 30 min at 80 °C with 80 W and water to solid ratio of 10, and with this method 115.47 ± 2.95 mg/g of GLPL yield was obtained. Additionally, the antioxidant and immunomodulatory activities of GLPL were investigated. The results showed that GLPL exhibited strong antioxidant effects, which included scavenging activities against DPPH radicals, hydrogen oxide and ABTS radicals with IC50 values of 0.23, 0.48 and 0.69 mg/mL, respectively. For immunomodulatory activities, GLPL was shown to strongly stimulate the proliferation of macrophages (158.02 ± 13.12%), the production of nitric oxide and phagocytosis (21.16 ± 1.65 ?M), and, at 40.00 ?g/mL, protected macrophage from Doxorubicin (DOX) (0.16 ± 0.003). PMID:24594153

Shi, Min; Yang, Yingnan; Hu, Xuansheng; Zhang, Zhenya

2014-07-15

34

Structure and Antitumor and Immunomodulatory Activities of a Water-Soluble Polysaccharide from Dimocarpus longan Pulp  

PubMed Central

A new water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR), gas chromatography (GC) and nuclear magnetic resonance (NMR) analysis. The results indicated that the molecular weight of the sample was 1.1 × 105 Da. Monosaccharide composition analysis revealed that LP1 was composed of Glc, GalA, Ara and Gal in a molar ratio of 5.39:1.04:0.74:0.21. Structural analysis indicated that LP1 consisted of a backbone of ?4)-?-d-Glcp-(1?4)-?-d-GalpA-(1?4)-?-d-Glcp-(1?4)-?-d-Glcp-(1? units with poly saccharide side chains composed of ?2)-?-d-Fruf-(1?2)-l-sorbose-(1? attached to the O-6 position of the ?-d-Glcp residues. In vitro experiments indicated that LP1 had significantly high antitumor activity against SKOV3 and HO8910 tumor cells, with inhibition percentages of 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon-? (IFN-?), increased the activity of murine macrophages and enhanced B- and T-lymphocyte proliferation. The results of this study demonstrate that LP1 has potential applications as a natural antitumor agent with immunomodulatory activity. PMID:24663085

Meng, Fa-Yan; Ning, Yuan-Ling; Qi, Jia; He, Zhou; Jie, Jiang; Lin, Juan-Juan; Huang, Yan-Jun; Li, Fu-Sen; Li, Xue-Hua

2014-01-01

35

Structure and antitumor and immunomodulatory activities of a water-soluble polysaccharide from Dimocarpus longan pulp.  

PubMed

A new water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR), gas chromatography (GC) and nuclear magnetic resonance (NMR) analysis. The results indicated that the molecular weight of the sample was 1.1 × 10(5) Da. Monosaccharide composition analysis revealed that LP1 was composed of Glc, GalA, Ara and Gal in a molar ratio of 5.39:1.04:0.74:0.21. Structural analysis indicated that LP1 consisted of a backbone of ? 4)-?-D-Glcp-(1 ? 4)-?-D-GALPA-(1 ? 4)-?-D-Glcp-(1 ? 4)-?-D-Glcp-(1 ? units with poly saccharide side chains composed of ? 2)-?-D-Fruf-(1 ? 2)-L-sorbose-(1 ? attached to the O-6 position of the ?-D-Glcp residues. In vitro experiments indicated that LP1 had significantly high antitumor activity against SKOV3 and HO8910 tumor cells, with inhibition percentages of 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon-? (IFN-?), increased the activity of murine macrophages and enhanced B- and T-lymphocyte proliferation. The results of this study demonstrate that LP1 has potential applications as a natural antitumor agent with immunomodulatory activity. PMID:24663085

Meng, Fa-Yan; Ning, Yuan-Ling; Qi, Jia; He, Zhou; Jie, Jiang; Lin, Juan-Juan; Huang, Yan-Jun; Li, Fu-Sen; Li, Xue-Hua

2014-01-01

36

Macrophage immunomodulatory activity of polysaccharides isolated from Opuntia polyacantha  

Microsoft Academic Search

Opuntia polyacantha (prickly pear cactus) has been used extensively for its nutritional properties; however, less is known regarding medicinal properties of Opuntia tissues. In the present study, we extracted polysaccharides from O. polyacantha and used size-exclusion chromatography to fractionate the crude polysaccharides into four polysaccharide fractions (designated as Opuntia polysaccharides C-I to C-IV). The average Mr of fractions C-I through

Igor A. Schepetkin; Gang Xie; Liliya N. Kirpotina; Robyn A. Klein; Mark A. Jutila; Mark T. Quinn

2008-01-01

37

Immunomodulatory activities of Ganoderma sinense polysaccharides in human immune cells.  

PubMed

Medicinal mushrooms have been traditionally used as food nutrient supplements in China for thousands of years. The present study aimed to evaluate the immunomodulatory activities of Ganoderma sinense (GS), an allied species of G. lucidum, using human peripheral blood mononuclear cells (PBMC). Our results showed that the polysaccharide-enriched fraction of GS hot water extract (400 ?g/ml) exhibited significant stimulatory effects on PBMC proliferation. When the fruiting bodies of GS were divided into pileus and stipe parts and were separately extracted, the GS stipe polysaccharide-enriched fraction (50-400 ?g/ml) showed concentration-dependent immunostimulating effects in PBMC. The productions of tumor necrosis factor-?, interleukin (IL)-10, and transforming growth factor -? were significantly enhanced by this fraction. In addition, the proportion of CD14(+) monocyte subpopulation within the PBMC was specifically increased. The IL-10 and IL-12 productions in monocyte-derived dendritic cells were significantly enhanced by GS stipe fraction. The composition of monosaccharides of this fraction was determined by ultra performance liquid chromatography and ion exchange chromatography. Our study demonstrated for the first time the immunostimulatory effects of GS stipe polysaccharide-enriched fraction on PBMC and dendritic cells. The findings revealed the potential use of GS (especially including the stipes of fruiting bodies) as adjuvant nutrient supplements for patients, who are receiving immunosuppressive chemotherapies. PMID:23859044

Yue, Grace G L; Chan, Ben C L; Han, Xiao-Qiang; Cheng, Ling; Wong, Eric C W; Leung, Ping Chung; Fung, Kwok Pui; Ng, Michelle C H; Fan, Kei; Sze, Daniel M Y; Lau, Clara B S

2013-01-01

38

Comparison of physicochemical properties and immunomodulatory activity of polysaccharides from fresh and dried litchi pulp.  

PubMed

Drying is commonly used for preservation and processing of litchi. However, its polysaccharide structure may be altered by the drying process, resulting in biological activity changes. Polysaccharides from fresh and dried litchi pulp (denoted as LPF and LPD, respectively) were isolated, investigated by GC-MS, GPC and UV/IR spectrum analysis and their antitumor and immunomodulatory activities were evaluated in vitro. LPD, the molecular weight of which was lower than that of LPF, contained more protein, uronic acid, arabinose, galactose and xylose. Compared with LPF, LPD exhibited a higher inhibitory effect on the proliferation of HepG2, Hela and A549 cells from 50-750 ?g/mL. LPD was also a better stimulator of spleen lymphocyte proliferation, NK cells cytotoxicity and macrophage phagocytosis from 50-400 ?g/mL. In summary, drying could change the physicochemical properties and enhance the bioactivity of polysaccharides from litchi pulp. This finding is supported by the fact that dried litchi pulps are used in Traditional Chinese Medicine. PMID:24691064

Huang, Fei; Zhang, Ruifen; Yi, Yang; Tang, Xiaojun; Zhang, Mingwei; Su, Dongxiao; Deng, Yuanyuan; Wei, Zhencheng

2014-01-01

39

Immunomodulatory Activity of Acidic Polysaccharides Isolated from Tanacetum vulgare L  

PubMed Central

Tanacetum vulgare L. (Tansy) has been extensively used in folk medicine for treatment of a variety of medical disorders. In the present study, we isolated and purified four acidic polysaccharide fractions (designated T-I to T-IV) from Tansy florets by the sequential use of hot-water extraction, ethanol precipitation, ultra-filtration, anion-exchange, and size-exclusion chromatography. The average Mr of fractions T-I through T-IV was estimated to be 326, 151, 64 and 9 kDa, respectively, as determined by high performance size-exclusion chromatography analysis. Sugar composition analysis revealed that Tansy polysaccharides consisted primarily of galacturonic acid, galactose, arabinose, and rhamnose. Fractions T-II through T-IV contained an arabinogalactan type II structure, as determined by reaction with Yariv reagent. High Mr fractions T-I and T-II exhibited potent macrophage/monocyte-activating activity, enhancing production of reactive oxygen species (ROS), nitric oxide (NO), and tumor necrosis factor ? (TNF-?) by J774.A1 murine macrophages, and activating nuclear factor ?B (NF-?B) in THP-1 human monocytes. In addition, Tansy polysaccharides stimulated human neutrophil function by greatly enhancing neutrophil myeloperoxidase (MPO) release. Furthermore, the low Mr fraction T-IV had potent complement-fixing activity, which may also contribute to the anti-inflammatory and would-healing properties of Tansy extracts. Taken together, our results provide a molecular basis to explain at least part of the beneficial therapeutic effects of Tansy extracts, and support the concept of using Tansy polysaccharides as an immunotherapeutic adjuvant. PMID:17996673

Xie, Gang; Schepetkin, Igor A.; Quinn, Mark T.

2008-01-01

40

Granulocyte-macrophage colony stimulating factor exerts protective and immunomodulatory effects in cortical trauma.  

PubMed

Neurodegeneration after traumatic brain injury is facilitated by innate and adaptive immunity and can be harnessed to affect brain repair. In mice subjected to controlled cortical impact (CCI), we show that treatment with granulocyte macrophage colony stimulating factor (GM-CSF) affects regulatory T cell numbers in the cervical lymph nodes coincident with decreased lesion volumes and increased cortical tissue sparing. This paralleled increases in neurofilament and diminished reactive microglial staining. Transcriptomic analysis showed that GM-CSF induces robust immune neuroprotective responses seven days following CCI. Together, these results support the therapeutic potential of GM-CSF for TBI. PMID:25468272

Kelso, Matthew L; Elliott, Bret R; Haverland, Nicole A; Mosley, R Lee; Gendelman, Howard E

2015-01-15

41

Lactobacillus acidophilus L-92 Cells Activate Expression of Immunomodulatory Genes in THP-1 Cells  

PubMed Central

To understand the immunomodulatory effects of Lactobacillus acidophilus L-92 cells suggested from our previous study of in vivo anti-allergy and anti-virus effects, host immune responses in macrophage-like THP-1 cells after 4?h (the early phase) and 24?h (the late phase) of cocultivation with L-92 cells were investigated by transcriptome analysis. In the early phase of L-92 treatment, various transcription regulator genes, such as, NFkB1, NFkB2, JUN, HIVEP2 and RELB, and genes encoding chemokines and cytokines, such as CCL4, CXCL11, CCL3 and TNF, were upregulated. Two transmembrane receptor genes, TLR7 and ICAM1, were also upregulated in the early phase of treatment. In contrast, many transmembrane receptor genes, such as IL7R, CD80, CRLF2, CD86, CD5, HLA-DQA1, IL2RA, IL15RA and CSF2RA, and some cytokine genes, including IL6, IL23A and CCL22, were significantly upregulated in the late phase after L-92 exposure. Some genes encoding cytokines, such as IL1A, IL1B and IL8, and the enzyme IDO1 were upregulated at both the early and the late phases of treatment. These results suggest that probiotic L-92 might promote Th1 and regulatory T-cell responses by activation of the MAPK signaling pathway, followed by the NOD-like receptor signaling pathway in THP-1 cells. PMID:25379363

YANAGIHARA, Sae; GOTO, Hiroaki; HIROTA, Tatsuhiko; FUKUDA, Shinji; OHNO, Hiroshi; YAMAMOTO, Naoyuki

2014-01-01

42

Lactobacillus acidophilus L-92 Cells Activate Expression of Immunomodulatory Genes in THP-1 Cells.  

PubMed

To understand the immunomodulatory effects of Lactobacillus acidophilus L-92 cells suggested from our previous study of in vivo anti-allergy and anti-virus effects, host immune responses in macrophage-like THP-1 cells after 4?h (the early phase) and 24?h (the late phase) of cocultivation with L-92 cells were investigated by transcriptome analysis. In the early phase of L-92 treatment, various transcription regulator genes, such as, NFkB1, NFkB2, JUN, HIVEP2 and RELB, and genes encoding chemokines and cytokines, such as CCL4, CXCL11, CCL3 and TNF, were upregulated. Two transmembrane receptor genes, TLR7 and ICAM1, were also upregulated in the early phase of treatment. In contrast, many transmembrane receptor genes, such as IL7R, CD80, CRLF2, CD86, CD5, HLA-DQA1, IL2RA, IL15RA and CSF2RA, and some cytokine genes, including IL6, IL23A and CCL22, were significantly upregulated in the late phase after L-92 exposure. Some genes encoding cytokines, such as IL1A, IL1B and IL8, and the enzyme IDO1 were upregulated at both the early and the late phases of treatment. These results suggest that probiotic L-92 might promote Th1 and regulatory T-cell responses by activation of the MAPK signaling pathway, followed by the NOD-like receptor signaling pathway in THP-1 cells. PMID:25379363

Yanagihara, Sae; Goto, Hiroaki; Hirota, Tatsuhiko; Fukuda, Shinji; Ohno, Hiroshi; Yamamoto, Naoyuki

2014-01-01

43

Immunomodulatory Activity of Oenothein B Isolated from Epilobium angustifolium1  

PubMed Central

Epilobium angustifolium has been traditionally used to treat of a number of diseases; however, not much is known regarding its effect on innate immune cells. Here, we report that extracts of E. angustifolium activated functional responses in neutrophils and monocyte/macrophages. Activity-guided fractionation, followed by mass spectroscopy and NMR analysis, resulted in the identification of oenothein B as the primary component responsible for phagocyte activation. Oenothein B, a dimeric hydrolysable tannin, dose-dependently induced a number of phagocyte functions in vitro, including intracellular Ca2+ flux, production of reactive oxygen species (ROS), chemotaxis, nuclear factor (NF)-?B activation, and proinflammatory cytokine production. Furthermore, oenothein B was active in vivo, inducing keratinocyte chemoattractant (KC) production and neutrophil recruitment to the peritoneum after intraperitoneal administration. Biological activity required the full oenothein B structure, as substructures of oenothein B (pyrocatechol, gallic acid, pyrogallol, 3,4-dihydroxybenzoic acid) were all inactive. The ability of oenothein B to modulate phagocyte functions in vitro and in vivo suggests that this compound is responsible for at least part of the therapeutic properties of E. angustifolium extracts. PMID:19846877

Schepetkin, Igor A.; Kirpotina, Liliya N.; Jakiw, Larissa; Khlebnikov, Andrei I.; Blaskovich, Christie L.; Jutila, Mark A.; Quinn, Mark T.

2009-01-01

44

QSAR and Docking Studies on Capsazepine Derivatives for Immunomodulatory and Anti-Inflammatory Activity  

PubMed Central

Capsazepine, an antagonist of capsaicin, is discovered by the structure and activity relationship. In previous studies it has been found that capsazepine has potency for immunomodulation and anti-inflammatory activity and emerging as a favourable target in quest for efficacious and safe anti-inflammatory drug. Thus, a 2D quantitative structural activity relationship (QSAR) model against target tumor necrosis factor-? (TNF-?) was developed using multiple linear regression method (MLR) with good internal prediction (r2?=?0.8779) and external prediction (r2pred?=?0.5865) using Discovery Studio v3.5 (Accelrys, USA). The predicted activity was further validated by in vitro experiment. Capsazepine was tested in lipopolysaccharide (LPS) induced inflammation in peritoneal mouse macrophages. Anti-inflammatory profile of capsazepine was assessed by its potency to inhibit the production of inflammatory mediator TNF-?. The in vitro experiment indicated that capsazepine is an efficient anti-inflammatory agent. Since, the developed QSAR model showed significant correlations between chemical structure and anti-inflammatory activity, it was successfully applied in the screening of forty-four virtual derivatives of capsazepine, which finally afforded six potent derivatives, CPZ-29, CPZ-30, CPZ-33, CPZ-34, CPZ-35 and CPZ-36. To gain more insights into the molecular mechanism of action of capsazepine and its derivatives, molecular docking and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were performed. The results of QSAR, molecular docking, in silico ADMET screening and in vitro experimental studies provide guideline and mechanistic scope for the identification of more potent anti-inflammatory & immunomodulatory drug. PMID:25003344

Shukla, Aparna; Sharma, Pooja; Prakash, Om; Singh, Monika; Kalani, Komal; Khan, Feroz; Bawankule, Dnyaneshwar Umrao; Luqman, Suaib; Srivastava, Santosh Kumar

2014-01-01

45

Immunomodulatory effects of clove (Syzygium aromaticum) constituents on macrophages: In vitro evaluations of aqueous and ethanolic components.  

PubMed

Abstract The present work sought to investigate potential suppressive effects on mouse macrophages by in vitro treatment with clove (Syzygium aromaticum) ethanolic extracted essential oil (containing eugenol) or its water-soluble extract. Using doses (ranging from 0.001-1000?µg/ml) of each material freshly prepared in the laboratory, cell survival and production of nitric oxide (NO), tumor necrosis factor (TNF)-?, interleukin (IL)-6, and IL-12 by the treated cells (that in all cases also had received LPS stimulation) were measured. Results indicated that, except at doses ?100?µg/ml, viability was unaffected in all groups. NO release by LPS-stimulated macrophages was generally significantly suppressed by either material; in contrast, low (i.e. 0.001-1?µg/ml) doses of either extract class appeared to enhance NO release by non-LPS (unstimulated)-treated macrophages. Among LPS-stimulated cells, TNF? release was also significantly affected by each extract; the ethanolic extract was suppressive at all doses tested, while the aqueous material was so up to 1?µg/ml and then became stimulatory. In contrast, nearly every dose of either extract appeared to stimulate IL-6 release from the LPS-treated cells. Effects on IL-12 production were overall inconsistent; in general, the ethanolic extract tended to be stimulatory of production by the LPS-treated cells. The data for the aqueous material showed no discernable pattern of effect. The results suggest that clove extracts do not have a distinct cytotoxic activity, but do impart potential anti- and pro-oxidant effects in cells, depending on their concentrations and on the activation state of the macrophages themselves at the time of exposure to the extracts. The impact of the extracts on macrophage cytokine release also displays a pattern of dose-relatedness. PMID:24873744

Dibazar, Shaghayegh Pishkhan; Fateh, Shirin; Daneshmandi, Saeed

2015-04-01

46

Macrophage Activation Syndrome in Autoimmune Disease  

Microsoft Academic Search

Macrophage activation syndrome (MAS) is a phenomenon characterized by cytopenia, organ dysfunction, and coagulopathy associated with an inappropriate activation of macrophages. Current diagnostic criteria are imprecise, but the syndrome is now recognized as a form of hemophagocytic lymphohistiocytosis that is characteristically associated with autoimmune diatheses. The diagnosis of incipient MAS in patients with autoimmune disease requires a high index of

Sean Deane; Carlo Selmi; Suzanne S. Teuber; M. Eric Gershwin

2010-01-01

47

Mechanisms of triglyceride accumulation in activated macrophages  

PubMed Central

LPS treatment of macrophages induces TG accumulation, which is accentuated by TG-rich lipoproteins or FFA. We defined pathways altered during macrophage activation that contribute to TG accumulation. Glucose uptake increased with activation, accompanied by increased GLUT1. Oxidation of glucose markedly decreased, whereas incorporation of glucose-derived carbon into FA and sterols increased. Macrophage activation also increased uptake of FFA, associated with an increase in CD36. Oxidation of FA was markedly reduced, whereas the incorporation of FA into TGs increased, associated with increased GPAT3 and DGAT2. Additionally, macrophage activation decreased TG lipolysis; however, expression of ATGL or HSL was not altered. Macrophage activation altered gene expression similarly when incubated with exogenous FA or AcLDL. Whereas activation with ligands of TLR2 (zymosan), TLR3 (poly I:C), or TLR4 (LPS) induced alterations in macrophage gene expression, leading to TG accumulation, treatment of macrophages with cytokines had minimal effects. Thus, activation of TLRs leads to accumulation of TG in macrophages by multiple pathways that may have beneficial effects in host defense but could contribute to the accelerated atherosclerosis in chronic infections and inflammatory diseases. PMID:22753953

Feingold, Kenneth R.; Shigenaga, Judy K.; Kazemi, Mahmood R.; McDonald, Carol M.; Patzek, Sophie M.; Cross, Andrew S.; Moser, Arthur; Grunfeld, Carl

2012-01-01

48

Immunomodulatory effects of cinobufagin isolated from Chan Su on activation and cytokines secretion of immunocyte in vitro.  

PubMed

The objective of this study was to evaluate the immunomodulatory effects of cinobufagin (CBG) isolated from Chan Su (Venenum Bufonis) in vitro. In this paper, our results show that CBG significantly stimulated cell proliferation of splenocytes and peritoneal macrophages (PM?) and markedly enhanced the phagocytic activation of PM?. CBG also significantly increased CD4(+)CD8(+) double-positive T-cell populations and the percentage of S-phase cells of splenic lymphocytes. The levels of several Th1 cytokines, including interferon-? and tumor necrosis factor-?, are significantly increased after CBG treatment, whereas the levels of the Th2 cytokine interleukin-4 and interleukin-10 are significantly decreased. As a result, the ratio of Th1/Th2 also increased. Taken together, these results indicated that CBG had potential immune system regulatory effects and suggested that this compound could be developed as a novel immunotherapeutic agent to treat immune-mediated diseases such as cancer. PMID:21534035

Wang, Xiao-Liang; Zhao, Guang-Hou; Zhang, Jin; Shi, Qi-Yun; Guo, Wei-Xiao; Tian, Xiu-Li; Qiu, Jia-Zhang; Yin, Li-Zi; Deng, Xu-Ming; Song, Yu

2011-05-01

49

Evaluation of immunomodulatory activity of "Shirishavaleha"-An Ayurvedic compound formulation in albino rats.  

PubMed

The immunomodulatory activity of Shirishavaleha prepared from two different parts of Shirisha (Albizia lebbeck Benth), i.e., Twak (Bark) and Sara (Heartwood) as main ingredients was evaluated for humoral antibody formation and cell-mediated immunity in established experimental models. The study used Wistar rats of either sex weighing 200 ± 40 g, while the test drug was administered orally at a dose of 1.8 g/kg. Hemagglutination titer and body weight were recorded to assess effects on humoral immunity; immunological paw edema was assessed for cell-mediated immunity. Shirishavaleha prepared from heartwood shows significant enhancement in antibody formation, attenuation of body weight changes, and suppression of immunological paw edema, while Shirishavaleha prepared from bark shows weak immunomodulatory activity. The study therefore concludes that Shirishavaleha prepared from heartwood has significant immunomodulatory activity. PMID:22253509

Yadav, Shyamlal Singh; Galib; Prajapati, P K; Ashok, B K; Ravishankar, B

2011-10-01

50

Molecular characterization and immunomodulatory activity of sulfated fucans from Agarum cribrosum.  

PubMed

The sulfated-fucans, known as fucoidans, were isolated from Agarum cribrosum and fractionated using ion-exchange chromatography to determine their molecular characteristics and in vitro immunomodulatory activity. The crude and fractionated fucoidans (F1 and F2) consisted mostly of carbohydrates (52.4-56.0%), sulfates (12.7-23.0%) and uronic acid (14.1-21.8%), with a small amount of proteins (3.9-9.3%), and included various levels of fucose (44.0-46.7%), mannose (18.9-26.8%), galactose (16.8-33.0%), xylose (10.7-17.0%) and glucose (3.5-9.5%). The crude and fractionated fucans contained one or two subfractions with average molecular weights (Mw) ranging from 110.1 × 10(3) to 2420 × 10(3)g/mol. The fractionated fucoidan, especially the F1 fraction, strongly stimulated murine macrophages (Raw 264.7 cells), producing a considerable amount of nitric oxide (NO) and inducing expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin-10 (IL-10) transcripts by activation of nuclear factor-kappa B (NF-?B) and mitogen-activated protein kinases (MAPKs) pathways. The maximally immunoenhancing F1 fraction was mainly composed of (1 ? 3)-linked fucose, (1 ? 2)-linked mannose and (1 ? 4)-linked glucuronic acid with sulfates at C-2 or both the C-2 and C-4 positions in (1 ? 2,3)- and (1 ? 2,3,4)-linked fucose residues. PMID:25256513

Cho, MyoungLae; Lee, Dong-Jin; Kim, Jin-Kyung; You, SangGuan

2014-11-26

51

New Lactococcus strain with immunomodulatory activity: enhancement of Th1-type immune response.  

PubMed

Few studies exist dealing with the probiotic activity of lactococci, which are commonly used as starter bacteria in the manufacture of many kinds of fermented dairy products. Fifteen strains of the genus Lactococcus were examined for their probiotic activities, such as immunomodulatory effects. Six strains induced the production of cytokines (IL-12, IL-6, and TNF-alpha) in macrophage-like cell line J774.1, and the highest induction was observed with Lactococcus lactis subsp. lactis G50. The cytokine induction in the J774.1 cell line was almost entirely sustained after heat-killing of the strain. Spleen cells from BALB/c mice fed G50 culture produced more IL-12 and IFN-gamma and slightly less IL-4 and IL-6 than the control (i.e., without strain G50), indicating that strain G50 can enhance Th1-type immune response in vivo. The effect of the oral administration of strain G50 on antibody response in mice was also investigated. Mice were immunized with ovomucoid (OVM), a potent egg allergen, and the antibody level in the serum was then determined. The total IgE antibody level in the group treated with strain G50 was significantly lower than that of the control. The response of OVM-specific IgG1 and IgE antibodies tended to be low in the group that was administered strain G50, compared with the response of the control group. These results suggest that strain G50 has an ability to suppress the Th2 response. Thus, Lactococcus lactis subsp. lactis G50 is a potential probiotic strain for the suppression of hypersensitive reactions caused by the Th2 response. PMID:14978331

Kimoto, Hiromi; Mizumachi, Koko; Okamoto, Takashi; Kurisaki, Jun-Ichi

2004-01-01

52

Macrophages express membrane bound form of APRIL that can generate immunomodulatory signals  

E-print Network

-phorbol 13- myristate acetate; RA, rheumatoid arthritis; siRNA, small interfering RNA; TACI, transmembrane activator and CAML [a calcium-modulating cyclophilin ligand] interactor; TNF, tumour necrosis factor; TNFSF

Lee, Won-Ha

53

Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects  

Microsoft Academic Search

The anti-tumour effects of thalidomide have been associated with its anti-angiogenic properties. Second generation thalidomide analogues are distinct compounds with enhanced therapeutic potential. Although these compounds are beginning to enter trials for the treatment of cancer there is very little information regarding the anti-angiogenic activity of these clinically relevant compounds. Furthermore, it is not known how the various immunomodulatory activities

K Dredge; J B Marriott; C D Macdonald; H-W Man; R Chen; G W Muller; D Stirling; A G Dalgleish

2002-01-01

54

Immunomodulatory Activity of the Water Extract from Medicinal Mushroom Inonotus obliquus  

PubMed Central

The immunomodulatory effect of aqueous extract of Inonotus obliquus, called as Chaga, was tested on bone marrow cells from chemically immunosuppressed mice. The Chaga water extract was daily administered for 24 days to mice that had been treated with cyclophosphamide (400 mg/kg body weight), immunosuppressive alkylating agent. The number of colony-forming unit (CFU)-granulocytes/macrophages (GM) and erythroid burst-forming unit (BFU-E), increased almost to the levels seen in non-treated control as early as 8 days after treatment. Oral administration of the extract highly increased serum levels of IL-6. Also, the level of TNF-? was elevated by the chemical treatment in control mice, whereas was maintained at the background level in the extract-treated mice, indicating that the extract might effectively suppress TNF-? related pathologic conditions. These results strongly suggest the great potential of the aqueous extract from Inonotus obliquus as immune enhancer during chemotherapy. PMID:24049493

2005-01-01

55

Immunomodulatory effects of NIM76, a volatile fraction from Neem oil  

Microsoft Academic Search

The immunomodulatory properties of NIM-76 have been described in this paper. Pre-treatment of rats with a single i.p. injection of NIM-76 resulted in an increase in polymorphonuclear (PMN) leukocytes with a concomitant decrease in lymphocyte counts. The immunomodulatory activity of NIM-76 was found to be concentration-dependent. At 120 mg\\/kg body weight, there was an enhanced macrophage activity and lymphocyte proliferation

M. SaiRam; S. K. Sharma; G. Ilavazhagan; Devendra Kumar; W. Selvamurthy

1997-01-01

56

Enhancement of ATP generation capacity, antioxidant activity and immunomodulatory activities by Chinese Yang and Yin tonifying herbs  

PubMed Central

Chinese tonifying herbs such as Herba Cistanche, Ganoderma and Cordyceps, which possess antioxidant and/or immunomodulatory activities, can be useful in the prevention and treatment of age-related diseases. Pharmacological studies on Yang and Yin tonifying herbs suggest that Yang tonifying herbs stimulate mitochondrial adenosine triphosphate (ATP) generation, presumably through the intermediacy of reactive oxidant species, leading to the enhancement of cellular/mitochondrial antioxidant status. Yin tonifying herbs, however, apart from possessing antioxidant properties, exert mainly immunomodulatory functions that may boost a weak immune system and may also suppress overreactive immune responses. The abilities of Yang and Yin Chinese tonifying herbs to enhance ATP generation and to exhibit antioxidant and/or immunomodulatory actions are the pharmacological basis for their beneficial effects on the retardation of aging. PMID:17386115

Ko, Kam Ming; Leung, Hoi Yan

2007-01-01

57

PROTEASOME ACTIVITY DECLINES IN AGED MACROPHAGES  

Technology Transfer Automated Retrieval System (TEKTRAN)

The ubiquitin-proteasome pathway is involved in regulation of a variety of biologically important processes including antigen presentation by macrophages. Age-related decrease in proteasome activity has been reported in other tissues. However, the effect of aging on the ubiquitin-proteasome pathway ...

58

PROTEASOME ACTIVITY DECLINES IN AGED MACROPHAGES  

Technology Transfer Automated Retrieval System (TEKTRAN)

The ubiquitin-proteasome pathway is involved in regulation of a variety of biologically important processes including antigen presentation by macrophages (Mf). Age-related decrease in proteasome activity has been reported in other tissues. However, the effect of aging on the ubiquitin-proteasome pat...

59

Brazilian Propolis Antileishmanial and Immunomodulatory Effects  

PubMed Central

The antileishmanial and immunomodulatory effects of propolis collected in Botucatu, Săo Paulo State, Brazil, were evaluated in Leishmania (Viannia) braziliensis experimental infection. The antileishmanial effect of propolis on promastigote forms was verified by reducing growth and by promoting morphologic alterations observed by scanning electron microscopy. In in vitro immunomodulatory assays, macrophages were pretreated with propolis and then infected with L. (V.) braziliensis. In vivo, supernatants from liver cells and peritoneal exudate of BALB/c mice pretreated with propolis and infected with Leishmania (107/mL promastigotes) were collected, and TNF-? and IL-12 were measured by ELISA. Macrophages incubated with propolis showed a significant increase in interiorization and further killing of parasites. An increased TNF-? production was seen in mice pretreated with propolis, whereas IL-12 was downregulated during the infection. In conclusion, Brazilian propolis showed a direct action on the parasite and displayed immunomodulatory effects on murine macrophages, even though the parasite has been reported to affect the activation pathways of the cell. The observed effects could be associated with the presence of phenolic compounds (flavonoids, aromatic acids, and benzopyranes), di- and triterpenes, and essential oils found in our propolis sample. PMID:23762152

da Silva, Suelen Santos; Thomé, Graciele da Silva; Cataneo, Allan Henrique Depieri; Miranda, Milena Menegazzo; Felipe, Ionice; Andrade, Célia Guadalupe Tardeli de Jesus; Watanabe, Maria Angélica Ehara; Piana, Gilce Maria; Sforcin, José Maurício; Pavanelli, Wander Rogério; Conchon-Costa, Ivete

2013-01-01

60

Assessing for unique immunomodulatory and neuroplastic profiles of physical activity subtypes: a focus on psychiatric disorders.  

PubMed

Physical activity (PA) is emerging as a safe and effective tool in the prevention and treatment of psychiatric disorders. PA subtypes include aerobic, resistance, flexibility, neuromotor (involving balance, agility and co-ordination), mind-body (e.g. tai chi, qi gong and yoga) and mixed type trainings. Evidence from clinical trials suggests that PA subtypes can have positive clinical effects, however the effects on the symptomatology may vary according to the PA subtype. It therefore stands to reason that various PA subtypes may modulate the immune system and neuroplastic processes differently. This systematic review aims to assess the immunomodulatory and neuroplastic profiles of various PA subtypes, particularly in unipolar depression and age-related cognitive decline (ARCD). The literature suggests several unique immunomodulatory and neuroplastic profiles for PA subtypes (i.e. resistance, aerobic and mind-body) in depression and ARCD. In depression, levels of various cytokines at baseline may predict treatment response to subtypes of PA and pharmacological agents. The pro-neuroplastic effects of resistance and aerobic PA in ARCD may differ due to variances in neurotrophin profiles. At this stage of literature in the field, it is difficult to draw firm conclusions on the specific immunomodulatory and neuroplastic pathways involved in these PA subtypes given of the small number of comparative studies and methodological heterogeneity between studies (e.g. study population age and illness severity, as well as duration and intensity of PA intervention). This important field requires well-designed, high-quality comparative studies to better describe unique immunomodulatory and neuroplastic profiles. PMID:24269526

Eyre, Harris A; Baune, Bernhard T

2014-07-01

61

Immunostimulatory Activity of Protein Hydrolysate from Oviductus Ranae on Macrophage In Vitro  

PubMed Central

Oviductus Ranae is the dry oviduct of Rana chensinensis, which is also called R. chensinensis oil. Oviductus Ranae is a valuable Chinese crude drug and is recorded in the Pharmacopoeia of the People's Republic of China. The aim of this study was to investigate the immunostimulatory activity of protein hydrolysate of Oviductus Ranae (ORPH) and to assess its possible mechanism. Immunomodulatory activity of ORPH was examined in murine macrophage RAW 264.7 cells. The effect of ORPH on the phagocytic activity of macrophages was determined by the neutral red uptake assay. After treatment with ORPH, NO production levels in the culture supernatant were investigated by Griess assay. The mRNA and protein expressions of inducible nitric oxide synthase (iNOS) were detected by RT-PCR and Western blotting. The production of TNF-?, IL-1?, and IL-6 after treatment with ORPH was measured using ELISA assay. In addition, NF-?B levels were also investigated by Western blot. The results showed that ORPH enhanced the phagocytosis of macrophage, increased productions of TNF-?, IL-1?, IL-6, and NO in RAW 264.7 cells, and upregulated the mRNA and protein expression of iNOS. Besides, NF-?B, levels in RAW 264.7 cells were elevated after ORPH treatment. These findings suggested that ORPH might stimulate macrophage activities by activating the NF-?B pathway. PMID:25610475

Huang, Di; Yang, Lubing; Wang, Chenlu; Ma, Sihui; Cui, Li; Huang, Shiyang; Sheng, Xia; Weng, Qiang; Xu, Meiyu

2014-01-01

62

Immunomodulatory action of triterpene glycosides isolated from the sea cucumber Actinocucumis typica. Structure-activity relationships.  

PubMed

Stimulation of lysosomal activity and ROS formation in mouse peritoneal macrophages by five triterpene glycosides, typicosides A1 (1), A2 (2), B1 (3), C1 (4) and C2 (5) has been studied and compared with their cytotoxic activities. Glycosides 1-3 possess moderate activities, but the most cytotoxic glycoside 5 is not active. Typicoside C1 (4), with low toxicity, was proved to be the most active concerning stimulation of ROS formation. This is the first example of a triterpene glycoside from sea cucumbers with low cytotoxicity, but which demonstrates a strong immunostimulatory effect on mouse peritoneal macrophages in vitro. PMID:25115075

Pislyagin, Evgeny A; Aminin, Dmitry L; Silchenko, Alexandra S; Avilov, Sergey A; Andryjashchenko, Pelageya V; Kalinin, Vladimir I; Padmakumar, Krishna

2014-06-01

63

Macrophage activation by glycoprotein isolated from Dioscorea batatas.  

PubMed

We demonstrate that glycoprotein isolated from Dioscorea batatas (GDB) activates macrophage function. Analysis of the infiltration of macrophages into peritoneal cavity showed GDB treatment significantly increased the recruitment of macrophages into the peritoneal cavity. In order to further confirm and investigate the mechanism of GDB on macrophage activation, we analyzed the effects of GDB on the cytokine expression including IL-1?, TNF-?, and IL-6 in mouse peritoneal macrophages. GDB increased the expression of IL-1?, TNF-?, and IL-6. Cytokine induction by GDB was further confirmed by RT-PCR and ELISA in mouse macrophage cell line, RAW264.7 cells. Treatment of RAW264.7 cells with GDB produced strong induction of NF-?B DNA binding and MAPK phosphorylation, markers for macrophage activation and important factors for cytokine gene expression. Collectively, this series of experiments indicates that GDB stimulates macrophage activation. PMID:24278568

Huong, Pham Thi Thu; Jeon, Young Jin

2011-09-01

64

Macrophage activation and polarization: nomenclature and experimental guidelines.  

PubMed

Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation-with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature. PMID:25035950

Murray, Peter J; Allen, Judith E; Biswas, Subhra K; Fisher, Edward A; Gilroy, Derek W; Goerdt, Sergij; Gordon, Siamon; Hamilton, John A; Ivashkiv, Lionel B; Lawrence, Toby; Locati, Massimo; Mantovani, Alberto; Martinez, Fernando O; Mege, Jean-Louis; Mosser, David M; Natoli, Gioacchino; Saeij, Jeroen P; Schultze, Joachim L; Shirey, Kari Ann; Sica, Antonio; Suttles, Jill; Udalova, Irina; van Ginderachter, Jo A; Vogel, Stefanie N; Wynn, Thomas A

2014-07-17

65

Lipoproteins inhibit macrophage activation by lipoteichoic acid  

Microsoft Academic Search

Regulation of lipid metabolism during infection is thought to be part of host defense, as lipoproteins neu- tralize endotoxin (LPS) and viruses. Gram-positive infec- tions also induce disturbances in lipid metabolism. There- fore, we investigated whether lipoproteins could inhibit the toxic effects of lipoteichoic acid (LTA), a fragment of gram- positive bacteria. LTA activated RAW264.7 macrophage cells, stimulating production of

Carl Grunfeld; Maureen Marshall; Judy K. Shigenaga; Arthur H. Moser; Peter Tobias; Kenneth R. Feingold

66

In vitro immunomodulatory activity of plants used by the Tacana ethnic group in Bolivia.  

PubMed

One hundred and seventy-eight ethanolic plant extracts from the pharmacopoeia of the Tacana, an ethnic group from Bolivia, were screened for immunomodulatory activity using complement cascade inhibition and ADP-induced platelet aggregation inhibition assays. Six impaired both complement pathways (classical and alternative): stem bark from Astronium urundeuvea (Anacardiaceae), Cochlospermum vitifolium (Cochlospermaceae), Terminalia amazonica (Combretaceae), Triplaris americana (Polygonaceae), Uncaria tomentosa (Rubiaceae) and Euterpe precatoria (Arecaceae) roots. Inhibition of complement cascade was independent of essential ion complexation, and was not due to direct hemolytic activity on target red blood cells. For A. urundeuvea, C. vitifolium, and T. amazonica, anti-inflammatory activity relied on cyclo-oxygenase inhibition. Four of these species (A. urundeuva, T. americana, U. tomentosa and E. precatoria) are used traditionally to treat inflammatory processes. PMID:15500263

Deharo, E; Baelmans, R; Gimenez, A; Quenevo, C; Bourdy, G

2004-09-01

67

Macrophage activation: a riddle of immunological resistance.  

PubMed

Various lines of defense against infection are present in all living creatures. The balance between symbiosis and parasitism is determined by the mechanisms through which the host resists infection and by the extent of injury induced by the parasite: both factors contribute to disease. Lines of host defense can be arbitrarily divided into three components: 1) barrier functions of skin and mucous membranes and their innate physical and secretory antimicrobial components; 2) elements of host defense that do not necessarily require prior exposure to an infectious agent or immunologic memory (mast cells, granulocytes, macrophages, NK cells, gamma/delta T cells); and 3) immune responses directed against specific epitopes on the infectious agent induced by prior exposure and immunologic memory (alpha/beta T cells, B cells). Analysis of such host defense mechanisms repeatedly documents tremendous redundancy and overlap between these lines of defense. Further, there is open communication, so that a change at any one level ripples throughout the system. Acquired nonspecific resistance to infection is an example of such a ripple. Host response to one infection alerts the immune system, so that the general level of resistance to other infectious agents is increased. This response is initiated by an immune response (third line of defense) but effected by nonspecific elements (second line of defense). The survival value of such responses is obvious. There are numerous examples in both mouse and man of the operation of these systems in response to infection. Further, the menus of antimicrobial components available to both mouse and man for resistance to infection are very similar, but not identical. Indeed, it is said that the genetic basis for differences between mice and man revolve around a difference of less than 10% in DNA sequences. But there are differences! Mouse macrophages produce IFN-beta in response to infection, human cells produce IFN-alpha. Mouse macrophages effect antimicrobial activity principally through induction of NO synthase and the generation of toxic nitrogen oxides. This pathway has yet to be described with human macrophages. In both man and mouse, F. tularensis is an obligate intracellular parasite of macrophages that requires an essential component provided by the cell for its replication. That mouse and man are not so different is well illustrated by the effector mechanisms induced by IFN-gamma for antimicrobial activity against F. tularensis.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8251575

Crawford, R M; Leiby, D A; Green, S J; Nacy, C A; Fortier, A H; Meltzer, M S

1994-01-01

68

Antitumor and immunomodulatory activity of water-soluble polysaccharide from Inonotus obliquus.  

PubMed

The medicinal mushroom Inonotus obliquus has been used as a folk remedy for a long time in Russia and East-European countries to treat gastrointestinal cancer, cardiovascular disease and diabetes. In our study, a water-soluble polysaccharide (ISP2a) was successfully purified from I. obliquus by DEAE-Sepharose CL-6B and Sepharose CL-6B column chromatography. In vivo ISP2a had not only shown antitumor activity, but also could significantly enhance the immune response of tumor-bearing mice. In addition, ISP2a significantly enhanced the lymphocyte proliferation and increased the production of TNF-?. Results of these studies demonstrated that ISP2a had a potential application as natural antitumor agent with immunomodulatory activity. PMID:22840014

Fan, Liuping; Ding, Shaodong; Ai, Lianzhong; Deng, Kequan

2012-10-01

69

Histiocytic glomerulopathy associated with macrophage activation syndrome.  

PubMed

We present an interesting case of a 37-year old man with acute renal failure following a febrile illness. Laboratory results showed features of macrophage activation syndrome (MAS) with anemia, thrombocytopenia, hypofibrinogenemia and elevated ferritin levels. Renal biopsy was then done to determine the cause of renal failure and showed unique glomerular findings with massive histiocytic infiltration ('histiocytic glomerulopathy') and evidence of endothelial injury. Recognizing that the histiocytic infiltrate and endothelial injury is a part of MAS is important because early recognition and treatment is of utmost importance since the disease can be fatal. PMID:25815171

Eirin, Alfonso; Irazabal, Maria V; Fervenza, Fernando C; Sethi, Sanjeev

2015-04-01

70

Histiocytic glomerulopathy associated with macrophage activation syndrome  

PubMed Central

We present an interesting case of a 37-year old man with acute renal failure following a febrile illness. Laboratory results showed features of macrophage activation syndrome (MAS) with anemia, thrombocytopenia, hypofibrinogenemia and elevated ferritin levels. Renal biopsy was then done to determine the cause of renal failure and showed unique glomerular findings with massive histiocytic infiltration (‘histiocytic glomerulopathy’) and evidence of endothelial injury. Recognizing that the histiocytic infiltrate and endothelial injury is a part of MAS is important because early recognition and treatment is of utmost importance since the disease can be fatal.

Eirin, Alfonso; Irazabal, Maria V.; Fervenza, Fernando C.; Sethi, Sanjeev

2015-01-01

71

Myelin alters the inflammatory phenotype of macrophages by activating PPARs  

PubMed Central

Background Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Recent studies have described an altered phenotype of macrophages after myelin internalization. However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear. Results We demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitric oxide production by macrophages through activation of peroxisome proliferator-activated receptor ?/? (PPAR?/?). Furthermore, uptake of PS by macrophages, after intravenous injection of PS-containing liposomes (PSLs), suppresses the production of inflammatory mediators and ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effect of PSLs in EAE animals is associated with a reduced immune cell infiltration into the central nervous system and decreased splenic cognate antigen specific proliferation. Interestingly, PPAR?/? is activated in foamy macrophages in active MS lesions, indicating that myelin also activates PPAR?/? in macrophages in the human brain. Conclusion Our data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression. Moreover, our results suggest that myelin-derived PS mediates PPAR?/? activation in macrophages after myelin uptake. The immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics. PMID:24252308

2013-01-01

72

Enhanced Immunomodulatory Activity of Gelatin-Encapsulated Rubus coreanus Miquel Nanoparticles  

PubMed Central

The aim of this work was to investigate the immunomodulatory activities of Rubus coreanus Miquel extract-loaded gelatin nanoparticles. The mean size of the produced nanoparticles was 143 ± 18 nm with a bandwidth of 76 nm in the size distribution and a maximum size of ~200 nm, which allows effective nanoparticle uptake by cells. Confocal imaging confirmed this, since the nanoparticles were internalized within 30 min and heterogeneously distributed throughout the cell. Zeta-potential measurements showed that from pH = 5 onwards, the nanoparticles were highly negatively charged, which prevents agglomeration to clusters by electrostatic repulsion. This was confirmed by TEM imaging, which showed a well dispersed colloidal solution. The encapsulation efficiency was nearly 60%, which is higher than for other components encapsulated in gelatin nanoparticles. Measurements of immune modulation in immune cells showed a significant effect by the crude extract, which was only topped by the nanoparticles containing the extract. Proliferation of B-, T- and NK cells was notably enhanced by Rubus coreanus-gelatin nanoparticles and in general ~2–3 times higher than control and on average ~2 times higher than ferulic acid. R. coreanus-gelatin nanoparticles induced cytokine secretion (IL-6 and TNF-?) from B- and T-cells on average at a ~2–3 times higher rate compared with the extract and ferulic acid. In vivo immunomodulatory activity in mice fed with R. coreanus-gelatin nanoparticles at 1 mL/g body weight showed a ~5 times higher antibody production compared to control, a ~1.3 times higher production compared to the extract only, and a ~1.6 times higher production compared to ferulic acid. Overall, our results suggest that gelatin nanoparticles represent an excellent transport vehicle for Rubus coreanus extract and extracts from other plants generally used in traditional Asian medicine. Such nanoparticles ensure a high local concentration that results in enhancement of immune cell activities, including proliferation, cytokine secretion, and antibody production. PMID:22272118

Seo, Yong Chang; Choi, Woon Yong; Lee, Choon Geun; Cha, Seon Woo; Kim, Young Ock; Kim, Jin-Chul; Drummen, Gregor P. C.; Lee, Hyeon Yong

2011-01-01

73

Oxygen-dependent Leishmanicidal activity of stimulated macrophages  

Microsoft Academic Search

Peritoneal macrophages pretreated with different stimulants were analysed and compared with their respective controls for their ability to kill intracellular pathogenic L. donovani, (MHOM\\/IN\\/1983\\/AG83) an isolate from Indian subcontinent. Stimulation of macrophages by zymosan showed a higher microbicidal activity as compared to that by PMA. A correlation between microbicidal activity of the macrophages and the parameters related to respiratory burst

R. Chakraborty; S. Mukherjee; M. K. Basu

1996-01-01

74

Genetically Engineered Immunomodulatory Streptococcus thermophilus Strains Producing Antioxidant Enzymes Exhibit Enhanced Anti-Inflammatory Activities  

PubMed Central

The aims of this study were to develop strains of lactic acid bacteria (LAB) having both immunomodulatory and antioxidant properties and to evaluate their anti-inflammatory effects both in vitro, in different cellular models, and in vivo, in a mouse model of colitis. Different Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus strains were cocultured with primary cultures of mononuclear cells. Analysis of the pro- and anti-inflammatory cytokines secreted by these cells after coincubation with candidate bacteria revealed that L. delbrueckii subsp. bulgaricus CRL 864 and S. thermophilus CRL 807 display the highest anti-inflammatory profiles in vitro. Moreover, these results were confirmed in vivo by the determination of the cytokine profiles in large intestine samples of mice fed with these strains. S. thermophilus CRL 807 was then transformed with two different plasmids harboring the genes encoding catalase (CAT) or superoxide dismutase (SOD) antioxidant enzymes, and the anti-inflammatory effects of recombinant streptococci were evaluated in a mouse model of colitis induced by trinitrobenzenesulfonic acid (TNBS). Our results showed a decrease in weight loss, lower liver microbial translocation, lower macroscopic and microscopic damage scores, and modulation of the cytokine production in the large intestines of mice treated with either CAT- or SOD-producing streptococci compared to those in mice treated with the wild-type strain or control mice without any treatment. Furthermore, the greatest anti-inflammatory activity was observed in mice receiving a mixture of both CAT- and SOD-producing streptococci. The addition of L. delbrueckii subsp. bulgaricus CRL 864 to this mixture did not improve their beneficial effects. These findings show that genetically engineering a candidate bacterium (e.g., S. thermophilus CRL 807) with intrinsic immunomodulatory properties by introducing a gene expressing an antioxidant enzyme enhances its anti-inflammatory activities. PMID:24242245

del Carmen, Silvina; de Moreno de LeBlanc, Alejandra; Martin, Rebeca; Chain, Florian; Langella, Philippe; Bermúdez-Humarán, Luis G.

2014-01-01

75

Granulocyte\\/macrophage-colony-stimulating factor augments lymphokine-activated killer activity from lymphocytes via macrophages in lung cancer patients  

Microsoft Academic Search

Introduction: Therapies with granulocyte\\/macrophage-colony-stimulating factor (GM-CSF) and interleukin(IL)-2 are designed to activate macrophages\\u000a and lymphocytes. We investigated whether combined treatment with GM-CSF and IL-2 induced macrophage-mediated antitumor activity\\u000a and\\/or T-cell-mediated antitumor activity in lung cancer patients. Patients and methods: Macrophages in the pleural cavity (PCM), lymphocytes in the pleural cavity (PLY), and peripheral blood lymphocytes (PBL)\\u000a were separated from 48

Keiji Takahashi; Seiya Saito; Yoshitaka Kamamura; Masatomo Katakawa; Yasumasa Monden

2000-01-01

76

Sulfated modification of longan polysaccharide and its immunomodulatory and antitumor activity in vitro.  

PubMed

A water-soluble polysaccharide fraction (LP1) was prepared from Dimocarpus longan Lour. by hot water extraction, DEAE-cellulose and Sephadex G-100 chromatography. Its sulfated derivative (LP1-S) was prepared by the sulfuric acid method. Preliminary tests in vitro showed LP1 and LP1-S could stimulate murine lymphocytes proliferation, increase pinocytic activity of murine macrophages and production of nitric oxide (NO), interleukin 6 (IL-6), IL-1? and tumor necrosis factor-alpha (TNF-?) in macrophages. Furthermore, LP1-S exhibited higher antiproliferative activity against human nasopharyngeal carcinoma HONE1 cells in vitro than LP1, which might be caused by the sulfate group in its structures. These results indicated that the LP1-S might be useful for developing safe antitumor drugs or health food. PMID:24680807

Jiang, Jie; Meng, Fa-Yan; He, Zhou; Ning, Yuan-Ling; Li, Xue-Hua; Song, Hui; Wang, Jing; Zhou, Rui

2014-06-01

77

Immunomodulatory activities of Yoyo bitters: recommended dose precipitated inflammatory responses in male Wistar rats.  

PubMed

This study investigated the immunomodulatory capabilities of the sub-chronic administration of Yoyo bitters in male Wistar rats. Eighteen rats weighing 86.2 +/- 4.43 g were randomly picked into three equal groups. The rats were acclimatized for 14 days, after which 0.308 and 0.462 mL kg(-1) b.wt. of Yoyo bitters were administered once daily to groups B and C respectively for 56 days, while group A received distilled water. The feed intake, body weight, blood glucose, interleukin 2 (IL-2), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha), haematological parameters, serum lipid profile and uric acid, liver reduced glutathione and malodialdehyde were determined. The feed intake, body weight and blood glucose concentrations were reduced (p < 0.05) at the doses. No changes were recorded in the concentration of serum IL-2 (p > 0.05), but IL-6 decreased (p < 0.05) in group B and increased (p < 0.05) in group C, while TNF-alpha were increased (p < 0.05) dose dependent. The haematological parameters were decreased at all the doses (p < 0.05), except the ESR, WBC and lymphocytes that were increased (p < 0.05) and platelets in group C (p < 0.05). The serum total cholesterol, TAG, LDL-C and atherogenic index were decreased (p < 0.05) and HDL-C increased (p < 0.05) in group B only. Serum uric acid was reduced (p < 0.05) in group B, but increased in group C with the concentration of liver MDA (p < 0.05). The study, therefore, established that a dose lower than the manufacturer's recommended dose presented the desired immunomodulatory activities and the habitual use of Yoyo bitters at the adult recommended dose calls for caution. PMID:24517005

Oyewo, E B; Adetutu, A; Adebisi, J A

2013-12-15

78

Antioxidant and Immunomodulatory Activity of the Alkaloidal Fraction of Cissampelos pareira Linn.  

PubMed Central

The alkaloidal fraction (AFCP) of roots of Cissampelos pareira Linn. was screened for in-vitro antioxidant activity and immunomodulatory activity in mice. The HPTLC finger print profile was also established for the identification of AFCP which was found to contain 0.176 % of berberine. AFCP possess strong antioxidant activity which was revealed by its ability to scavenge the stable free radical DPPH, superoxide ion and to inhibit lipid peroxidation in rat liver homogenate induced by iron/ADP/Ascorbate complex. AFCP was found to have significant immunosuppressive activity at lower doses (25 and 50 mg/kg) while no activity was observed at higher doses (75 and 100 mg/kg). Humoral antibody titre was significantly (p<0.01) lowered by AFCP at the doses of 25 and 50 mg/kg. Delayed type hypersensitivity response was also significantly (p<0.01) suppressed by the AFCP at the dose of 75 mg/kg. Thus the present study revealed the immunosuppressive and antioxidant activities of the alkaloidal fraction of C. pareira roots. PMID:21179368

Bafna, Anand; Mishra, Shrihari

2010-01-01

79

Screening of immunomodulatory activity of total and protein extracts of some Moroccan medicinal plants.  

PubMed

Herbal and traditional medicines are being widely used in practice in many countries for their benefits of treating different ailments. A large number of plants in Morocco were used in folk medicine to treat immune-related disorders. The objective of this study is to evaluate the immunomodulatory activity of protein extracts (PEs) of 14 Moroccan medicinal plants. This activity was tested on the proliferation of immune cells. The prepared total and PEs of the plant samples were tested using MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide) assay on the splenocytes with or without stimulation by concanavalin-A (Con-A), a mitogenic agent used as positive control. The results of this study indicated different activity spectra. Three groups of activities were observed. The first group represented by Citrullus colocynthis, Urtica dioica, Elettaria cardamomum, Capparis spinosa and Piper cubeba showed a significant immunosuppressive activity. The second group that showed a significant immunostimulatory activity was represented by Aristolochia longa, Datura stramonium, Marrubium vulgare, Sinapis nigra, Delphynium staphysagria, Lepidium sativum, Ammi visnaga and Tetraclinis articulata. The rest of the plant extracts did not alter the proliferation induced by Con-A. This result was more important for the PE than for the total extract. In conclusion, this study revealed an interesting immunomodulating action of certain PEs, which could explain their traditional use. The results of this study may also have implications in therapeutic treatment of infections, such as prophylactic and adjuvant with cancer chemotherapy. PMID:22301818

Daoudi, Abdeljlil; Aarab, Lotfi; Abdel-Sattar, Essam

2013-04-01

80

JUNB is a key transcriptional modulator of macrophage activation.  

PubMed

Activated macrophages are crucial for restriction of microbial infection but may also promote inflammatory pathology in a wide range of both infectious and sterile conditions. The pathways that regulate macrophage activation are therefore of great interest. Recent studies in silico have putatively identified key transcription factors that may control macrophage activation, but experimental validation is lacking. In this study, we generated a macrophage regulatory network from publicly available microarray data, employing steps to enrich for physiologically relevant interactions. Our analysis predicted a novel relationship between the AP-1 family transcription factor Junb and the gene Il1b, encoding the pyrogen IL-1?, which macrophages express upon activation by inflammatory stimuli. Previously, Junb has been characterized primarily as a negative regulator of the cell cycle, whereas AP-1 activity in myeloid inflammatory responses has largely been attributed to c-Jun. We confirmed experimentally that Junb is required for full expression of Il1b, and of additional genes involved in classical inflammation, in macrophages treated with LPS and other immunostimulatory molecules. Furthermore, Junb modulates expression of canonical markers of alternative activation in macrophages treated with IL-4. Our results demonstrate that JUNB is a significant modulator of both classical and alternative macrophage activation. Further, this finding provides experimental validation for our network modeling approach, which will facilitate the future use of gene expression data from open databases to reveal novel, physiologically relevant regulatory relationships. PMID:25472994

Fontana, Mary F; Baccarella, Alyssa; Pancholi, Nidhi; Pufall, Miles A; Herbert, De'Broski R; Kim, Charles C

2015-01-01

81

Dextrans produced by lactic acid bacteria exhibit antiviral and immunomodulatory activity against salmonid viruses.  

PubMed

Viral infections in the aquaculture of salmonids can lead to high mortality and substantial economic losses. Thus, there is industrial interest in new molecules active against these viruses. Here we describe the production, purification, and the physicochemical and structural characterization of high molecular weight dextrans synthesized by Lactobacillus sakei MN1 and Leuconostoc mesenteroides RTF10. The purified dextrans, and commercial dextrans with molecular weights ranging from 10 to 2000kDa, were assayed in infected BF-2 and EPC fish cell-line monolayers for antiviral activity. Only T2000 and dextrans from MN1 and RTF10 had significant antiviral activity. This was similar to results obtained against infectious pancreatic necrosis virus. However the dextran from MN1 showed ten-fold higher activity against hematopoietic necrosis virus than T2000. In vivo assays using the MN1 polymer confirmed the in vitro results and revealed immunomodulatory activity. These results together with the high levels of dextran production (2gL(-1)) by Lb. sakei MN1, indicate the compounds potential utility as an antiviral agent in aquaculture. PMID:25839823

Nácher-Vázquez, Montserrat; Ballesteros, Natalia; Canales, Ángeles; Rodríguez Saint-Jean, Sylvia; Pérez-Prieto, Sara Isabel; Prieto, Alicia; Aznar, Rosa; López, Paloma

2015-06-25

82

Alternatively Activated Macrophages in Types 1 and 2 Diabetes  

PubMed Central

Macrophages are innate immune cells derived from monocytes, which, in turn, arise from myeloid precursor cells in the bone marrow. Macrophages have many important roles in the innate and adaptive immune response, as well as in tissue homeostasis. Two major populations have been defined: The classically activated macrophages that respond to intracellular pathogens by secreting proinflammatory cytokines and reactive oxygen species and alternatively activated macrophages which are induced during Th2 responses displaying anti-inflammatory activities. Both macrophage populations are central players in diabetes, the first one triggering inflammatory responses which initiates insulitis and pancreatic ? cell death during type 1 diabetes, whereas the second population decreases hyperglycemia, insulitis, and inflammation in the pancreas, thereby negatively regulate type 1 diabetes. Obesity is an important factor in the development of type 2 diabetes; classically activated macrophages are a dominant cell population involved in the establishment of the inflammatory profile, insulin resistance, and activation of inflammatory signals during the development and progression of this disease. In contrast, alternatively activated macrophages regulate the release of proinflammatory cytokines, attenuating adipose tissue inflammation. Here, we review the advantages and disadvantages of these two macrophage populations with regard to their roles in types 1 and 2 diabetes. PMID:23326021

Espinoza-Jiménez, Arlett; Peón, Alberto N.; Terrazas, Luis I.

2012-01-01

83

Evaluation of a topical herbal drug for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis  

PubMed Central

Background: Antibiotics have been in use in the treatment of bovine mastitis since decades; however, their use is associated with cost issues and human health concern. Use of herbal drugs does not generally carry these disadvantages. Many plants/herbs have been evaluated in the treatment of bovine mastitis with additional property of immunomodulation in affected mammary gland. Aim: To evaluate a topical herbal drug in two breeds of cattle for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis. Materials and Methods: The response to treatment was evaluated by enumerating somatic cell count (SCC), determining total bacterial load, and studying the expression of different cytokines (interleukin [IL]-6, IL-8, IL-12, granulocyte macrophage-colony stimulating factor, interferon (IFN)-? and tumor necrosis factor [TNF]-?). Results: The pre- and post-treatment SCC in mastitic quarters statistically did not differ significantly, however, total bacterial load declined significantly from day 0 onwards in both the breeds. Highly significant differences (P < 0.01) were observed in all the cytokines on day 0, 5, and 21 postlast treatment in both the breeds. The expression level of all the cytokines showed a significant increase on day 5, while a decrease was noticed on day 21 in both the breeds of cattle. The comparison of cytokine expression profiles between crossbred and Gir cattle revealed a significant difference in expression of IL-6 and TNF-?. However, other cytokines exhibited a similar pattern of expression in both breeds, which was non-significant. Conclusion: The topical herbal drug exhibited antibacterial and immunomodulatory activities in subclinical mastitis and thus the work supports its use as alternative herbal therapy against subclinical udder infection in bovines. PMID:25558168

Bhatt, Vaibhav D.; Shah, Tejas M.; Nauriyal, Dev S.; Kunjadia, Anju P.; Joshi, Chaitanya G.

2014-01-01

84

Tityus serrulatus venom and toxins Ts1, Ts2 and Ts6 induce macrophage activation and production of immune mediators.  

PubMed

Scorpion envenomation induces a systemic immune response, and neurotoxins of venom act on specific ion channels, modulating neurotransmitter release or activity. However, little is known about the immunomodulatory effects of crude venom from scorpion Tityus serrulatus (TsV) or its toxins (Ts1, Ts2 and Ts6) in combination with lipopolysaccharide (LPS). To investigate the immunomodulatory effects of TsV and its toxins (Ts1, Ts2 and Ts6), J774.1 cells were stimulated with different concentrations (25, 50 and 100 ?g/mL) of venom or toxins pre-stimulated or not with LPS (0.5 ?g/mL). Macrophage cytotoxicity was assessed, and nitric oxide (NO) and cytokine production were analyzed utilizing the culture supernatants. TsV and its toxins did not produce cytotoxic effects. Depending on the concentrations used, TsV, Ts1 and Ts6 stimulated the production of NO, interleukin (IL)-6 and tumor necrosis factor (TNF)-? in J774.1 cells, which were enhanced under LPS co-stimulation. However, LPS + Ts2 inhibited NO, IL-6 and TNF-? production, and Ts2 alone stimulated the production of IL-10, suggesting an anti-inflammatory activity for this toxin. Our findings are important for the basic understanding of the mechanisms involved in macrophage activation following envenomation; additionally, these findings may contribute to the discovery of new therapeutic compounds to treat immune-mediated diseases. PMID:21549737

Zoccal, Karina Furlani; Bitencourt, Claudia da Silva; Secatto, Adriana; Sorgi, Carlos Artério; Bordon, Karla de Castro Figueredo; Sampaio, Suely Vilela; Arantes, Eliane Candiani; Faccioli, Lúcia Helena

2011-06-01

85

Mycobacterial lipoarabinomannan inhibits gamma interferon-mediated activation of macrophages.  

PubMed Central

The principal efferent role of the macrophage in acquired resistance to intracellular pathogens depends on activation by T-cell lymphokines, primarily gamma interferon (IFN-gamma). However, mouse macrophages that are heavily burdened with Mycobacterium leprae are refractory to activation by IFN-gamma and are thus severely compromised in their capacity for both enhanced microbicidal and tumoricidal activities. We report here that lipoarabinomannan (LAM), a highly immunogenic lipopolysaccharide that is a prominent component of the cell walls of M. leprae and M. tuberculosis, was a potent inhibitor of IFN-gamma-mediated activation of mouse macrophages in vitro. Inhibition of macrophage activation by LAM required preincubation for approximately 24 h, resulting in uptake of LAM into cytoplasmic vacuoles of macrophages. Intact LAM was necessary to inhibit IFN-gamma-mediated activation, as this property was lost when the acyl side chains were removed from LAM by mild alkaline hydrolysis. In addition, LAM was an abundant constituent of macrophages isolated from lepromatous granulomas of M. leprae-infected nude mice and likely contributed to the defective activation of granuloma macrophages by IFN-gamma. Images PMID:3128482

Sibley, L D; Hunter, S W; Brennan, P J; Krahenbuhl, J L

1988-01-01

86

Immunomodulatory activity of a Chinese herbal drug Yi Shen Juan Bi in adjuvant arthritis  

PubMed Central

Objective: To investigate the immunomodulating mechanisms of a Chinese herbal medicine Yi Shen Juan Bi (YJB) in treatment of adjuvant arthritis (AA) in rats. Materials and Methods: Levels of serum tumor necrosis factor alpha (TNF-?) and interleukin-1? (IL-1?) were measured by the Enzyme-Linked Immunosorbent Assay (ELISA). Expression of TNF-? mRNA and IL-1? mRNA in synovial cells was measured with the semi-quantitative technique of reverse transcription-polymerase chain reaction (RT-PCR), while caspase-3 was examined by western blot analysis. Results: The administration of YJB significantly decreased the production of serum TNF-? and IL-1?. It also decreased significantly the TNF-? mRNA, IL-1? mRNA, and caspase-3 expression in synoviocytes. Conclusions: YJB produces the immunomodulatory effects by downregulating the over-activated cytokines, while it activates caspase-3, which is the key executioner of apoptosis in the immune system. This may be the one of the underlying mechanisms that explains how YJB treats the rheumatoid arthritis. PMID:20711367

Perera, Pathirage Kamal; Li, Yunman; Peng, Cheng; Fang, Weirong; Han, Caifeng

2010-01-01

87

Characterization of Two Homogalacturonan Pectins with Immunomodulatory Activity from Green Tea  

PubMed Central

Two natural homogalacturonan (HG) pectins (MW ca. 20 kDa) were isolated from green tea based on their immunomodulatory activity. The crude tea polysaccharides (TPS1 and TPS2) were obtained from green tea leaves by hot water extraction and followed by 40% and 70% ethanol precipitation, respectively. Two homogenous water soluble polysaccharides (TPS1-2a and TPS1-2b) were obtained from TPS1 after purification with gel permeation, which gave a higher phagocytic effect than TPS2. A combination of composition, methylation and configuration analyses, as well as NMR (nuclear magnetic resonance) spectroscopy revealed that TPS1-2a and TPS1-2b were homogalacturonan (HG) pectins consisting of a backbone of 1,4-linked ?-d-galacturonic acid (GalA) residues with 28.4% and 26.1% of carboxyl groups as methyl ester, respectively. The immunological assay results demonstrated that TPS1-2, which consisted mainly of HG pectins, showed phagocytosis-enhancing activity in HL-60 cells. PMID:24901527

Wang, Huijun; Wei, Guodong; Liu, Fei; Banerjee, Gautam; Joshi, Manoj; Bligh, S. W. Annie; Shi, Songshan; Lian, Hui; Fan, Hongwei; Gu, Xuelan; Wang, Shunchun

2014-01-01

88

Immunomodulatory effects of phytocompounds characterized by in vivo transgenic human GM-CSF promoter activity in skin tissues  

Microsoft Academic Search

To investigate the immunomodulatory activities of phytocompounds for potential therapeutics, we devised an in vivo, transgenic,\\u000a human cytokine gene promoter assay using defined epidermal skin cells as test tissue. Test compounds were topically applied\\u000a to mouse skin before or after gene gun transfection, using a cytokine gene promoter-driven luciferase reporter. Croton oil,\\u000a an inflammation inducer, induced transgenic GM-CSF and TNF-? promoter

Pei-Fen Su; Vanisree Staniforth; Chin-Jin Li; Chien-Yu Wang; Ming-Tsang Chiao; Sheng-Yang Wang; Lie-Fen Shyur; Ning-Sun Yang

2008-01-01

89

Maternal immune activation leads to activated inflammatory macrophages in offspring  

PubMed Central

Several epidemiological studies have shown an association between infection or inflammation during pregnancy and increased risk of autism in the child. In addition, animal models have illustrated that maternal inflammation during gestation can cause autism-relevant behaviors in the offspring; so called maternal immune activation (MIA) models. More recently, permanent changes in T cell cytokine responses were reported in children with autism and in offspring of MIA mice; however, the cytokine responses of other immune cell populations have not been thoroughly investigated in these MIA models. Similar to changes in T cell function, we hypothesized that following MIA, offspring will have long-term changes in macrophage function. To test this theory, we utilized the poly (I:C) MIA mouse model in C57BL/6J mice and examined macrophage cytokine production in adult offspring. Pregnant dams were given either a single injection of 20 mg/kg polyinosinic–polycytidylic acid, poly (I:C), or saline delivered intraperitoneally on gestational day 12.5. When offspring of poly (I:C) treated dams reached 10 weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFN-?/LPS. Following stimulation with LPS alone, or the combination of IFN-?/LPS, macrophages from offspring of poly (I:C) treated dams produced higher levels of IL-12(p40) (p < 0.04) suggesting an increased M1 polarization. In addition, even without the presence of a polarizing cytokine or LPS stimulus, macrophages from offspring of poly (I:C) treated dams exhibited a higher production of CCL3 (p = 0.05). Moreover, CCL3 levels were further increased when stimulated with LPS, or polarized with either IL-4/LPS or IFN-?/LPS (p < 0.05) suggesting a general increase in production of this chemokine. Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood. PMID:24566386

Onore, Charity E.; Schwartzer, Jared J.; Careaga, Milo; Bennan, Robert F.; Ashwood, Paul

2015-01-01

90

Antiorthostatic suspension stimulates profiles of macrophage activation in mice  

NASA Technical Reports Server (NTRS)

The antiorthostatic suspension model simulates certain physiological effects of spaceflight. We have previously reported BDF1 mice suspended by the tail in the antiorthostatic orientation for 4 days express high levels of resistance to virulent Listeria monocytogenesinfection. In the present study, we examined whether the increased resistance to this organism correlates with profiles of macrophage activation, given the role of the macrophage in killing this pathogen in vivo. We infected BDF1 mice with a lethal dose of virulent L. monocytogenes on day 4 of antiorthostatic suspension and 24 h later constructed profiles of macrophage activation. Viable listeria could not be detected in mice suspended in the antiorthostatic orientation 24 h after infection. Flow cytometric analysis revealed the numbers of granulocytes and mononuclear phagocytes in the spleen of infected mice were not significantly altered as a result of antiorthostatic suspension. Splenocytes from antiorthostatically suspended infected mice produced increased titers of IL-1. Serum levels of neopterin, a nucleotide metabolite secreted by activated macrophages, were enhanced in mice infected during antiorthostatic suspension, but not in antiorthostatically suspended naive mice. Splenic macrophages from mice infected on day 4 of suspension produced enhanced levels of lysozyme. In contrast to the results from antiorthostatically suspended infected mice, macrophages from antiorthostatically suspended uninfected mice did not express enhanced bactericidal activities. The collective results indicate that antiorthostatic suspension can stimulate profiles of macrophage activation which correlate with increased resistance to infection by certain classes of pathogenic bacteria.

Miller, E. S.; Bates, R. A.; Koebel, D. A.; Sonnenfeld, G.

1999-01-01

91

Preliminary immunomodulatory activities of methanol extracts of Eclipta alba and Centella asiatica.  

PubMed

An attempt has been made to assess the immunomodulatory activity of methanol extracts of whole plant of E. alba (1.6% wedelolactone) and C. asiatica (0.18% of asiaticoside) at five dose levels (dose-response relationship) ranging from 100 to 500 mg/kg body wt. using carbon clearance, antibody titer and cyclophosphamide immunosuppression parameters. In the case of E. alba, the phagocytic index and antibody titer increased significantly and the F ratios of the phagocytic index and WBC count were also significant. Regression analysis showed linearity in patterns of the dose-response relationship, greatest in the case of the phagocytic index, moderate in the WBC count and lowest in the antibody titer. For C. asiatica, significant increases in the phagocytic index and total WBC count were observed and the F ratio of the phagocytic index was also significant. Regressed values revealed maximum linearity in the case of the phagocytic index, moderate linearity in the total WBC count and lowest linearity in the antibody response. PMID:15185851

Jayathirtha, M G; Mishra, S H

2004-01-01

92

Modelling and analysis of macrophage activation pathways   

E-print Network

Macrophages are present in virtually all tissues and account for approximately 10% of all body mass. Although classically credited as the scavenger cells of innate immune system, ridding a host of pathogenic material and ...

Raza, Sobia

2011-11-25

93

HDAC6 Deacetylase Activity Is Critical for Lipopolysaccharide-Induced Activation of Macrophages  

PubMed Central

Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders. PMID:25330030

Liu, Zhu; Ran, Jie; Li, Yuanyuan; Wang, Jian; Yang, Yang; Zhou, Jun; Li, Dengwen; Liu, Min

2014-01-01

94

Lysis of inducer T cell clones by activated macrophages and macrophage- like cell lines  

PubMed Central

We describe a sequence of reciprocal interactions between cloned inducer T cells and antigen-presenting cells (APC) that results in selective depletion of the antigen-reactive inducer cells. We show that corecognition of antigen and I-A by hapten-reactive inducer T cell clones results in (a) release of macrophage-activating factor (MAF) and other lymphokines, (b) expression of lytic activity by a subset of MAF- sensitized APC after triggering, and (3) lysis (mediated by the activated and triggered macrophage) of the inducer T cell clone and other cells in the vicinity. We suggest that this sequence of steps may limit the extent of macrophage-mediated tissue destruction by depleting the specific inducer T cell clones that initiate the response. PMID:6194244

1983-01-01

95

Increased uptake of folate conjugates by activated macrophages in experimental hyperlipemia  

Microsoft Academic Search

In the pathogenesis of atherosclerosis, macrophages become activated and play a crucial role in plaque formation. Activated synovial macrophages have recently been shown to express receptors for folic acid. We have determined whether activated macrophages also over-express folate receptor (FR) in atherosclerosis. Most normal cells express little or no FR, and, if FR is present on activated macrophages, folate-linked compounds

Felicia Antohe; Luminita Radulescu; Elena Puchianu; Michael D. Kennedy; Philip S. Low; Maya Simionescu

2005-01-01

96

Astragalus embranaceus extract activates immune response in macrophages via heparanase.  

PubMed

Astragalus membranaceus (AM), a traditional Chinese medicinal herb, has immunoregulatory properties in many diseases. We investigated the effects and mechanism of Astragalus membranaceus extract (AME) in the macrophage migration and immune response mediator release. The viability of Ana-1 macrophages treated with AME was evaluated by the MTT method. The secretion and mRNA levels of IL-1? and TNF-a were measured by ELISA and RT-PCR, respectively. Macrophage migration was assayed by transwell assay. The activity of heparanase (HPA) was determined by a heparin-degrading enzyme assay. Our results didn't show any toxicity of AME in macrophages. AME increased the activity of HPA, cell migration, mRNA levels and secretion of IL-1? and TNF-a in macrophages. Pretreatment with anti-HPA antibody reduced cell migration, secretion of IL-1? and TNF-a did not change the mRNA levels of IL-1? and TNF-a significantly in AME-treated macrophages. This suggests that AME may increase the release of immune response mediator and cell migration via HPA to activate immune response in macrophages. PMID:22695229

Qin, Qiaojing; Niu, Jianying; Wang, Zhaoxia; Xu, Wangjie; Qiao, Zhongdong; Gu, Yong

2012-01-01

97

Role for activated macrophages in resistance against Trichinella spiralis.  

PubMed

To determine whether activated macrophages are important in resistance against the intestinal phase of nematode parasites, we studied Trichinella spiralis infections in mice with normal macrophages and in mice with macrophages activated by either chronic Toxoplasma gondii or acute Listeria monocytogenes infections. The peak T. spiralis adult worm burden in the intestines of normal C57BL/6 or Swiss Webster mice occurred from 6 to 14 days after infection. Subsequent expulsion of worms from the intestines occurred from 8 to 20 days after infection. C57BL/6 mice chronically infected with T. gondii and then challenged with T. spiralis larvae had significantly lower peak intestinal worm burdens (P < 0.05) than normal C57BL/6 mice similarly challenged. Swiss Webster mice infected 7 or 13 days earlier with L. monocytogenes and then challenged with T. spiralis larvae had significantly lower peak worm burdens (P < 0.01) than uninfected mice. The time of expulsion of adult worms was not affected by either infection. Swiss Webster mice infected 42 days earlier with L. monocytogenes (i.e., possessing lymphocytes sensitized to L. monocytogenes but not possessing activated macrophages) did not have a lower worm burden than uninfected mice. Serum factors (e.g., antibody) did not appear to play a role because normal mice injected with serum from L. monocytogenes-infected mice had worm burdens similar to those of mice injected with normal serum. The histopathology of intestines of mice infected with T. gondii or L. monocytogenes was the same as that of normal mice. When T. spiralis larvae were incubated with normal macrophages or macrophages from T. spiralis-infected mice in vitro for 24 h, the number of larvae with adherent T. spiralis macrophages was significantly (P < 0.005) greater than the number of larvae with adherent normal macrophages. These studies suggest a role for activated macrophages in resistance to T. spiralis. PMID:99366

Wing, E J; Remington, J S

1978-08-01

98

Liver enzyme-mediated oxidation of Echinacea purpurea alkylamides: production of novel metabolites and changes in immunomodulatory activity.  

PubMed

The medicinal plant Echinacea is widely used to treat upper respiratory infections and is reported to stimulate the human immune system. A major constituent class of Echinacea, the alkylamides, has immunomodulatory effects. Recent studies show that alkylamides are oxidized by cytochrome P450 enzymes, but the immunomodulatory activity of these products is unknown. The objectives of this study were to characterize the products formed by incubation of an Echinacea extract and an isolated alkylamide with human liver microsomes, and to evaluate the influence of Echinacea alkylamides and metabolites on cytokine production by Jurkat human T cells. A novel class of carboxylic acid alkylamide metabolites was identified and shown to be the major constituents present after 2-h incubation of alkylamides with human liver microsomes. Echinacea alkylamides suppressed IL-2 secretion by stimulated T cells, and this effect was significantly lessened upon oxidation of the alkylamides to carboxylic acids and hydroxylated metabolites. These findings highlight the importance of considering the influence of liver enzyme metabolism when evaluating the immunomodulatory effects of alkylamides. PMID:17054047

Cech, Nadja B; Tutor, Katrina; Doty, Bethany A; Spelman, Kevin; Sasagawa, Masa; Raner, Gregory M; Wenner, Cynthia A

2006-12-01

99

Macrophage activation by polysaccharide isolated from Astragalus membranaceus  

Microsoft Academic Search

We show that APS, a polysaccharide isolated from the roots of Astragalus membranaceus, significantly induces nitric oxide (NO) production and inducible NO synthase (iNOS) transcription through the activation of nuclear factor-?B\\/Rel (NF-?B\\/Rel). In vivo administration of APS induced NO production by peritoneal macrophages of B6C3F1 mice. APS also dose-dependently induced the production of NO in isolated mouse peritoneal macrophages and

Kun Yeong Lee; Young Jin Jeon

2005-01-01

100

Immunomodulatory properties of surfactant preparations.  

PubMed

Surfactant replacement significantly decreased acute pulmonary morbidity and mortality among preterm neonates with respiratory distress syndrome. Besides improving lung function and oxygenation, surfactant is also a key modulator of pulmonary innate and acquired immunity regulating lung inflammatory processes. In this review, we describe the immunomodulatory features of surfactant preparations. Various surfactant preparations decrease the proinflammatory cytokine and chemokine release, the oxidative burst activity, and the nitric oxide production in lung inflammatory cells such as alveolar neutrophils, monocytes and macrophages; they also affect lymphocyte proliferative response and immunoglobulin production, as well as natural killer and lymphokine-activated killer cell activity. In addition, surfactant preparations are involved in airway remodeling, as they decrease lung fibroblast proliferation capacity and the release of mediators involved in remodeling. Moreover, they increase cell transepithelial resistance and VEGF synthesis in lung epithelial cells. A number of different signaling pathways and molecules are involved in these processes. Because the inhibition of local immune response may decrease lung injury, surfactant therapeutic efficacy may be related not only to its biophysical characteristics but, at least in part, to its anti-inflammatory features and its effects on remodeling processes. However, further studies are required to identify which surfactant preparation ensures the highest anti-inflammatory activity, thereby potentially decreasing the inflammatory process underlying respiratory distress syndrome. In perspective, detailed characterization of these anti-inflammatory effects could help to improve the next generation of surfactant preparations. PMID:23428105

Bersani, Iliana; Kunzmann, Steffen; Speer, Christian P

2013-01-01

101

Measuring Matrix Metalloproteinase Activity in Macrophages and Polymorphonuclear Leukocytes  

PubMed Central

Macrophages and polymorphonuclear cells (PMNs) represent an essential part of the innate immune system. These cells mediate a wide spectrum of immunological functions including bacterial defense, immune modulation, and inflammation; they are necessary for tissue homeostasis and also contribute to pathologies such as malignancy, autoimmunity, and chronic inflammation. Both macrophages and PMNs express a set of matrix metalloproteinases (MMPs), zinc-dependent endopeptidases that are involved in a variety of biological functions such as the turnover of extracellular matrix (ECM) components, angiogenesis, and the regulation of inflammation. Given the link between unregulated MMP function and diseases such as chronic inflammation or cancer, it is not surprising that these enzymes have been implicated as key effectors in clinical studies. Thus, it is important to widen our knowledge about the role of these enzymes in macrophage and PMN biology. Here, we briefly discuss the general role of inflammatory cell–derived MMPs and describe methods to analyze their activity in macrophages and PMN. PMID:21462166

Kessenbrock, Kai; Brown, Markus; Werb, Zena

2012-01-01

102

Carbohydrate composition and immunomodulatory activity of different glycoforms of ?1-acid glycoprotein  

Microsoft Academic Search

The acute phase protein, ?1-acid glycoprotein (AGP), is a normal constituent of human blood (0.2–1 mg ml?1) and its glycosylation\\u000a and concentration in the blood change during inflammation. In this review of our recent work, we discuss the immunomodulatory\\u000a properties of AGP in connection with the structure of its carbohydrate chains.\\u000a \\u000a AGP samples prepared from normal donor serum (nAGP), serum

Svetlana D. Shiyan; Nicolai V. Bovin

1997-01-01

103

Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis  

PubMed Central

All homeotherms utilize thermogenesis to maintain core body temperature, ensuring that cellular functions and physiologic processes can ensue in cold environments1-3. In the prevailing model, when the hypothalamus senses cold temperatures, it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue (BAT) and white adipose tissue (WAT)4,5. Acting via the ?3-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes6, whereas it stimulates the expression of thermogenic genes, such as PPAR? coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1), and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes7-9. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report an unexpected requirement for the interleukin 4 (IL4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Cold exposure rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in BAT and lipolysis in WAT. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL4 increased thermogenic gene expression, fatty acid mobilization, and energy expenditure, all in a macrophage-dependent manner. We have thus discovered a surprising role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold. PMID:22101429

Nguyen, Khoa D.; Qiu, Yifu; Cui, Xiaojin; Goh, Y.P. Sharon; Mwangi, Julia; David, Tovo; Mukundan, Lata; Brombacher, Frank; Locksley, Richard M.; Chawla, Ajay

2011-01-01

104

Activation of spleen cells by ArtinM may account for its immunomodulatory properties.  

PubMed

ArtinM is a D-mannose-binding lectin extracted from Artocarpus heterophyllus that promotes interleukin-12 production by macrophages and dendritic cells. This property is considered responsible for T helper 1 immunity induced in vivo after ArtinM administration. In this study, we investigated the effect of native (jArtinM) and recombinant (rArtinM) forms of lectin on murine spleen cells and isolated T lymphocytes. We found that ArtinM binds to the surface of spleen cells. This interaction, which was blocked by D-mannose, induced cell activation, as manifested by increased mitochondrial activity, interleukin-2 production, and cell proliferation. We verified that a 30-times higher concentration of rArtinM was required to trigger optimal activation of spleen cells compared with that needed with jArtinM, although these proteins have identical sugar recognition properties and use the same signaling molecules to trigger cell activation. Because the distinction between native and recombinant is restricted to their tertiary structure (tetrameric and monomeric, respectively), we postulated that the multi-valence of jArtinM accounts for its superiority in promoting clustering of cell surface glycoreceptors and activation. The jArtinM and rArtinM activation effect exerted on spleen cells was reproduced on purified CD4(+) T cells. Our results suggest that ArtinM interaction with T cells leads to responses that may act in concert with the interleukin-12 produced by antigen-presenting cells to modulate immunity toward the T helper 1 axis. Further studies are necessary to dissect ArtinM/T-cell interactions to more fully understand the immunomodulation induced by carbohydrate recognition. PMID:24842046

Silva, Thiago Aparecido da; Souza, Maria Aparecida de; Cecílio, Nerry Tatiana; Roque-Barreira, Maria Cristina

2014-09-01

105

Modulation of macrophage activity by aflatoxins B1 and B2 and their metabolites aflatoxins M1 and M2.  

PubMed

Aflatoxins are natural contaminants frequently found both in food and feed. Many of them exert immunomodulatory properties in mammals; therefore, the aim of the current study was to investigate immune-effects of AFB1, AFB2, AFM1 and AFM2, alone and differently combined, in J774A.1 murine macrophages. MTT assay showed that AFB1, alone and combined with AFB2, possess antiproliferative activity only at the highest concentration; such effect was not shown by their hydroxylated metabolites, AFM1 and AFM2, respectively. However, the immunotoxic effects of the aflatoxins evaluated in the current study may be due to the inhibition of production of active oxygen metabolites such as NO. Cytofluorimetric assay in macrophages exposed to aflatoxins (10-100 ?M) revealed that their cytoxicity is not related to apoptotic pathways. Nevertheless, a significant increase of the S phase cell population accompanied by a decrease in G0/G1 phase cell population was observed after AFB1 treatment. In conclusion, the results of the current study suggest that aflatoxins could compromise the macrophages functions; in particular, co-exposure to AFB1, AFB2, AFM1 and AFM2 may exert interactions which can significantly affect immunoreactivity. PMID:22402176

Bianco, G; Russo, R; Marzocco, S; Velotto, S; Autore, G; Severino, L

2012-05-01

106

Effect of lipopolysaccharide on protein accumulation by murine peritoneal macrophages: the correlation to activation for macrophage tumoricidal function  

SciTech Connect

The protein synthetic patterns of tumoricidal murine peritoneal macrophage populations have been compared to those of non-tumoricidal populations utilizing two dimensional polyacrylamide gel electrophoresis (2D PAGE) of (/sup 35/S)-methionine-labeled proteins. While the protein synthetic patterns exhibited by resident, inflammatory and activated macrophages had numerous common features which distinguished them from the other normal non-macrophage cell types examined, unique proteins also distinguished each macrophage population from the others. Peritoneal macrophages elicited by treatment with heat killed Propionibacterium acnes, the live, attenuated Mycobacterium bovis strain BCG, Listeria monocytogenes and the protozoan flagellate Trypanosoma rhodesiense, all exhibited tumoricidal activity in 16h or 72h functional assays, and shared a common protein synthetic profile which differentiated them from the synthetic patterns characteristic of the non-tumoricidal resident and inflammatory macrophages.

Tannenbaum, C.S.

1987-01-01

107

Diphenyl diselenide-modulation of macrophage activation: down-regulation of classical and alternative activation markers.  

PubMed

Diphenyl diselenide (PhSe)(2), a simple organoselenium compound, possesses interesting pharmacological properties that are under extensive research. As macrophages respond to microenvironmental stimuli and can display activities engaged in the initiation and the resolution of inflammation, in the present report we describe the ability of (PhSe)(2) to modulate the macrophage activation. Our data indicate that (PhSe)(2) could inhibit the NO production in a dose-dependent fashion in peritoneal macrophages activated by LPS or treated with vehicle alone. We could demonstrate that this effect correlated with a reduction in the expression of the inducible NO synthase in (PhSe)(2)-treated cells. Furthermore, (PhSe)(2) suppressed the production of reactive oxygen species, diminished the activity of the arginase enzyme, and the accumulation of nitrotyrosine modified proteins in LPS-stimulated macrophages. This compound also diminished the antigen presentation capacity of classically activated macrophages, as it reduced MHCII and CD86 expression. In addition, (PhSe)(2) modulated the alternative activation phenotype of macrophages. Dexamethasone-activated macrophages presented higher production of IL-10 and CD206, which were both down-regulated by the addition of (PhSe)(2). These results suggest that (PhSe)(2) possesses antioxidant and anti-inflammatory activities in classically-activated macrophages. We could demonstrate that (PhSe)(2) can be also utilized to modulate the alternative activation phenotype of macrophages. PMID:22215443

Rupil, Lucía L; de Bem, Andreza F; Roth, German A

2012-08-01

108

Peroxisome Proliferator-Activated Receptor-? Regulates the Expression of Alveolar Macrophage Macrophage Colony-Stimulating Factor  

PubMed Central

Macrophage CSF (M-CSF) regulates monocyte differentiation, activation, and foam cell formation. We have observed that it is elevated in human pulmonary alveolar proteinosis (PAP) and in the GM-CSF knockout mouse, a murine model for PAP. A potential regulator of M-CSF, peroxisome proliferator-activated receptor-? (PPAR?), is severely deficient in both human PAP and the GM-CSF knockout mouse. To investigate the role of PPAR? in alveolar macrophage homeostasis, we generated myeloidspecific PPAR? knockout mice using the Lys-Cre method to knock out the floxed PPAR? gene. Similar to the GM-CSF-deficient mouse, absence of alveolar macrophage PPAR? resulted in development of lung pathology resembling PAP in 16-wk-old mice, along with excess M-CSF gene expression and secretion. In ex vivo wild-type alveolar macrophages, we observed that M-CSF itself is capable of inducing foam cell formation similar to that seen in PAP. Overexpression of PPAR? prevented LPS-stimulated M-CSF production in RAW 264.7 cells, an effect that was abrogated by a specific PPAR? antagonist, GW9662. Use of proteasome inhibitor, MG-132 or a PPAR? agonist, pioglitazone, prevented LPS-mediated M-CSF induction. Using chromatin immunoprecipitation, we found that PPAR? is capable of regulating M-CSF through transrepression of NF-?B binding at the promoter. Gel-shift assay experiments confirmed that pioglitazone is capable of blocking NF-?B binding. Taken together, these data suggest that M-CSF is an important mediator of alveolar macrophage homeostasis, and that transcriptional control of M-CSF production is regulated by NF-?B and PPAR?. PMID:18566389

Bonfield, Tracey L.; Thomassen, Mary Jane; Farver, Carol F.; Abraham, Susamma; Koloze, Mary T.; Zhang, Xia; Mosser, David M.; Culver, Daniel A.

2010-01-01

109

Immunomodulatory activities of polysaccharides isolated from Taxillus chinensis and Uncaria rhyncophylla.  

PubMed

Taxillus chinensis and Uncaria rhyncophylla are the herbs used in traditional Chinese anticancer formulations. During the past decade, research on plant polysaccharides has gained importance due to their therapeutic value and minimum side effects. In this study, hot water extraction method was employed to isolate polysaccharides from the stems of T. chinensis and stems with hooks of U. rhyncophylla. Size-exclusion chromatography was then used for further fractionation. Separated fractions from T. chinensis were designated as TCP-1, TCP-2 and TCP-3 and those from U. rhyncophylla were termed UC-1 and UC-2. Their sugar compositions were estimated using gas chromatography that revealed the presence fructose, glucose, xylose, arbinose, and rhamnose. Amino acid analysis of these fractions has indicated that they are protein-bound polysaccharides. The antioxidant activities were investigated using DPPH and yeast assays. The ability of these polysaccharide fractions to stimulate mouse macrophages was measured using Griess reagent and ELISA test. The results revealed that some of the isolated fractions (TCP-2, TCP-3, UC-1 and UC-2) displayed significant antioxidant activities and were also found to be effective immunomodulators in a concentration-dependent manner. Outcomes of this research strongly indicate that U. rhyncophylla and T. chinensis have therapeutic potential to be used for the treatment of cancer. PMID:24053827

Zhang, Lin; Koyyalamudi, Sundar Rao; Jeong, Sang Chul; Reddy, Narsimha; Bailey, Trevor; Longvah, T

2013-11-01

110

Monocyte macrophage differentiation in vitro: Fibronectin-dependent upregulation of certain macrophage-specific activities.  

PubMed

Transendothelial migration of monocytes followed by their differentiation into macrophages involves interaction of monocytes with subendothelial matrix. The influence of extracellular matrix on monocyte-macrophage differentiation was studied using an in vitro model system with human PBMC maintained on different matrix protein substrata. Upregulation of macrophage specific marker activities such as endocytosis of modified proteins, changes in expression of cell surface antigen, and production of matrix metalloproteinases was studied. Cells maintained on Fibronectin (Fn) showed significantly higher rate of endocytosis and production of MMP2 and MMP9 when compared to other matrix protein substrata. Immunoblot analysis, ELISA, and zymography showed that Fn-dependent upregulation of MMPs was blocked by antibodies to alpha(5)beta(1) integrin indicating that the Fn effect was mediated by integrins. The Fn effect on mo-mPhi was blocked by genistein and herbimycin. As monocytes differentiate to macrophages there was an increase in the rate of production of Fn. These results indicate the influence of the microenvironment of the cell, particularly Fn, on mo-mPhi differentiation and integrin-mediated downstream signaling through focal adhesion kinase and Src type tyrosine kinase is involved in this. PMID:17115276

Sudhakaran, P R; Radhika, A; Jacob, S S

2007-01-01

111

Inflammasome Activation: How Macrophages Watch What They Eat  

E-print Network

Inflammasome Activation: How Macrophages Watch What They Eat Russell E. Vance1,* 1Division of lysozyme in the phagosome and activation of the Nlrp3 inflammasome, a cytosolic regulator of inflammation ``inflammasomes,'' which reside in the cytosol and respond to a variety of infectious or noxious stimuli

Vance,. Russell

112

Lysophosphatidylcholine stimulates phospholipase D activity in mouse peritoneal macrophages  

Microsoft Academic Search

Lysophosphatidylcholine (lysoPC) is a bioactive phospholipid that is involved in atherogenesis and inflam- matory processes. However, the present understanding of mechanisms whereby lysophosphatidylcholine exerts its patho- physiological actions is incomplete. In the present work, we show that lysoPC stimulates phospholipase D (PLD) activity in mouse peritoneal macrophages. PLD activation leads to the generation of important second messengers such as phosphatidic

Antonio Gómez-Muńoz; Lori O'Brien; Rajinder Hundal; Urs P. Steinbrecher

113

Acute immunomodulatory effects of iron polyisomaltosate in rats.  

PubMed

Anti-anaemic drug ferric-sorbitol citrate showed immunomodulatory effects, activating NF-kappaB in peritoneal macrophages, which consequently secrete tumour necrosis factor-alpha (TNF-alpha). TNF-alpha activates NF-kappaB in spleen cells. The aim of this study was to investigate the effect of iron polyisomaltosate, an iron (Fe(3+)) compound, on serum iron, interleukin-6 (IL-6) and serotonin (5-HT) concentration, neutrophil activity, and NF-kappaB activation in peritoneal macrophages and spleen cells in rats. Female Wistar rats were injected i.p. with 7.5mg iron/kg of iron polyisomaltosate 1.5, 3, 6, 24 and 48h before sacrifice. Serum iron, 5-HT and IL-6 concentration was determined by colorimetric, spectrofluorimetric and ELISA methods, neutrophil activity by a chemiluminescence assay, and NF-kappaB expression/activation by a Dot-Blot method. Iron polyisomaltosate significantly increased serum iron and 5-HT concentrations during the first 6h, IL-6 levels 3 and 6h, and diminished respiratory burst of granulocytes 1.5h after the injection. Iron polyisomaltosate stimulated activation of p65, p50 and RelB subunits of NF-kappaB in the peritoneal macrophages after 6h, and RelB subunit was additionally increased after 24 and 48h. In the spleen cells iron polyisomaltosate stimulated p65 subunit after 48h and RelB subunit after 24h. The results showed time-dependent immunomodulatory effects of iron polyisomaltosate. These effects might be achieved via induction of the intracellular signalling for NF-kappaB activation in peritoneal macrophages and later in spleen cells, together with increase of serum 5-HT, and IL-6 but with diminished respiratory burst of granulocytes. Iron polyisomaltosate presumably activated reactive oxygen species resulting in the stimulation of the acute phase reactants in the liver. PMID:19167990

Poljak-Blazi, Marija; Jaganjac, Morana; Mustapic, Maja; Pivac, Nela; Muck-Seler, Dorotea

2009-01-01

114

ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages.  

PubMed

Differentiation to different types of macrophages determines their distinct functions. Tumor-associated macrophages (TAMs) promote tumorigenesis owing to their proangiogenic and immune-suppressive functions similar to those of alternatively activated (M2) macrophages. We report that reactive oxygen species (ROS) production is critical for macrophage differentiation and that inhibition of superoxide (O(2-)) production specifically blocks the differentiation of M2 macrophages. We found that when monocytes are triggered to differentiate, O(2-) is generated and is needed for the biphasic ERK activation, which is critical for macrophage differentiation. We demonstrated that ROS elimination by butylated hydroxyanisole (BHA) and other ROS inhibitors blocks macrophage differentiation. However, the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated (M1), but not M2, macrophages. More importantly, the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment. PMID:23752925

Zhang, Yan; Choksi, Swati; Chen, Kun; Pobezinskaya, Yelena; Linnoila, Ilona; Liu, Zheng-Gang

2013-07-01

115

In vitro evaluation of antibacterial and immunomodulatory activities of Pelargonium reniforme, Pelargonium sidoides and the related herbal drug preparation EPs 7630.  

PubMed

The importance of Pelargonium species, most notably Pelargonium reniforme and Pelargonium sidoides, in traditional medicine in the Southern African region is well documented. Nowadays, a modern aqueous-ethanolic formulation of the roots of P. sidoides (EPs) 7630) is successfully employed for the treatment of ear, nose and throat disorders as well as respiratory tract infections. To provide a scientific basis of its present utilization in phytomedicine, EPs 7630, extracts and isolated constituents of the titled Pelargoniums with emphasis on P. sidoides were evaluated for antibacterial activity and for their effects on nonspecific immune functions. The samples exhibited merely moderate direct antibacterial capabilities against a spectrum of Gram-positive and Gram-negative bacteria. Functional bioassays including an in vitro model for intracellular diseases, a fibroblast-lysis assay (tumour necrosis factor (TNF) activity), a fibroblast-virus protection assay (IFN activity) and a biochemical assay for nitric oxides revealed significant immunomodulatory properties. Gene expression experiments (iNOS, IFN-alpha, IFN-gamma, TNF-alpha, Interleukin (IL)-1, IL-10, IL12, IL-18) not only confirmed functional data, they also clearly showed differences in the response of infected macrophages when compared to that of noninfected cells. ELISA confirmed the protein production of TNF-alpha, IL-1alpha and IL-12, while FACS analyses reaffirmed the cytokines IL-1alpha and IL-12 at the singular cell level. The current data provide convincing support for the improvement of immune functions at various levels, hence, validating the medicinal uses of EPs 7630. Despite considerable efforts, the remedial effects cannot yet be related to a chemically defined principle. PMID:17188480

Kolodziej, Herbert; Kiderlen, Albrecht F

2007-01-01

116

Dysregulation of Macrophage Activation Profiles by Engineered Nanoparticles  

PubMed Central

Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pre-treatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pre-treatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pre-treatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from a M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNF? production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia, and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures. PMID:23808590

Kodali, Vamsi; Littke, Matthew H.; Tilton, Susan C.; Teeguarden, Justin G.; Shi, Liang; Frevert, Charles W.; Wang, Wei; Pounds, Joel G.; Thrall, Brian D.

2013-01-01

117

Dysregulation of Macrophage Activation Profiles by Engineered Nanoparticles  

SciTech Connect

Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pre-treatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pre-treatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pre-treatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from a M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNF? production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia, and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures.

Kodali, Vamsi K.; Littke, Matt H.; Tilton, Susan C.; Teeguarden, Justin G.; Shi, Liang; Frevert, Charles W.; Wang, Wei; Pounds, Joel G.; Thrall, Brian D.

2013-07-09

118

Free radical scavenging and immunomodulatory activities of Ganoderma lucidum polysaccharides derivatives.  

PubMed

Polysaccharides extracted from the fruit body of Ganoderma lucidum were sulfated and carboxymethylated as reported. Free radical scavenging and immunomodulatory effects of sulfated and carboxymethylated polysaccharides were studied. Generally, sulfated polysaccharides showed better bioactivities than that of carboxymethylated polysaccharides. The two derivatives were injected intraperitoneally with or without 5-fluorouracil over a period of 7 days in BALB/c female mice. The polysaccharide derivatives increased mouse thymus and spleen index, an indication of improved immunity in mice. At the same time, they improved superoxide dismutase and glutathione peroxidase contents in the mice body. PMID:23044102

Wang, Jianguo; Wang, Yutang; Liu, Xuebo; Yuan, Yahong; Yue, Tianli

2013-01-01

119

Activation and increment of alveolar macrophages induced by nitrogen dioxide  

SciTech Connect

Male Wistar rats were exposed to 4 ppm nitrogen dioxide (NO/sub 2/) for 10 d, and at intervals alveolar macrophages were collected by pulmonary lavage. A metabolic enhancement of alveolar macrophages was observed on d 4 of exposure. The specific activities of glucose-6-phosphate dehydrogenase and glutathione peroxidase of the peroxidative metabolic pathway increased to 1.29-fold and 1.17-fold those of the control values, respectively. The specific activities of succinate-cytochrome c reductase of the mitochondrial respiratory system and pyruvate kinase of the glycolytic pathway also increased to 1.17-fold and 1.20-fold those of the control values, respectively. In addition, the incorporation of (/sup 3/H)leucine and (/sup 14/C)thymidine into alveolar macrophages were elevated to 1.77-fold and 1.84-fold those of the control values, respectively. The activities of all enzymes tested decreased to control levels by d 10. The number of alveolar macrophages collected from exposed animals increased to 1.24-fold that of the control value of d 7 and was maintained at a significantly higher level until d 10. Alveolar macrophages were heterogeneous in size (7-21 ..mu..m in diameter), and most of them were distributed between 11 and 17 ..mu..m in diameter. Exposures to 4 ppm NO/sub 2/ increased significantly the cells of 9-13 ..mu..m in diameter on the seventh day. These results show that exposures to 4 ppm NO/sub 2/ cause a metabolic enhancement and subsequent increase in alveolar macrophages.

Mochitate, K.; Takahashi, Y.; Ohsumi, T.; Miura, T.

1986-01-01

120

Proteinase-Activated Receptor-1 and Immunomodulatory Effects of a PAR1-Activating Peptide in a Mouse Model of Prostatitis  

PubMed Central

Background. Nonbacterial prostatitis has no established etiology. We hypothesized that proteinase-activated receptor-1 (PAR1) can play a role in prostatitis. We therefore investigated the effects of PAR1 stimulation in the context of a new model of murine nonbacterial prostatitis. Methods. Using a hapten (ethanol-dinitrobenzene sulfonic acid- (DNBS-)) induced prostatitis model with both wild-type and PAR1-null mice, we examined (1) the location of PAR1 in the mouse prostate and (2) the impact of a PAR1-activating peptide (TFLLR-NH2: PAR1-TF) on ethanol-DNBS-induced inflammation. Results. Ethanol-DNBS-induced inflammation was maximal at 2 days. In the tissue, PAR1 was expressed predominantly along the apical acini of prostatic epithelium. Although PAR1-TF on its own did not cause inflammation, its coadministration with ethanol-DNBS reduced all indices of acute prostatitis. Further, PAR1-TF administration doubled the prostatic production of interleukin-10 (IL-10) compared with ethanol-DNBS treatment alone. This enhanced IL-10 was not observed in PAR1-null mice and was not caused by the reverse-sequence receptor-inactive peptide, RLLFT-NH2. Surprisingly, PAR1-TF, also diminished ethanol-DNBS-induced inflammation in PAR1-null mice. Conclusions. PAR1 is expressed in the mouse prostate and its activation by PAR1-TF elicits immunomodulatory effects during ethanol-DNBS-induced prostatitis. However, PAR1-TF also diminishes ethanol-DNBS-induced inflammation via a non-PAR1 mechanism by activating an as-yet unknown receptor. PMID:24459330

Stanton, M. Mark; Nelson, Lisa K.; Benediktsson, Hallgrimur; Hollenberg, Morley D.; Buret, Andre G.; Ceri, Howard

2013-01-01

121

Dopamine receptor activation increases HIV entry into primary human macrophages.  

PubMed

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

Gaskill, Peter J; Yano, Hideaki H; Kalpana, Ganjam V; Javitch, Jonathan A; Berman, Joan W

2014-01-01

122

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages  

PubMed Central

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

2014-01-01

123

Immunomodulatory activity of methanolic extracts of fruits and bark of Ficus glomerata Roxb. in mice and on human neutrophils  

PubMed Central

Objective: To evaluate the immunomodulatory activity of methanolic extracts of fruit and bark of Ficus glomerata Roxb. on cyclophosphamide-induced myelosuppression in mice and the phagocytic effect on human neutrophils. Materials and Methods: Methanolic extracts of fruits and bark of Ficus glomerata Roxb. at two dose levels of 250and 500 mg/kg p.o. were administered for 13 days to albino mice and cyclophosphamide (30 mg/kg i.p.) was administered on 11th,12th, and 13th days, 1 hour after the administration of the respective treatment. On 14th day blood was collected and the hematological parameters were evaluated. The two extracts in the concentration range 100,50,25,12 and 6.25 ?g were also tested for phagocytic effect on human neutrophils using the in vitro models–nitroblue tetrazolium (NBT) dye test, phagocytosis of Candida albicans, and chemotaxis assay. Results: Methanolic extracts of fruit and bark of Ficus glomerata Roxb. showed significant counteracting effect (P < 0.01) to cyclophosphamide-induced reduction in total WBC, differential leucocyte count, platelet counts, RBC counts, and hemoglobin levels. The extracts of the plant in the concentration range 100,50,25,12, and 6.25 ?g also showed significant (P < 0.01) phagocytic effect on human neutrophils in the parameters studied. Conclusion: Methanolic extracts of fruits and bark of Ficus glomerata Roxb. exhibited immunomodulatory property in both in vivo and in vitro models. PMID:23716887

Heroor, Sanjeev; Beknal, Arun Kumar; Mahurkar, Nitin

2013-01-01

124

Dynamics of lung macrophage activation in response to helminth infection  

Technology Transfer Automated Retrieval System (TEKTRAN)

Most of our understanding of the development and phenotype of alternatively activated macrophages (AAM) has been obtained from studies investigating the response of bone marrow- and peritoneal-derived cells to IL-4 or IL-13 stimulation. Comparatively little is known about the development of the AAM...

125

[Severe macrophage activation syndrome following visceral leishmaniasis in a child].  

PubMed

Visceral leishmaniasis (VL) is a parasitic disease that is a public health problem in Morocco and is one of the frequent infectious causes of macrophage activation syndrome (MAS). The combination of clinical and laboratory criteria, even very unspecific, make it possible to diagnose MAS, but a definitive diagnosis requires cytological examination. Rapid treatment is essential. The outcome was favorable. PMID:24876180

Oudaina, W; Assini, K; El Ouardi, M; Tligui, H

2014-01-01

126

Diet Modifies the Neuroimmune System by Influencing Macrophage Activation  

ERIC Educational Resources Information Center

It has long been appreciated that adequate nutrition is required for proper immune function and it is now recognized that dietary components contribute to modulation of immune cells, subsequently impacting the whole body's response during an immune challenge. Macrophage activation plays a critical role in the immune system and directs the…

Sherry, Christina Lynn

2009-01-01

127

Extracts of the rat tapeworm, Hymenolepis diminuta, suppress macrophage activation in vitro and alleviate chemically induced colitis in mice.  

PubMed

Analysis of parasite-host interactions can reveal the intricacies of immunity and identify ways to modulate immunopathological reactions. We assessed the ability of a phosphate-buffered saline-soluble extract of adult Hymenolepis diminuta to suppress macrophage (human THP-1 cell line, murine peritoneal macrophages) activity in vitro and the impact of treating mice with this extract on colitis induced by dinitrobenzene sulfonic acid (DNBS). A high-molecular-mass fraction of adult H. diminuta (HdHMW) or excretory/secretory products reduced macrophage activation: lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) and poly(I:C)-induced TNF-alpha and IL-6 were suppressed by HdHMW. The active component in the HdHMW extract was minimally sensitive to boiling and trypsin digestion, whereas the use of sodium metaperiodate, as a general deglycosylation strategy, indicated that the immunosuppressive effect of HdHMW was at least partially dependent on a glycan: treating the HdHMW with neuraminidase and alpha-mannosidase failed to inhibit its blockade of LPS-induced TNF-alpha production by THP-1 macrophages. Mice treated with DNBS developed colitis, as typified by wasting, shortening of the colon, macroscopic and microscopic tissue damage, and an inflammatory infiltrate. Mice cotreated with HdHMW (three intraperitoneal injections) displayed significantly less inflammatory disease, and this was accompanied by reduced TNF-alpha production and increased IL-10 and IL-4 production by mitogen-stimulated spleen cells. However, cotreatment of mice with neutralizing anti-IL-10 antibodies had only a minor impact on the anticolitic effect of the HdHMW. We speculate that purification of the immunosuppressive factor(s) from H. diminuta has the potential to lead to the development of novel immunomodulatory drugs to treat inflammatory disease. PMID:20028812

Johnston, M J G; Wang, A; Catarino, M E D; Ball, L; Phan, V C; MacDonald, J A; McKay, D M

2010-03-01

128

Immunomodulatory activities of kolaviron, a mixture of three related biflavonoids of Garcinia kola Heckel.  

PubMed

The immunomodulatory properties of kolaviron (KV), a mixture of three related biflavonoids of Garcinia kola Heckel (Clusiaceae), were investigated. The study was conducted using in vitro and in vivo immunocompetent and immunocompromised animal models. KV (250 and 500 mg/kg) produced a dose-dependent and significant (p < 0.05) inhibition of delayed-type hypersensitivity in rats and also caused a significant (p < 0.05) increase in the primary and secondary sheep erythrocytes-specific antibody titres in rats. In vitro, KV inhibited the classical complement system at concentrations greater than 100 microg/ml. The administration of KV ameliorated the cyclophosphamide-induced leukopenia and increased the proportion of lymphocytes count in rats after 14 days of treatment. Administration of KV on alternate days after immunosuppression with cyclophospamide increased the rate of excision wound closure and reduced epithelialization period from 21.75 to 15.5 days. This study established the immunomodulatory and immunorestorative properties of KV, which could be harnessed for possible clinical benefits to immunodeficient patients. PMID:18569087

Nworu, C S; Akah, P A; Esimone, C O; Okoli, C O; Okoye, F B C

2008-01-01

129

Modulation of nitric oxide synthase activity in macrophages  

PubMed Central

L-Arginine is converted to the highly reactive and unstable nitric oxide (NO) and L-citrulline by an enzyme named nitric oxide synthase (NOS). NO decomposes into other nitrogen oxides such as nitrite (NO2-) and nitrate (NO2-), and in the presence of superoxide anion to the potent oxidizing agent peroxynitrite (ONOO?). Activated rodent macrophages are capable of expressing an inducible form of this enzyme (iNOS) in response to appropriate stimuli, i.e., lipopolysaccharide (LPS) and interferon-? (IFN?). Other cytokines can modulate the induction of NO biosynthesis in macrophages. NO is a major effector molecule of the anti-microbial and cytotoxic activity of rodent macrophages against certain micro-organisms and tumour cells, respectively. The NO synthesizing pathway has been demonstrated in human monocytes and other cells, but its role in host defence seems to be accessory. A delicate functional balance between microbial stimuli, host-derived cytokines and hormones in the microenvironment regulates iNOS expression. This review will focus mainly on the known and proposed mechanisms of the regulation of iNOS induction, and on agents that can modulate NO release once the active enzyme has been expressed in the macrophage. PMID:18475620

Jorens, P. G.; Matthys, K. E.

1995-01-01

130

NADPH oxidase restrains the matrix metalloproteinase activity of macrophages.  

PubMed

Matrix metalloproteinases (MMPs) regulate numerous functions in normal and disease processes; thus, irreversibly blocking their activity is a key step in regulating MMP catalysis. We previously showed in vitro that oxidizing intermediates generated by phagocytes inactivate MMPs by modifying specific amino acids. To assess whether this mechanism operates in vivo, we focused on MMP-12, a macrophage-specific MMP known to mediate emphysema in mouse models. We found that mice lacking gp91(phox), a phagocyte-specific component of the NADPH oxidase, developed extensive, spontaneous emphysematous destruction of their peripheral air spaces, whereas mice deficient in both NADPH oxidase and MMP-12 were protected from spontaneous emphysema. Although gp91(phox)-null and wild-type macrophages produced equivalent levels of MMP-12 protein, the oxidant-deficient cells had greater MMP-12 activity than wild-type macrophages. These findings indicate that reactive intermediates provide a physiological mechanism to protect tissues from excessive macrophage-mediated damage during inflammation. PMID:15983040

Kassim, Sean Y; Fu, Xiaoyun; Liles, W Conrad; Shapiro, Steven D; Parks, William C; Heinecke, Jay W

2005-08-26

131

Effects of Echinacea extracts on macrophage antiviral activities.  

PubMed

Type I interferons are a class of cytokines synthesized by leukocytes such as macrophages that limit viral replication. We hypothesized that one mechanism whereby Echinacea spp. extracts may enhance immunity is through modulating interferon-associated macrophage pathways. We used herpes simplex viral infection in the murine macrophage cell line RAW264.7 and monitored virus-induced cell death, interferon secretion, and two intracellular proteins that indicate activation of interferon pathways. Cells were incubated with control media or extracts from four different species (E. angustifolia, E. purpurea, E. tennesseensis, E. pallida). Cells incubated with extracts prior to infection showed very modest enhancement of viability, and no increase in the secretion of interferons alpha or beta as compared to control cells. Virus-infected macrophages treated with extracts from E. purpurea showed a small (<2-fold) induction of guanylate binding protein (GBP) production, but no effect of extracts from other species was observed. In virus-infected cells, all the extracts increased the amount of inducible nitric oxide synthase (iNOS) protein, and this effect varied by type of extraction preparation. Together, these results suggest that any potential antiviral activities of Echinacea spp. extracts are likely not mediated through large inductions of Type I interferon, but may involve iNOS. PMID:20041425

Senchina, David S; Martin, Aisha E; Buss, Janice E; Kohut, Marian L

2010-06-01

132

Lactobacillus acidophilus CP23 with weak immunomodulatory activity lacks anchoring structure for surface layer protein.  

PubMed

To determine the reason for the low levels of Surface layer protein A (SlpA) on CP23 cells, which might play a crucial role in the immunomodulatory effect of Lactobacillus acidophilus, the DNA sequence of the slpA gene of CP23 and L-92 strains, including the upstream region, were analyzed. Unexpectedly, there was no significant difference in the predicted amino acid sequence of the C-terminus needed for cell anchoring, and only an additional Ala-Val-Ala sequence inserted in the N-terminal region of the mature CP23 protein. Therefore, anchoring of SlpA on the cell wall of CP23 and L-92 was evaluated by a reconstitution assay, which showed that SlpA released by LiCl treatment from both CP23 and L-92 was successfully anchored on LiCl-treated L-92 cells, but not on LiCl-treated CP23 cells. Moreover, quantitative analysis of SlpA protein in the culture medium of CP23 and L-92 by ELISA revealed higher levels of SlpA secretion in CP23 cells than in L-92 cells. Collectively, these results suggest that the lower levels of SlpA on the surface of CP23 cells might be caused by less cell wall capacity for SlpA anchoring, leading to an accumulation of SlpA in the culture medium of CP23 cells. The present study supports the importance of cell surface structure of L. acidophilus L-92 for SlpA anchoring on the cell surface needed for immunomodulatory effect. PMID:25454604

Yanagihara, Sae; Kato, Shinji; Ashida, Nobuhisa; Yamamoto, Naoyuki

2015-05-01

133

A patatin-like protein protects Toxoplasma gondii from degradation in activated macrophages  

E-print Network

A patatin-like protein protects Toxoplasma gondii from degradation in activated macrophages Dana G The apicomplexan parasite Toxoplasma gondii is able to suppress nitric oxide production in activated macrophages at the same rate as wild-type parasites in naĂŻve macrophages, but unlike wild type, the mutant was degraded

Sheridan, Jennifer

134

Evaluation of immunomodulatory and antitumor activity of all trans retinoic acid (ATRA) in solid tumor bearing mice.  

PubMed

Natural or synthetic agents can modify the immune system and, in some cases, impart a therapeutic benefit. Cancer, a disease of uncontrolled growth and spread of abnormal cells, is a major cause of death. The Vitamin A metabolite all-trans retinoic acid (ATRA) and its other active derivatives are potent modulators of cell growth and differentiation, and because it has an influence on cancer, it can be used as a chemotherapeutic and -preventive agent. To evaluate the immunomodulatory activity of ATRA, the impact of treatment on various parameters, e.g. delayed-type hypersensitivity (DTH), bone marrow cellularity, hematology, and levels of esterase-positive cells, was assessed in Balb/c mice. To evaluate antitumor effects of ATRA, tumor volume and host survival rate were monitored in B16F10 melanoma cell-injected mice. The results showed that administration of ATRA (0.60?mg/kg/dose, IP) caused a decrease in DTH (footpad thickness) in response to challenge with sheep red blood cells (SRBC) in SRBC-sensitized hosts. ATRA also caused increases in WBC counts and bone marrow cell numbers. In tumor-inoculated mice, ATRA caused tumor growth suppression and gave rise to a heightened survival rate. It was also found that ATRA had differential effects on serum levels of reduced glutathione (GSH) and nitric oxide (NO) was reduced in serum. Based on these results, we conclude that ATRA has a potent immunomodulatory potential but also could significantly impact upon solid tumor growth and prolong host survival. PMID:22900644

Siddikuzzaman; Berlin, Grace V M

2013-02-01

135

Activation of RAW264.7 macrophages by the polysaccharide from the roots of Actinidia eriantha and its molecular mechanisms.  

PubMed

The polysaccharide from the roots of Actinidia eriantha (AEPS), a potent antitumor agent and immunological adjuvant, was investigated for the immunomodulatory effects on RAW264.7 macrophages and its molecular mechanisms. AEPS could significantly enhance the pinocytic and phagocytic activity, induce the production of NO, TNF-?, IL-10, IL-1? and IL-6, and promote the expression of accessory and costimulatory molecules in RAW264.7 cells. PCR array assay revealed that AEPS up-regulated 28 genes including TLRs (TLR2, TLR8, TLR9), proinflammatory factors (IL-1?, G-CSF, IL-1?, GM-CSF, IL-6, COX-2, TNF-?, IFN-?, CXCL10, CCL2, TNF-?, IL-10), and the genes involved in NF-?B signaling pathway, and down-regulated 6 genes such as TLR3, TLR4, PGLYRP1, EIF2?K2, MAP3K1 and IRF1. AEPS was further showed to promote cytoplasmic I?B-? degradation and increase nuclear NF-?B p65 levels in RAW264.7 cells. These results suggested that AEPS activated RAW264.7 macrophages and elicited a M1 and M2 response through TLRs/NF-?B signaling pathway. PMID:25659714

Sun, Hongxiang; Zhang, Juan; Chen, Fengyang; Chen, Xiangfeng; Zhou, Zhihua; Wang, Hui

2015-05-01

136

Water Extract of Deer Bones Activates Macrophages and Alleviates Neutropenia  

PubMed Central

Extracts from deer bones, called nok-gol in Korean, have long been used to invigorate Qi. While neutropenia is not well detected in normal physiological condition, it could be a cause of severe problems to develop diseases such as infectious and cancerous diseases. Thus, a prevention of neutropenia in normal physiology and pathophysiological states is important for maintaining Qi and preventing disease progress. In cell biological aspects, activated macrophages are known to prevent neutropenia. In this study, we demonstrate that water extract of deer bone (herein, NG) prevents neutropenia by activating macrophages. In mouse neutropenia model system in vivo where ICR mice were treated with cyclophosphamide to immunosuppress, an oral administration of NG altered the number of blood cells including lymphocytes, neutrophils, basophils, and eosinophils. This in vivo effect of NG was relevant to that of granulocyte colony stimulating factor (G-CSF) that was known to improve neutropenia. Our in vitro studies further showed that NG treatment increased intracellular reactive oxygen species (ROS) and promoted macrophagic differentiation of mouse monocytic Raw264.7 cells in a dose-dependent manner. In addition, NG enhanced nitric oxide (NO) synthesis and secretions of cytokines including IL-6 and TNF-?. Consistently, NG treatment induced phosphorylation of ERK, JNK, IKK, I?B?, and NF-?B in Raw264.7 cells. Thus, our data suggest that NG is helpful for alleviating neutropenia. PMID:23840259

Choi, Han-Seok; Kim, Soon Re; Hong, Se Hyang; Ku, Jin Mo; Kim, Min Kyoung; Seo, Hye Sook; Cho, Sung-Gook; Shin, Sangtae; Shin, Yong Cheol; Ko, Seong-Gyu

2013-01-01

137

Investigating the function of a novel protein from Anoectochilus formosanus which induced macrophage differentiation through TLR4-mediated NF-?B activation.  

PubMed

Anoectochilus formosanus is a therapeutic orchid appreciated as a traditional Chinese medicine in Asia. The extracts of A. formosanus have been reported to possess hepatoprotective, anti-inflammatory, and anti-tumor activates. A novel protein was isolated from A. formosanus, and its immunomodulatory effect on murine peritoneal macrophage was investigated. Macrophages obtained from ascites of thioglycollate-induced BALB/c were co-cultured with IPAF (0-20 ?g/ml) for 24 h and then harvested for flow cytometry analysis. The cytokine/chemokine production was measured by real time PCR and ELISA. The interaction between IPAF and toll like receptors (TLRs) was investigated by TLR gene knockout (KO) mice and fluorescence labeled IPAF. The activation of NF-?B was assessed by EMSA. IPAF stimulated the TNF-? and IL-1? production, upregulated the CD86 and MHC II expression, and enhanced the phagocytic activity of macrophages. IPAF induced gene expression of IL-12 and Th1-assosiated cytokines/chemokines. The stimulating effect of IPAF was impaired, and the IPAF-macrophage interaction was reduced in TLR4(-/-) C57BL/10ScNJ mice. In addition, IPAF stimulated expressions of TLR signal-related genes and the activation of NF-?B. IPAF could induce classical activated macrophage differentiation via TLR4-dependent NF-?B activation and had potential of IPAF to modulate the Th1 response. These findings provided valuable information regarding the immune modulatory mechanism of A. formosanus, and indicated the possibility of IPAF as a potential peptide drug. PMID:22749731

Kuan, Yen-Chou; Lee, Wan-Tzu; Hung, Chih-Liang; Yang, Ching; Sheu, Fuu

2012-09-01

138

Immunomodulatory activity of butanol fraction of Gentiana olivieri Griseb. on Balb/C mice  

PubMed Central

Objective To explore the immunomodulatory properties of 80% ethanol extract and butanol fraction of Gentiana olivieri (G. olivieri) Griseb on Balb/C mice. Methods The study was performed with basic models of immunomodulation such as the humoral antibody response (hemoglutination antibody titres), cell mediated immune response (delayed type hypersensitivity and in vivo carbon clearance or phagocytosis). Ethanol (80%) extract of flowering aerial parts of G. olivieri and its butanol fraction were administered p.o. (orally) to the mice. Levamisole, 2.5 mg/kg was used as standard drug. Results There was a potentiation of immune response to sheep red blood cells by cellular and humoral mediated mechanisms comparable to levamisole (2.5 mg/kg) by both 80% ethanol extract and the butanol fraction at doses of 50-200 mg/kg in male Balb/C mice. Both significantly (P<0.01) potentiated the humoral immune response in cyclophosphamide (250 mg/kg) immunosupressed mice at 100 and 200 mg/kg of each extract and fraction as compared to control. The potentiation of delayed type hypersensitivity response was statistically significant (P<0.01) at 200 mg/kg of ethanol extract and 100, 200 mg/kg of butanol fraction as compared to control. The phagocytosis was significant at 200 mg/kg with butanol fraction of G. olivieri. Conclusions The results reveal the immunostimulant effects of plant G. olivieri in mice by acting through cellular and humoral immunity in experimental models of immunity in mice. Butanol fraction is the most effective at a dose level of 200 mg/kg. PMID:23569945

Singh, Satnam; CPS, Yadav; Noolvi, Malleshappa N

2012-01-01

139

Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria.  

PubMed

Alveolar macrophages are the first line of host defence against mycobacteria, but an insufficient host response allows survival of bacteria within macrophages. We aimed to investigate the role of Toll-like receptor 9 (TLR9) activation in macrophage defence against mycobacteria. Human in vitro differentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were markedly activated by DNA isolated from attenuated mycobacterial strains (H37Ra and Mycobacterium bovis BCG) as assessed by measuring cytokine expression by real-time PCR, whereas synthetic phosphorothioate-modified oligonucleotides had a much lower potency to activate human macrophages. Intracellular replication of H37Ra was higher in macrophages isolated from TLR9-deficient mice than in macrophages from wild-type mice, whereas H37Rv showed equal survival in cells from wild-type or mutant mice. Increased bacterial survival in mouse macrophages was accompanied by altered cytokine production as determined by Luminex bead assays. In vivo infection experiments also showed differential cytokine production in TLR9-deficient mice compared to wild-type animals. Both human monocyte-derived macrophages as well as human alveolar macrophages showed reduced activation upon treatment with DNA isolated from bacteria from virulent (M. bovis and H37Rv) compared to attenuated mycobacteria. We suggest attenuated TLR9 activation contributes to the insufficient host response against virulent mycobacteria. PMID:20375564

Kiemer, Alexandra K; Senaratne, Ryan H; Hoppstädter, Jessica; Diesel, Britta; Riley, Lee W; Tabeta, Koichi; Bauer, Stefan; Beutler, Bruce; Zuraw, Bruce L

2009-01-01

140

Mycobacterium leprae-burdened macrophages are refractory to activation by gamma interferon.  

PubMed Central

Mycobacterium leprae grows to enormous numbers in the nu/nu mouse footpad, producing granulomas resembling those of lepromatous leprosy in humans. Footpad granuloma cells gorged with M. leprae were established in primary cell culture to examine their functional capabilities. These cells were classified as macrophages by the following criteria: positive staining for nonspecific esterase, reduction of Nitro Blue Tetrazolium during phagocytosis of Candida albicans, possession of Fc receptors, and possession of Mac-1 antigen. Footpad macrophages also phagocytized and supported the intracellular growth of Toxoplasma gondii. However, unlike peritoneal macrophages, footpad macrophages could not be activated to kill or inhibit T. gondii by macrophage-activating factor produced by mitogen-stimulated spleen cells or by recombinant gamma interferon. Thus, although the lepromatous macrophages appeared to be normal in many of their functions, they were defective in response to macrophage-activating signals. Images PMID:3100449

Sibley, L D; Krahenbuhl, J L

1987-01-01

141

Multimodality PET/MR imaging agents targeted to activated macrophages  

PubMed Central

The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles (IONPs) have become a popular platform for the fabrication of PET/MRI probes due to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this paper, we report the synthesis of dextran coated iron oxide nanoparticles labeled with the positron emitter 64Cu to generate a PET/MRI probe, and modified with small molecular maleic anhydride to increase negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-64Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand-receptor found on activated macrophages but not on normal vessel walls. MDIO-64Cu-DOTA has an average iron oxide core size of 7-8 nm, an average hydrodynamic diameter of 62.7 nm, an r1 relaxivity of 16.8 mM?1·s?1, and an r2 relaxivity of 83.9 mM?1·s?1 (37 °C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR-A. In comparison with the non-modified analog, the accumulation of maleylated DIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-64Cu-DOTA for identification of vulnerable atherosclerotic plaques (VAP) via the targeting of macrophages. PMID:24166283

Tu, Chuqiao; Ng, Thomas S. C.; Jacobs, Russell E.; Louie, Angelique Y.

2013-01-01

142

Immunomodulatory activity of a plant extract containing human papillomavirus 16-E7 protein in human monocyte-derived dendritic cells.  

PubMed

This study reports the immunomodulatory activity on human monocyte derived dendritic cells (MDDCs) of a vaccine preparation shown to be effective against an HPV16-related tumour in an animal model. The vaccine is composed of extract from Nicotiana benthamiana leaves containing HPV16 E7 protein expressed by a potato virus X-derived vector (NbPVX-E7). The effect of the extract was evaluated on MDDC differentiation and maturation by monitoring the phenotypic expression of specific markers. The results show that NbPVX-E7 does not induce monocyte differentiation to dendritic cells, but does induce MDDC maturation. Plant extract does not influence MDDC-uptake of E7-FITC while it significantly improves the Ovalbumin-FITC uptake, considered as a model antigen. Importantly, NbPVX-E7-pulsed MDDCs/PBMCs are able to prime human blood-derived lymphocytes from healthy individuals to induce HPV16 E7-specific cytotoxic activity. This is a propaedeutic study for a possible use of E7-containing plant extract in human immunotherapy of HPV-related lesions. PMID:20074460

Di Bonito, P; Grasso, F; Mangino, G; Massa, S; Illiano, E; Franconi, R; Fanales-Belasio, E; Falchi, M; Affabris, E; Giorgi, C

2009-01-01

143

Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages  

PubMed Central

BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT) has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA) of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS) and interferon - gamma (IFN-?) (activation) for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2). Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT) assay (after 1, 3 and 5 days) in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm) macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm) macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle. PMID:25076002

Souza, Nadhia H. C.; Ferrari, Raquel A. M.; Silva, Daniela F. T.; Nunes, Fabio D.; Bussadori, Sandra K.; Fernandes, Kristianne P. S.

2014-01-01

144

Depletion of alveolar macrophages prolongs survival in response to acute pneumovirus infection  

PubMed Central

Alveolar macrophages are immunoregulatory effector cells that interact directly with respiratory virus pathogens in vivo. We examined the role of alveolar macrophages in acute infection with pneumonia virus of mice (PVM), a rodent pneumovirus that replicates the clinical sequelae of severe human respiratory syncytial virus disease. We show that PVM replicates in primary mouse macrophage culture, releasing infectious virions and proinflammatory cytokines. Alveolar macrophages isolated from PVM-infected mice express activation markers Clec43 and CD86, cytokines TNF?, IL-1, IL-6, and numerous CC and CXC chemokines. Alveolar macrophage depletion prior to PVM infection results in small but statistically significant increases in virus recovery but paradoxically prolonged survival. In parallel, macrophage depleted PVM-infected mice exhibit enhanced NK cell recruitment and increased production of IFN? by NK, CD4+ and CD8+ T cells. These results suggest a protective, immunomodulatory role for IFN?, as overproduction secondary to macrophage depletion may promote survival despite increased virus recovery. PMID:22129848

Rigaux, Peter; Killoran, Kristin E.; Qiu, Zhijun; Rosenberg, Helene F.

2011-01-01

145

Intravenous immunoglobulin promotes antitumor responses by modulating macrophage polarization.  

PubMed

Intravenous Igs (IVIg) therapy is widely used as an immunomodulatory strategy in inflammatory pathologies and is suggested to promote cancer regression. Because progression of tumors depends on their ability to redirect the polarization state of tumor-associated macrophages (from M1/immunogenic/proinflammatory to M2/anti-inflammatory), we have evaluated whether IVIg limits tumor progression and dissemination through modulation of macrophage polarization. In vitro, IVIg inhibited proinflammatory cytokine production from M1 macrophages and induced a M2-to-M1 polarization switch on human and murine M2 macrophages. In vivo, IVIg modified the polarization of tumor-associated myeloid cells in a Fc?r1? chain-dependent manner, modulated cytokine blood levels in tumor-bearing animals, and impaired tumor progression via Fc?RIII (CD16), Fc?RIV, and FcR? engagement, the latter two effects being macrophage mediated. Therefore, IVIg immunomodulatory activity is dependent on the polarization state of the responding macrophages, and its ability to trigger a M2-to-M1 macrophage polarization switch might be therapeutically useful in cancer, in which proinflammatory or immunogenic functions should be promoted. PMID:25326025

Domínguez-Soto, Angeles; de las Casas-Engel, Mateo; Bragado, Rafael; Medina-Echeverz, José; Aragoneses-Fenoll, Laura; Martín-Gayo, Enrique; van Rooijen, Nico; Berraondo, Pedro; Toribio, María L; Moro, María A; Cuartero, Isabel; Castrillo, Antonio; Sancho, David; Sánchez-Torres, Carmen; Bruhns, Pierre; Sánchez-Ramón, Silvia; Corbí, Angel L

2014-11-15

146

Oxidized LDL Induces Alternative Macrophage Phenotype through Activation of CD36 and PAFR  

PubMed Central

OxLDL is recognized by macrophage scavenger receptors, including CD36; we have recently found that Platelet-Activating Factor Receptor (PAFR) is also involved. Since PAFR in macrophages is associated with suppressor function, we examined the effect of oxLDL on macrophage phenotype. It was found that the presence of oxLDL during macrophage differentiation induced high mRNA levels to IL-10, mannose receptor, PPAR? and arginase-1 and low levels of IL-12 and iNOS. When human THP-1 macrophages were pre-treated with oxLDL then stimulated with LPS, the production of IL-10 and TGF-? significantly increased, whereas that of IL-6 and IL-8 decreased. In murine TG-elicited macrophages, this protocol significantly reduced NO, iNOS and COX2 expression. Thus, oxLDL induced macrophage differentiation and activation towards the alternatively activated M2-phenotype. In murine macrophages, oxLDL induced TGF-?, arginase-1 and IL-10 mRNA expression, which were significantly reduced by pre-treatment with PAFR antagonists (WEB and CV) or with antibodies to CD36. The mRNA expression of IL-12, RANTES and CXCL2 were not affected. We showed that this profile of macrophage activation is dependent on the engagement of both CD36 and PAFR. We conclude that oxLDL induces alternative macrophage activation by mechanisms involving CD36 and PAFR. PMID:24062612

Rios, Francisco J.; Koga, Marianna M.; Pecenin, Mateus; Gidlund, Magnus; Jancar, S.

2013-01-01

147

Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2.  

PubMed

Monocytes are a population of leukocytes that terminally differentiate into macrophages and DCs. Whereas these differentiated progeny have inflammatory and resident--which are more immunomodulatory--phenotypes, less has been reported on the plasticity of monocytes themselves. We found that MSCs, a population of somatic stem cells, can rapidly induce human and murine monocytes through secretion of HGF to acquire an immunomodulatory phenotype to suppress T cell effector function. MSCs are multilineage postnatal progenitor cells with strong immunomodulatory effects toward T lymphocytes, NK lymphocytes, and DCs, but less is known regarding their interactions with monocytes. We found that CD14(+) human monocytes express c-Met, the receptor for HGF, and both depletion of HGF-treated CD14(+) monocytes and knockdown of HGF secretion in MSCs abrogate the suppression of anti-CD3/28-activated T cell proliferation. HGF-treated monocytes remain undifferentiated and can alter activated T cell cytokine expression from a Th1 toward Th2 profile. Moreover, monocytes cocultured with MSCs or treated with HGF alone can produce high levels of IL-10, a potent immunomodulatory cytokine. Injection of HGF to WT mice also results in an increase in IL-10(+)-expressing monocytes from the spleen, a known reservoir for circulating monocytes. Mechanistically, HGFs modulate IL-10 production in monocytes through the ERK1/2 pathway. Our data demonstrate further the pleomorphic nature of MSC immunomodulation, as well as highlight the important role of immunomodulatory monocytes in altering T cell effector function. PMID:24714552

Chen, Pei-Min; Liu, Ko-Jiunn; Hsu, Pei-Ju; Wei, Chung-Fan; Bai, Chyi-Huey; Ho, Ling-Jun; Sytwu, Huey-Kang; Yen, B Linju

2014-08-01

148

Recombinant Expression of a Novel Fungal Immunomodulatory Protein with Human Tumor Cell Antiproliferative Activity from Nectria haematococca  

PubMed Central

To our best knowledge, all of the fungal immunomodulatory proteins (FIPs) have been successfully extracted and identified in Basidomycetes, with only the exception of FIP from ascomycete Nectria haematococca (FIP-nha) discovered through homology alignment most recently. In this work, a gene encoding FIP-nha was synthesized and recombinantly expressed in an Escherichia coli expression system. SDS-PAGE and MALDI-MS analyses of recombinant FIP-nha (rFIP-nha) indicated that the gene was successfully expressed. The yield of the bioactive FIP-nha protein was 42.7 mg/L. In vitro assays of biological activity indicated that the rFIP-nha caused hemagglutination of human and rabbit red blood cells, significantly stimulated mouse spleen lymphocyte proliferation, and enhanced expression of interleukin-2 (IL-2) released from mouse splenocytes, revealing a strong antitumor effect against HL60, HepG2 and MGC823. Through this work, we constructed a rapid and efficient method of FIP production, and suggested that FIP-nha is a valuable candidate for use in future medical care and pharmaceutical products. PMID:25272229

Li, Shuying; Nie, Ying; Ding, Yang; Shi, Lijun; Tang, Xuanming

2014-01-01

149

Interaction of human leukocytes and Entamoeba histolytica. Killing of virulent amebae by the activated macrophage.  

PubMed

Capable effector mechanisms in the human immune response against the cytolytic, protozoan parasite Entamoeba histolytica have not been described. To identify a competent human effector cell, we studied the in vitro interactions of normal human polymorphonuclear neutrophils, peripheral blood mononuclear cells (PBMC), monocytes (MC), and MC-derived macrophages with virulent axenic amebae (strain HMI-IMSS). Amebae killed neutrophils, PBMC, MC, and MC-derived macrophages (P less than 0.001), without loss of parasite viability. The addition of heat-inactivated immune serum did not enable leukocytes to kill amebae, nor did it protect these host cells from amebae. MC-derived macrophages, activated with lymphokine elicited by the mitogens conconavalin A, phytohemagglutinin, or an amebic soluble protein preparation (strain HK9), killed 55% of amebae by 3 h in a trypan blue exclusion assay (P less than 0.001); during this time, 40% of the activated macrophages died. Lysis of amebae was confirmed using 111Indium oxine radiolabeled parasites and was antibody independent. Macrophage death appeared to be due to the deleterious effect of lysed amebae rather than the contact-dependent effector mechanisms of E. histolytica. Adherence between activated macrophages and amebae was greater than that between other leukocytes and amebae (P less than 0.001). Microscopic observations, kinetic analysis of the killing of amebae by activated macrophages, and suspension of amebae with adherent activated macrophages in a 10% dextran solution indicated that contact by activated macrophages was necessary to initiate the killing of amebae. Catalase but not superoxide dismutase inhibited the amebicidal capacity of activated macrophages (P less than 0.001). However, activated macrophages from an individual with chronic granulomatous disease were able to kill amebae, but not as effectively as normal cells (P less than 0.01). In summary, activated MC-derived macrophages killed virulent E. histolytica trophozoites through a contact-dependent, antibody-independent mechanism involving oxidative-dependent and -independent processes. PMID:2863284

Salata, R A; Pearson, R D; Ravdin, J I

1985-08-01

150

Conditioned medium from alternatively activated macrophages induce mesangial cell apoptosis via the effect of Fas  

SciTech Connect

During inflammation in the glomerulus, the proliferation of myofiroblast-like mesangial cells is commonly associated with the pathological process. Macrophages play an important role in regulating the growth of resident mesangial cells in the glomeruli. Alternatively activated macrophage (M2 macrophage) is a subset of macrophages induced by IL-13/IL-4, which is shown to play a repair role in glomerulonephritis. Prompted by studies of development, we performed bone marrow derived macrophage and rat mesangial cell co-culture study. Conditioned medium from IL-4 primed M2 macrophages induced rat mesangial cell apoptosis. The pro-apoptotic effect of M2 macrophages was demonstrated by condensed nuclei stained with Hoechst 33258, increased apoptosis rates by flow cytometry analysis and enhanced caspase-3 activation by western blot. Fas protein was up-regulated in rat mesangial cells, and its neutralizing antibody ZB4 partly inhibited M2 macrophage-induced apoptosis. The up-regulated arginase-1 expression in M2 macrophage also contributed to this apoptotic effect. These results indicated that the process of apoptosis triggered by conditioned medium from M2 macrophages, at least is partly conducted through Fas in rat mesangial cells. Our findings provide compelling evidence that M2 macrophages control the growth of mesangial cells in renal inflammatory conditions. - Highlights: • Conditioned-medium from M2 macrophages induces rat mesangial cell (MsC) apoptosis. • M2 macrophage conditioned medium exerts its pro-apoptotic effects via Fas ligand. • Arginase-1 activity in M2 macrophages plays a role in inducing apoptosis in rat MsC.

Huang, Yuan; Luo, Fangjun; Li, Hui; Jiang, Tao; Zhang, Nong, E-mail: nzhang@fudan.edu.cn

2013-11-15

151

A Novel Immunomodulatory Hemocyanin from the Limpet Fissurella latimarginata Promotes Potent Anti-Tumor Activity in Melanoma  

PubMed Central

Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-? production and higher numbers of tumor-infiltrating CD4+ lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-?) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy. PMID:24466345

Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabián; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C.; Manubens, Augusto; De Ioannes, Alfredo E.; Becker, María Inés

2014-01-01

152

Differential Inflammasome Activation in M1 and M2a Pulmonary Macrophages  

E-print Network

Differential Inflammasome Activation in M1 and M2a Pulmonary Macrophages Emily K. Kobos, Virginia M There are differing levels of inflammasome activation in macrophage subsets based on IL-1 production and caspase-1 relationship with inflammasome activation will also need to be determined Figure 3: Silica induced pro-IL-1

Vonessen, Nikolaus

153

Requirement for multiple activation signals by anti-inflammatory feedback in macrophages  

Microsoft Academic Search

Pathogen killing is one of the primary roles of macrophages, utilizing potent effectors such as nitric oxide (NO) and involving other cellular machinery including iron regulatory apparatus. Macrophages become strongly activated upon receipt of appropriate signaling with cytokines and pathogen-derived endotoxins. However, they must resist activation in the absence of decisive signaling due to the energetic demands of activation coupled

J. Christian J. Ray; Denise E. Kirschner

2006-01-01

154

[Immunomodulatory effects of lenalidomide].  

PubMed

Immunomodulatory drugs (IMiDs) including lenalidomide, a single compound shows various pharmacological action such as the stimulation of T cells and natural killer (NK) cells, the suppression hematopoietic tumor proliferation, suppression of neo-vascularisation, and anti-inflammatory action. It has been thought that IMiDs stimulates CD8+ cytotoxic T cells primarily, it is recently shown that they also stimulate CD4+ helper-T cells similarly. Lenalidomide stimulates T cells and NK-cell through production of Th1 type cytokines IL-2 and IFN-? from CD4+ helper-T cells. Lenalidomide also activate T cells indirectly by inhibiting regulatory T cells and myeloid derived suppressor cells (MDSC) which inhibit the activation of T cells, but controversy still exist about effects on regulatory T cells. PMID:25626322

Handa, Hiroshi; Saitoh, Takayuki; Murakami, Hirokazu

2015-01-01

155

[Macrophage activation syndrome and autoimmunity due to visceral leishmaniasis].  

PubMed

Hemophagocytic syndromes are a heterogeneous group of diseases characterized by an excessive immune response, mediated by activated cytotoxic T cells and macrophages. Among hemophagocytic syndromes, genetic and secondary forms can be distinguished. We report on the case of a male newborn who presented with macrophage activation syndrome associated with lymphoproliferation with favorable outcome under prednisone and cyclosporin. Hemopathy, infection, or genetic lymphohistiocytosis were initially ruled out. Severe autoimmunity was suspected because of positive antinuclear antibodies and Farr test associated with anemia and a positive Coombs test as well as cytolytic hepatitis with anti-liver, kidney microsome (LKM) antibodies. Treatment was therefore intensified by adding mycophenolate mofetil. This led to an unexpected deterioration of general health and lab exam results with recurrence of fever and inflammation. The initial investigations were revisited and completed by a liver biopsy, which revealed the presence of numerous leishmania parasites at the amastigote stage, enabling the diagnosis of visceral leishmaniasis. The patient's condition dramatically improved under liposomal amphotericin B treatment. Our observation shows that visceral leishmaniasis can present as lupus-like syndrome with lymphoproliferation. Moreover, the lack of leishmania on marrow aspiration cannot rule out the diagnosis of visceral leishmaniasis. Detection of leishmania by serological or molecular tests is mandatory in case of hepatosplenomegaly with hemophagocytic syndrome together with autoantibodies, in order to avoid useless and life-threatening exposure to immunosuppressive treatments. PMID:25617995

Higel, L; Froehlich, C; Pages, M-P; Dupont, D; Collardeau-Frachon, S; Dijoud, F; Cochat, P; Belot, A

2015-04-01

156

Phenotypic Diversity and Emerging New Tools to Study Macrophage Activation in Bacterial Infectious Diseases  

PubMed Central

Macrophage polarization is a concept that has been useful to describe the different features of macrophage activation related to specific functions. Macrophage polarization is responsible for a dichotomic approach (killing vs. repair) of the host response to bacteria; M1-type conditions are protective, whereas M2-type conditions are associated with bacterial persistence. The use of the polarization concept to classify the features of macrophage activation in infected patients using transcriptional and/or molecular data and to provide biomarkers for diagnosis and prognosis has most often been unsuccessful. The confrontation of polarization with different clinical situations in which monocytes/macrophages encounter bacteria obliged us to reappraise this concept. With the exception of M2-type infectious diseases, such as leprosy and Whipple’s disease, most acute (sepsis) or chronic (Q fever, tuberculosis) infectious diseases do not exhibit polarized monocytes/macrophages. This is also the case for commensals that shape the immune response and for probiotics that alter the immune response independent of macrophage polarization. We propose that the type of myeloid cells (monocytes vs. macrophages) and the kinetics of the immune response (early vs. late responses) are critical variables for understanding macrophage activation in human infectious diseases. Explorating the role of these new markers will provide important tools to better understand complex macrophage physiology. PMID:25346736

Ka, Mignane B.; Daumas, Aurélie; Textoris, Julien; Mege, Jean-Louis

2014-01-01

157

A salicylate-based small molecule HS-Cm exhibits immunomodulatory effects and inhibits dipeptidyl peptidase-IV activity in human T cells.  

PubMed

Activated T cells are key players in chronic inflammatory diseases, including atherosclerosis. Salicylates, like aspirin, display not only anti-inflammatory, anti-thrombotic, anti-atherosclerotic activities, but also immunomodulatory effects in T cells at high dosages. Here, we aimed to identify potent immunomodulators for T cells through cell-based screening from a mini-library of 300 salicylate-based small molecules, and elucidate the mechanisms. Human peripheral blood T cells were isolated from buffy coat. Phorbol 12-myristate 13-acetate plus ionomycin (P/I) was used to stimulate T cells. Cytokine production was measured by enzyme-linked immunosorbent assays. T cell activation markers were determined by flow cytometry. The activation of transcription factors and kinases was analyzed by western blotting, electrophoretic mobility shift assay, or kinase assay. Through library screening, we identified a small molecule named HS-Cm [C13H9ClFNO2; N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide] that exhibited potent immunomodulatory effects on T cells with low cytotoxicity. In P/I-stimulated T cells, HS-Cm inhibited the production of interleukin-2, tumor necrosis factor-alpha, and interferon-gamma and suppressed the expression of surface activation markers CD25, CD69, and CD71, but not CD45RO. HS-Cm down-regulated DNA-binding activities of activator protein-1 and nuclear factor-kappa B, but not nuclear factor of activated T-cells, through inhibiting c-Jun N-terminal kinase/p38 and inhibitor of kappaB alpha (I?B?) kinase (IKK)/I?B? pathways, respectively. On the basis of structure-activity relationship, HS-Cm exerted considerable inhibition of dipeptidyl-peptidase IV/CD26 activity in T cells. Our results suggested that the small molecule HS-Cm exhibiting immunomodulatory effects on T cells may be useful for therapeutics in chronic inflammatory diseases, like atherosclerosis, diabetes and autoimmune arthritis. PMID:24491838

Liou, Jun-Ting; Huang, Hsu-Shan; Chiang, Meng-Lin; Lin, Chin-Sheng; Yang, Shih-Ping; Ho, Ling-Jun; Lai, Jenn-Haung

2014-03-01

158

Putting on the Brakes: Cyclic AMP as a Multipronged Controller of Macrophage Function  

NSDL National Science Digital Library

Macrophages orchestrate innate immune responses in tissues by activating various proinflammatory signaling programs. A key mechanism for preventing inflammatory disease states that result from excessive activation of such programs is the generation of the second messenger cyclic adenosine monophosphate (cAMP) by ligation of certain guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs). The pleiotropic actions of this cyclic nucleotide on various inflammatory functions of macrophages are mediated by diverse molecular mechanisms, including the assembly of distinct multiprotein complexes. A better understanding of crosstalk between cAMP signaling and proinflammatory pathways in macrophages may provide a basis for improved immunomodulatory strategies.

Marc Peters-Golden (Ann Arbor; University of Michigan Medical School REV)

2009-06-16

159

Macrophages sense and kill bacteria through carbon monoxide–dependent inflammasome activation  

PubMed Central

Microbial clearance by eukaryotes relies on complex and coordinated processes that remain poorly understood. The gasotransmitter carbon monoxide (CO) is generated by the stress-responsive enzyme heme oxygenase-1 (HO-1, encoded by Hmox1), which is highly induced in macrophages in response to bacterial infection. HO-1 deficiency results in inadequate pathogen clearance, exaggerated tissue damage, and increased mortality. Here, we determined that macrophage-generated CO promotes ATP production and release by bacteria, which then activates the Nacht, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome, intensifying bacterial killing. Bacterial killing defects in HO-1–deficient murine macrophages were restored by administration of CO. Moreover, increased CO levels enhanced the bacterial clearance capacity of human macrophages and WT murine macrophages. CO-dependent bacterial clearance required the NALP3 inflammasome, as CO did not increase bacterial killing in macrophages isolated from NALP3-deficient or caspase-1–deficient mice. IL-1? cleavage and secretion were impaired in HO-1–deficient macrophages, and CO-dependent processing of IL-1? required the presence of bacteria-derived ATP. We found that bacteria remained viable to generate and release ATP in response to CO. The ATP then bound to macrophage nucleotide P2 receptors, resulting in activation of the NALP3/IL-1? inflammasome to amplify bacterial phagocytosis by macrophages. Taken together, our results indicate that macrophage-derived CO permits efficient and coordinated regulation of the host innate response to invading microbes. PMID:25295542

Wegiel, Barbara; Larsen, Rasmus; Gallo, David; Chin, Beek Yoke; Harris, Clair; Mannam, Praveen; Kaczmarek, Elzbieta; Lee, Patty J.; Zuckerbraun, Brian S.; Flavell, Richard; Soares, Miguel P.; Otterbein, Leo E.

2014-01-01

160

Immunomodulatory affect of R10 fraction of garlic extract on natural killer activity  

Microsoft Academic Search

Naturally occurring modulators of carcinogenesis, including dietary compounds, can either stimulate or inhibit cancer development. Mechanisms responsible for these effects are unknown. Garlics used in this study were freshly prepared, and their effectiveness in augmenting natural killer (NK) activity was evaluated. Administration of 20 mg\\/kg produced an optimum augmentation of NK activity. A glycoprotein with MW of about 14 kDa

Zuhair M Hassan; Roya Yaraee; Narges Zare; Tooba Ghazanfari; Abul Hassan Sarraf Nejad; Bijhan Nazori

2003-01-01

161

LIVER X RECEPTOR (LXR) ACTIVATION NEGATIVELY REGULATES VISFATIN EXPRESSION IN MACROPHAGES  

E-print Network

1 LIVER X RECEPTOR (LXR) ACTIVATION NEGATIVELY REGULATES VISFATIN EXPRESSION IN MACROPHAGES Thérèse Communications 2011;404(1):458-62" DOI : 10.1016/j.bbrc.2010.12.002 #12;2 ABSTRACT Adipose tissue macrophages. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR) are nuclear receptors

Paris-Sud XI, Université de

162

Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages  

SciTech Connect

Research highlights: {yields} Synthetic LXR ligands decreased visfatin expression in human macrophages. {yields} LXR activation leads to a modest and transient decrease of NAD{sup +} concentration. {yields} LXR activation decreased PPAR{gamma}-induced visfatin in human macrophages. -- Abstract: Adipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR){gamma} are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPAR{gamma} target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD{sup +} concentration was observed. Interestingly, LXR activation decreased the PPAR{gamma}-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPAR{gamma} pathways in human macrophages.

Mayi, Therese Hervee; Rigamonti, Elena [Univ Lille Nord de France, F-59000 Lille (France) [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France) [France; UDSL, F-59000 Lille (France) [France; Institut Pasteur de Lille, F-59019 Lille (France); Pattou, Francois [Univ Lille Nord de France, F-59000 Lille (France) [Univ Lille Nord de France, F-59000 Lille (France); Department of Endocrine Surgery, University Hospital, Lille (France); U859 Biotherapies for Diabetes, INSERM, Lille (France); Staels, Bart, E-mail: bart.staels@pasteur-lille.fr [Univ Lille Nord de France, F-59000 Lille (France) [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France) [France; UDSL, F-59000 Lille (France) [France; Institut Pasteur de Lille, F-59019 Lille (France); Chinetti-Gbaguidi, Giulia [Univ Lille Nord de France, F-59000 Lille (France) [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France) [France; UDSL, F-59000 Lille (France) [France; Institut Pasteur de Lille, F-59019 Lille (France)

2011-01-07

163

Activation of Olfactory Receptors on Mouse Pulmonary Macrophages Promotes Monocyte Chemotactic Protein-1 Production  

PubMed Central

Background Emerging evidence suggests that non-olfactory tissues and cells can express olfactory receptors (ORs), however, the exact function of ectopic OR expression remains unknown. We have previously shown in mouse models that a unique cooperation between interferon-? (IFN-?) and lipopolysaccharide (LPS) drives the activation of pulmonary macrophages and leads to the induction of pathogenic responses in the respiratory tract. Further, through gene array studies, we have shown that activation of macrophages by these molecules results in the selective expression of a number of ORs. In this study, we validated the expression of these ORs in mouse airway and pulmonary macrophages in response to IFN-? and LPS (?/LPS) stimulation, and further explored the effect of odorant stimulation on macrophage function. Methodology/Principal Findings OR expression in airway and pulmonary macrophages in response to IFN-?, LPS or ?/LPS treatments was assessed by microarray and validated by q-PCR. OR expression (e.g. OR622) on macrophages was confirmed by visualization in immunofluoresence assays. Functional responses to odorants were assessed by quantifying inflammatory cytokine and chemokine expression using q-PCR and cell migration was assessed by a modified Boyden chamber migration assay. Our results demonstrate that eight ORs are expressed at basal levels in both airway and pulmonary macrophages, and that ?/LPS stimulation cooperatively increased this expression. Pulmonary macrophages exposed to the combined treatment of ?/LPS+octanal (an odorant) exhibited a 3-fold increase in MCP-1 protein production, compared to cells treated with ?/LPS alone. Supernatants from ?/LPS+octanal exposed macrophages also increased macrophage migration in vitro. Conclusions/Significance Eight different ORs are expressed at basal levels in pulmonary macrophages and expression is upregulated by the synergistic action of ?/LPS. Octanal stimulation further increased MCP-1 production and the motility of macrophages. Our results suggest that ORs may mediate macrophage function by regulating MCP-1 production and cell migration. PMID:24278251

Li, Jing Jing; Tay, Hock L.; Plank, Maximilian; Essilfie, Ama-Tawiah; Hansbro, Philip M.; Foster, Paul S.; Yang, Ming

2013-01-01

164

Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas M1-macrophage-related molecules such as integrin {alpha}X, IL-1{beta}, MIP2{alpha} and leptin were decreased at rosiglitazone-treated incisional sites. Moreover, transplantation of rosiglitazone-treated peritoneal macrophages into the incisional sites significantly attenuated hyperalgesia. We speculate that local administration of rosiglitazone significantly alleviated the development of postincisional pain, possibly through regulating macrophage polarity at the inflamed site. PPAR{gamma} signaling in macrophages may be a potential therapeutic target for the treatment of acute pain development.

Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)] [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)] [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

2012-09-14

165

Macrophage activation by polysaccharide biological response modifier isolated from Aloe vera L. var. chinensis (Haw.) Berg  

Microsoft Academic Search

A mannose-rich polysaccharide biological response modifier (BRM), derived from Aloe vera L. var. chinensis (Haw.) Berg., was demonstrated to be a potent murine B- and T-cell stimulator in our previous study. We here report the stimulatory activity of PAC-I on murine peritoneal macrophage. The polysaccharide when injected into mice enhanced the migration of macrophages to the peritoneal cavity. Peritoneal macrophage

C. Liu; M. Y. K. Leung; J. C. M. Koon; L. F. Zhu; Y. Z. Hui; B. Yu; K. P. Fung

2006-01-01

166

Liposome encapsulated all trans retinoic acid (ATRA) has enhanced immunomodulatory and inflammation reducing activities in mice model.  

PubMed

The all trans retinoic acid (ATRA) is found to have a promising regulatory effect on immune system and inflammatory responses in experimental research. The purpose of this study was to investigate whether this therapeutic efficiency of ATRA could be enhanced by encapsulating into a liposome formulation composed of Distearoyl-L-phosphatidylcholine (DSPC) and cholesterol utilizing a well-established mice model. The humoral antibody titer (HA), delayed-type hypersensitivity (DTH), bone marrow cellularity, hematology, and levels of ?- esterase-positive cells, were taken as parameters to assess the level of immunomodulation in the sheep red blood cells (SRBC) immunized and challenged BALB/c mice. The anti-inflammatory effect of encapsulated ATRA was evaluated by the size changes in the induced inflammation edema in the mice paw as well as its histopathology. The results showed a significant immunostimulatory effect for both the free and encapsulated ATRA as indicated by the increase in the levels of total leukocyte, bone marrow and ?-esterase positive cells and decreased Hb level respectively. We have also observed an enhanced specific antibody hemagglutinin titre value and the DTH response developed in response to SRBC challenge in these treatments. Both the immunostimulatory as well as inflammation reducing property were significantly higher in encapsulated ATRA treated group of mice over that of in free ATRA treated group of mice. Based on these results, we conclude that the encapsulated ATRA has a higher potency over free ATRA in its immunomodulatory activity and also has a significant impact on reducing inflammation in BALB/c mice model. PMID:25594892

Grace, V M Berlin; Siddikuzzaman; Rimashree, B

2015-01-01

167

I?B kinase activity drives fetal lung macrophage maturation along a non-M1/M2 paradigm.  

PubMed

In preterm infants, exposure to inflammation increases the risk of bronchopulmonary dysplasia, a chronic, developmental lung disease. Although macrophages are the key cells that initiate lung inflammation, less is known about lung macrophage phenotype and maturation. We hypothesized that fetal lung macrophages mature into distinct subpopulations during mouse development, and that activation could influence macrophage maturation. Expression of the fetal macrophage markers CD68, CD86, CD206, Ym1, fibrinogen-like protein 2, and indolamine-2, 3-dioxygenase was developmentally regulated, with each marker having different temporal patterns. Flow cytometry analysis showed macrophages within the fetal lung were less diverse than the distinctly separate subpopulations in newborn and adult lungs. Similar to adult alveolar macrophages, fetal lung macrophages responded to the TLR4 agonist LPS and the alternative activation cytokines IL-4 and IL-13. Using a macrophage-specific constitutively active I?B Kinase transgenic model (IKFM), we demonstrated that macrophage activation increased proinflammatory gene expression and reduced the response of fetal lung macrophages to IL-4 and IL-13. Activation also increased fetal lung macrophage proliferation. Fetal IKFM lungs contained increased percentages of more mature, CD11b(low)F4/80(high) cells that also expressed higher levels of the alternative activation markers CD204 and CD206. Development of fetal lung macrophages into mature alveolar macrophages may therefore include features of both proinflammatory and alternative activation paradigms. PMID:24981452

Stouch, Ashley N; Zaynagetdinov, Rinat; Barham, Whitney J; Stinnett, Amanda M; Slaughter, James C; Yull, Fiona E; Hoffman, Hal M; Blackwell, Timothy S; Prince, Lawrence S

2014-08-01

168

Secreted Toxoplasma gondii molecules interfere with expression of MHC-II in interferon gamma-activated macrophages.  

PubMed

The obligate intracellular protozoan parasite Toxoplasma gondii interferes with major histocompatibility complex class II antigen presentation to dampen host CD4(+) T cell responses. While it is known that T. gondii inhibits major histocompatibility complex class II gene transcription and expression in infected host cells, the mechanism of this host manipulation is unknown. Here, we show that soluble parasite proteins inhibit IFN?-induced expression of major histocompatibility complex class II on the surface of the infected cell in a dose-dependent response that was abolished by protease treatment. Subcellular fractionation of T. gondii tachyzoites revealed that the major histocompatibility complex class II inhibitory activity co-partitioned with rhoptries and/or dense granules. However, parasite mutants deleted for single rhoptries or dense granules genes (ROP1, 4/7, 14, 16 and 18 or GRA 2-9 and 12 knock-out strains) retained the ability to inhibit expression of major histocompatibility complex class II. In addition, excreted/secreted antigens released by extracellular tachyzoites displayed immunomodulatory activity characterized by an inhibition of major histocompatibility complex class II expression, and reduced expression and release of TNF? by macrophages. Tandem MS analysis of parasite excreted/secreted antigens generated a list of T. gondii secreted proteins that may participate in major histocompatibility complex class II inhibition and the modulation of host immune functions. PMID:25720921

Leroux, Louis-Philippe; Dasanayake, Dayal; Rommereim, Leah M; Fox, Barbara A; Bzik, David J; Jardim, Armando; Dzierszinski, Florence S

2015-04-01

169

A subpopulation of CD163 positive macrophages is classically activated in psoriasis  

PubMed Central

Macrophages are important cells of the innate immune system, and their study is essential to gain greater understanding of the inflammatory nature of psoriasis. We used immunohistochemistry and double-label immunofluorescence to characterize CD163+ macrophages in psoriasis. Dermal macrophages were increased in psoriasis compared to normal skin and were identified by CD163, RFD7, CD68, LAMP2, Stabilin-1, and MARCO. CD163+ macrophages expressed C-lectins CD206/MMR and CD209/DC-SIGN, as well as co-stimulatory molecules CD86 and CD40. They did not express mature DC markers CD208/DC-LAMP, CD205/DEC205 or CD83. Microarray analysis of in vitro derived macrophages treated with IFN? showed that many of the genes upregulated in macrophages were found in psoriasis, including STAT1, CXCL9, Mx1 and HLA-DR. CD163+ macrophages produced inflammatory molecules IL-23p19 and IL-12/23p40 as well as TNF and iNOS. These data demonstrate that CD163 is a superior marker of macrophages, and identifies a subpopulation of “classically activatedmacrophages in psoriasis. We conclude that macrophages are likely to be contributing to the pathogenic inflammation in psoriasis, a prototypical Th1 and Th17 disease, by releasing key inflammatory products. PMID:20555352

Fuentes-Duculan, Judilyn; Suárez-Farińas, Mayte; Zaba, Lisa C.; Nograles, Kristine E.; Pierson, Katherine C.; Mitsui, Hiroshi; Pensabene, Cara A.; Kzhyshkowska, Julia; Krueger, James G.; Lowes, Michelle A.

2010-01-01

170

Adenosine promotes alternative macrophage activation via A2A and A2B receptors  

PubMed Central

Adenosine has been implicated in suppressing the proinflammatory responses of classically activated macrophages induced by Th1 cytokines. Alternative macrophage activation is induced by the Th2 cytokines interleukin (IL)-4 and IL-13; however, the role of adenosine in governing alternative macrophage activation is unknown. We show here that adenosine treatment of IL-4- or IL-13-activated macrophages augments the expression of alternative macrophage markers arginase-1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and macrophage galactose-type C-type lectin-1. The stimulatory effect of adenosine required primarily A2B receptors because the nonselective adenosine receptor agonist 5?-N-ethylcarboxamidoadenosine (NECA) increased both arginase activity (EC50=261.8 nM) and TIMP-1 production (EC50=80.67 nM), and both pharmacologic and genetic blockade of A2B receptors prevented the effect of NECA. A2A receptors also contributed to the adenosine augmentation of IL-4-induced TIMP-1 release, as both adenosine and NECA were less efficacious in augmenting TIMP-1 release by A2A receptor-deficient than control macrophages. Of the transcription factors known to drive alternative macrophage activation, CCAAT-enhancer-binding protein ? was required, while cAMP response element-binding protein and signal transducer and activator of transcription 6 were dispensable in mediating the effect of adenosine. We propose that adenosine receptor activation suppresses inflammation and promotes tissue restitution, in part, by promoting alternative macrophage activation.—Csóka, B., Selmeczy, Z., Koscsó, B., Németh, Z. H., Pacher, P., Murray, P. J., Kepka-Lenhart, D., Morris S. M., Jr., Gause, W. C., Leibovich, S. J., Haskó, G. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. PMID:21926236

Csóka, Balázs; Selmeczy, Zsolt; Koscsó, Balázs; Németh, Zoltán H.; Pacher, Pál; Murray, Peter J.; Kepka-Lenhart, Diane; Morris, Sidney M.; Gause, William C.; Leibovich, S. Joseph; Haskó, György

2012-01-01

171

Reaching the threshold: a multilayer pathogenesis of macrophage activation syndrome.  

PubMed

Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases. The condition is considered part of secondary hemophagocytic lymphohistiocytoses (HLH). There are similarities in genetic background, pathogenesis, and clinical and laboratory features with primary HLH (p-HLH). We describe findings in mouse models of secondary HLH, comparing them with models of p-HLH and the cellular and molecular mechanisms involved, and relate them to recent findings in patients with secondary HLH. A multilayer model is presented in which background inflammation, infections, and genetics all contribute in different proportions and in several ways. Once the "threshold" has been reached, inflammatory cytokines are the final effectors, independent of the interplay between different upstream pathogenic factors. PMID:23588947

Strippoli, Raffaele; Caiello, Ivan; De Benedetti, Fabrizio

2013-06-01

172

Sericins exhibit ROS-scavenging, anti-tyrosinase, anti-elastase, and in vitro immunomodulatory activities.  

PubMed

Some biological properties of Bombyx mori sericins from twenty strains were investigated, fourteen fed with artificial diet, two with fresh mulberry leaves and four with both diets. Sericin exhibited ROS-scavenging, anti-tyrosinase and anti-elastase properties, the strain significantly influenced these properties, while diet only influenced the anti-tyrosinase activity. Sericins were clustered into 5 groups and one sericin from each group was further studied: sericins showed anti-proliferative activity on in vitro stimulated peripheral blood mononuclear cells; some strains decreased in vitro secretion of IFN?, while no effects were observed on TNF? and IL10 release. Therefore, a mixture of sericins extracted from the most promising strains may be useful for dermatological and cosmetic use. PMID:23541552

Chlapanidas, Theodora; Faragň, Silvio; Lucconi, Giulia; Perteghella, Sara; Galuzzi, Marta; Mantelli, Melissa; Avanzini, Maria Antonietta; Tosca, Marta Cecilia; Marazzi, Mario; Vigo, Daniele; Torre, Maria Luisa; Faustini, Massimo

2013-07-01

173

Immunomodulatory activities of a new pentapeptide (Bursopentin) from the chicken bursa of Fabricius.  

PubMed

The bursa of Fabricius (BF) is a central immune organ in birds, and some peptides from chicken BF have demonstrated important immune functions. Here, a new 626.27 Da pentapeptide, Bursopentin (BP5, Cys-Lys-Arg-Val-Tyr) was isolated and purified by reverse-phase high-performance liquid chromatography. In this study, we examined the effects of BP5 on antigen-specific immune response in BALB/c mice sensitized with inactivated avian influenza virus (AIV) [A/Duck/Jiangsu/NJ08/05 (AIV H9N2 subtype)]. The results suggested that BP5 enhanced anti-hemagglutinin antibody (IgG, the isotypes IgG1 and IgG2a) production, induced both of Th1- (IL-2 and IFN-?) and Th2-type (IL-4 and -10) cytokines, increased proliferations of splenic lymphocyte subsets CD4+ T cells (CD3+CD4+), CD8+ T cells (CD3+CD8+) and B cells, and enhanced cytotoxic T-lymphocyte activity of the activated splenocytes against NIH3T3 cells. The effects of BP5 on the proliferation of isolated T- and/or B-cell populations of BALB/c mice were assessed, and the data suggested that BP5 promoted spleen lymphocyte proliferation by activating B cells directly and T cells indirectly. Further analysis revealed that B-lymphocyte proliferation induced by BP5 is mediated by reactive oxygen species generated from thiol auto-oxidation of BP5. Furthermore, our data indicated that protein kinase C, mitogen-activated protein kinase, and nuclear factor kappa B are involved in the signal transductions during the BP5-induced B lymphocyte proliferation. This study indicates that BP5 could be a potential immunomodulator for future immuno-pharmacological use. PMID:20582606

Li, D Y; Geng, Z R; Zhu, H F; Wang, C; Miao, D N; Chen, P Y

2011-02-01

174

Macrophages Contribute to the Cyclic Activation of Adult Hair Follicle Stem Cells  

PubMed Central

Skin epithelial stem cells operate within a complex signaling milieu that orchestrates their lifetime regenerative properties. The question of whether and how immune cells impact on these stem cells within their niche is not well understood. Here we show that skin-resident macrophages decrease in number because of apoptosis before the onset of epithelial hair follicle stem cell activation during the murine hair cycle. This process is linked to distinct gene expression, including Wnt transcription. Interestingly, by mimicking this event through the selective induction of macrophage apoptosis in early telogen, we identify a novel involvement of macrophages in stem cell activation in vivo. Importantly, the macrophage-specific pharmacological inhibition of Wnt production delays hair follicle growth. Thus, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel, additional cue that regulates their regenerative activity. This finding may have translational implications for skin repair, inflammatory skin diseases and cancer. PMID:25536657

Castellana, Donatello; Paus, Ralf; Perez-Moreno, Mirna

2014-01-01

175

Macrophage Activation in Acute Exacerbation of Idiopathic Pulmonary Fibrosis  

PubMed Central

Background Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a common cause of disease acceleration in IPF and has a major impact on mortality. The role of macrophage activation in AE of IPF has never been addressed before. Methods We evaluated BAL cell cytokine profiles and BAL differential cell counts in 71 IPF patients w/wo AE and in 20 healthy volunteers. Twelve patients suffered from AE at initial diagnosis while sixteen patients developed AE in the 24 months of follow-up. The levels of IL-1ra, CCL2, CCL17, CCL18, CCL22, TNF-?, IL-1?, CXCL1 and IL-8 spontaneously produced by BAL-cells were analysed by ELISA. Results In patients with AE, the percentage of BAL neutrophils was significantly increased compared to stable patients. We found an increase in the production rate of the pro-inflammatory cytokines CXCL1 and IL-8 combined with an increase in all tested M2 cytokines by BAL-cells. An increase in CCL18 levels and neutrophil counts during AE was observed in BAL cells from patients from whom serial lavages were obtained. Furthermore, high baseline levels of CCL18 production by BAL cells were significantly predictive for the development of future AE. Conclusions BAL cell cytokine production levels at acute exacerbation show up-regulation of pro-inflammatory as well as anti-inflammatory/ M2 cytokines. Our data suggest that AE in IPF is not an incidental event but rather driven by cellular mechanisms including M2 macrophage activation. PMID:25590613

Schupp, Jonas Christian; Binder, Harald; Jäger, Benedikt; Cillis, Giuseppe; Zissel, Gernot; Müller-Quernheim, Joachim; Prasse, Antje

2015-01-01

176

Urokinase Plasminogen Activator Induces Pro-Fibrotic/M2 Phenotype in Murine Cardiac Macrophages  

PubMed Central

Objective Inflammation and fibrosis are intertwined in multiple disease processes. We have previously found that over-expression of urokinase plasminogen activator in macrophages induces spontaneous macrophage accumulation and fibrosis specific to the heart in mice. Understanding the relationship between inflammation and fibrosis in the heart is critical to developing therapies for diverse myocardial diseases. Therefore, we sought to determine if uPA induces changes in macrophage function that promote cardiac collagen accumulation. Methods and Results We analyzed the effect of the uPA transgene on expression of pro-inflammatory (M1) and pro-fibrotic (M2) genes and proteins in hearts and isolated macrophages of uPA overexpressing mice. We found that although there was elevation of the pro-inflammatory cytokine IL-6 in hearts of transgenic mice, IL-6 is not a major effector of uPA induced cardiac fibrosis. However, uPA expressing bone marrow-derived macrophages are polarized to express M2 genes in response to IL-4 stimulation, and these M2 genes are upregulated in uPA expressing macrophages following migration to the heart. In addition, while uPA expressing macrophages express a transcriptional profile that is seen in tumor–associated macrophages, these macrophages promote collagen expression in cardiac but not embryonic fibroblasts. Conclusions Urokinase plasminogen activator induces an M2/profibrotic phenotype in macrophages that is fully expressed after migration of macrophages into the heart. Understanding the mechanisms by which uPA modulates macrophage function may reveal insights into diverse pathologic processes. PMID:23536772

Helterline, Deri; Ramsey, Stephen A.; Bertko, Kate; Plummer, Tabitha; Plawman, Abigail; Gold, Elizabeth; Stempien-Otero, April

2013-01-01

177

Effect of gamma irradiation on mistletoe (Viscum album) lectin-mediated toxicity and immunomodulatory activity.  

PubMed

This study evaluated the effect of gamma irradiation on the reduction of the toxicity of mistletoe lectin using both in vitro and in vivo models. To extract the lectin from mistletoe, an (NH4)2SO4 precipitation method was employed and the precipitant purified using a Sepharose 4B column to obtain the pure lectin fraction. Purified lectin was then gamma-irradiated at doses of 0, 5, 10, 15, and 20 kGy, or heated at 100 °C for 30 min. Toxic effects of non-irradiated, irradiated, and heat-treated lectins were tested using hemagglutination assays, cytotoxicity assays, hepatotoxicity, and a mouse survival test and immunological response was tested using cytokine production activity. Hemagglutination of lectin was remarkably decreased (P < 0.05) by irradiation at doses exceeding 10 kGy and with heat treatment. However, lectin irradiated with 5 kGy maintained its hemagglutination activity. The cytotoxicity of lectin was decreased by irradiation at doses over 5 kGy and with heat treatment. In experiments using mouse model, glutamate oxaloacetate transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels were decreased in the group treated with the 5 kGy irradiated and heat-treated lectins as compared to the intact lectin, and it was also shown that 5 kGy irradiated and heat-treated lectins did not cause damage in liver tissue or mortality. In the result of immunological response, tumor necrosis factor (TNF-?) and interleukin (IL-6) levels were significantly (P < 0.05) increased in the 5 kGy gamma-irradiated lectin treated group. These results indicate that 5 kGy irradiated lectin still maintained the immunological response with reduction of toxicity. Therefore, gamma-irradiation may be an effective method for reducing the toxicity of lectin maintaining the immune response. PMID:23847758

Sung, Nak-Yun; Byun, Eui-Baek; Song, Du-Sup; Jin, Yeung-Bae; Kim, Jae-Kyung; Park, Jong-Heum; Song, Beom-Seok; Jung, Pil-Mun; Byun, Myung-Woo; Lee, Ju-Woon; Park, Sang-Hyun; Kim, Jae-Hun

2013-01-01

178

Macrophage Migration Inhibitory Factor (MIF) Enzymatic Activity and Lung Cancer  

PubMed Central

The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif P1G). Primary tumor growth was significantly attenuated in both Mif-KO and Mif P1G mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems. PMID:25826675

Mawhinney, Leona; Armstrong, Michelle E; O’ Reilly, Ciaran; Bucala, Richard; Leng, Lin; Fingerle-Rowson, Gunter; Fayne, Darren; Keane, Michael P; Tynan, Aisling; Maher, Lewena; Cooke, Gordon; Lloyd, David; Conroy, Helen; Donnelly, Seamas C

2014-01-01

179

Macrophage Migration Inhibitory Factor (MIF) Enzymatic Activity and Lung Cancer.  

PubMed

The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif (P1G)). Primary tumor growth was significantly attenuated in both Mif-KO and Mif (P1G) mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems. PMID:25826675

Mawhinney, Leona; Armstrong, Michelle E; O' Reilly, Ciaran; Bucala, Richard; Leng, Lin; Fingerle-Rowson, Gunter; Fayne, Darren; Keane, Michael P; Tynan, Aisling; Maher, Lewena; Cooke, Gordon; Lloyd, David; Conroy, Helen; Donnelly, Seamas C

2015-01-01

180

Mechanistic study of macrophage activation by LPS stimulation using fluorescence imaging techinques  

NASA Astrophysics Data System (ADS)

Lipopolysaccharide (LPS), a structural component of the outer membrane of gram negative bacteria, has been suggested that stimulates macrophages secrete a wide variety of inflammatory mediators, such as nitric oxide (NO). However, the cellular mechanisms of NO generation in macrophage by LPS stimulation are not well known. In this study, LPS stimulated NO generation in macrophage was determined by measuring fluorescence changes with a NO specific probe DAF-FM DA. Using the fluorescence resonance energy transfer (FRET) techniques, we found an increase of protein kinase C (PKC) activation was dynamically monitored in macrophages treated with LPS. Nuclear factor kappa B (NF-?B) translocated from the cytoplasm to the nucleus in macrophage was measured by confocal laser scanning microscopy. Moreover, the PKC inhibitor GÖ6983 inhibited LPS-stimulated NF-?B activation and NO production. These results indicated that LPS stimulated NF-?B mediated NO production by activating PKC.

Lu, Cuixia; Zhou, Feifan; Chen, Wei R.; Xing, Da

2012-03-01

181

Mechanistic study of macrophage activation by LPS stimulation using fluorescence imaging techinques  

NASA Astrophysics Data System (ADS)

Lipopolysaccharide (LPS), a structural component of the outer membrane of gram negative bacteria, has been suggested that stimulates macrophages secrete a wide variety of inflammatory mediators, such as nitric oxide (NO). However, the cellular mechanisms of NO generation in macrophage by LPS stimulation are not well known. In this study, LPS stimulated NO generation in macrophage was determined by measuring fluorescence changes with a NO specific probe DAF-FM DA. Using the fluorescence resonance energy transfer (FRET) techniques, we found an increase of protein kinase C (PKC) activation was dynamically monitored in macrophages treated with LPS. Nuclear factor kappa B (NF-?B) translocated from the cytoplasm to the nucleus in macrophage was measured by confocal laser scanning microscopy. Moreover, the PKC inhibitor GÖ6983 inhibited LPS-stimulated NF-?B activation and NO production. These results indicated that LPS stimulated NF-?B mediated NO production by activating PKC.

Lu, Cuixia; Zhou, Feifan; Chen, Wei R.; Xing, Da

2011-11-01

182

Activated alveolar macrophages in subclinical pulmonary inflammation in collagen vascular diseases.  

PubMed Central

A study was initiated to determine whether alveolar macrophages from patients with collagen vascular diseases but free of pulmonary symptoms were spontaneously activated and whether they released various mediators related to the pathogenesis of pulmonary fibrosis. Alveolar macrophages obtained by bronchoalveolar lavage from 32 patients with proved collagen vascular disease but no evidence of lung disease were compared with those from 10 patients with collagen vascular disease with interstitial lung disease (CVD-ILD) and from 10 healthy controls. The total number of alveolar macrophages did not differ between patients with collagen vascular disease and controls but were substantially increased in the CVD-ILD group. Alveolar macrophages from 31 of the 32 patients with collagen vascular disease and from all 10 in the CVD-ILD group had at least one criterion of activation. Neutrophil chemotactic activity was detected in supernatants from alveolar macrophage culture in 23 of the 32 patients with collagen vascular disease and from nine of the 10 in the CVD-ILD group; fibronectin secretion by alveolar macrophages was increased in 12 of the 32 patients with collagen vascular disease and in nine of the 10 in the CVD-ILD group. Furthermore, alveolar macrophages from 20 of the 32 patients with collagen vascular disease and four of the 10 CVD-ILD patients spontaneously released increased amounts of superoxide anion. Thus alveolar macrophages were spontaneously activated in a high proportion of patients with collagen vascular disease. Images PMID:2832961

Wallaert, B; Bart, F; Aerts, C; Ouaissi, A; Hatron, P Y; Tonnel, A B; Voisin, C

1988-01-01

183

Molecular Interaction and Enzymatic Activity of Macrophage Migration Inhibitory Factor with Immunorelevant Peptides*  

E-print Network

Molecular Interaction and Enzymatic Activity of Macrophage Migration Inhibitory Factor T cell responses. Migration inhibitory factor (MIF) is a member of the thioredoxin family and has been in class II antigen presen- tation and/or as a chaperone is discussed. The macrophage migration inhibitory

Strominger, Jack L.

184

Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice  

PubMed Central

The majority of acute clinical manifestations of atherosclerosis are due to the physical rupture of advanced atherosclerotic plaques. It has been hypothesized that macrophages play a key role in inducing plaque rupture by secreting proteases that destroy the extracellular matrix that provides physical strength to the fibrous cap. Despite reports detailing the expression of multiple proteases by macrophages in rupture-prone regions, there is no direct proof that macrophage-mediated matrix degradation can induce plaque rupture. We aimed to test this hypothesis by retrovirally overexpressing the candidate enzyme MMP-9 in macrophages of advanced atherosclerotic lesions of apoE–/– mice. Despite a greater than 10-fold increase in the expression of MMP-9 by macrophages, there was only a minor increase in the incidence of plaque fissuring. Subsequent analysis revealed that macrophages secrete MMP-9 predominantly as a proform, and this form is unable to degrade the matrix component elastin. Expression of an autoactivating form of MMP-9 in macrophages in vitro greatly enhances elastin degradation and induces significant plaque disruption when overexpressed by macrophages in advanced atherosclerotic lesions of apoE–/– mice in vivo. These data show that enhanced macrophage proteolytic activity can induce acute plaque disruption and highlight MMP-9 as a potential therapeutic target for stabilizing rupture-prone plaques. PMID:16374516

Gough, Peter J.; Gomez, Ivan G.; Wille, Paul T.; Raines, Elaine W.

2006-01-01

185

Studies on cytolytic mechanisms of activated macrophages and monocytes  

SciTech Connect

Pulmonary alveolar macrophages (PAM) and peripheral blood monocytes (PBMo) of the miniature swine can be converted to cytolytically active cells by treating with phorbol myristic acetate (PMA) or combined stimulation with recombinant human interferon - ..gamma.. (rHuIFN-..gamma..) and lipopolysaccharide (LPS). These activated PAM and PBMo become cytolytic to various targets by producing neutral proteases. H/sub 2/O/sub 2/ and cytotoxic factors. While the PAM stimulated by PMA was most active in generating H/sub 2/O/sub 2/ as well as neutral proteases, the PBMo stimulated with PMA was able to produce only H/sub 2/O/sub 2/. The mechanism of killing by PAM seemed to vary with type of target cells: H/sub 2/O/sub 2/ was effective in killing of PRBC, SRBC, and K562, but proteases were responsible for the lysis of U937 and WEHI-164. In contrast to PMA stimulation, combined stimulation with rHuIFN-..gamma.. and LPS was very effective in generation of cytotoxic factors from PAM and PBMo. These cytotoxic factors were directly toxic to various target cells including WEHI-164, U937, K562, and CRBC, but not to autologous target such as PRBC.

Chung, T.; Kim, Y.B.

1986-03-05

186

Effect of influenza infection on the phagocytic and bactericidal activities of pulmonary macrophages.  

PubMed Central

The effect of mouse-adapted influenza A/PR/8/34 virus on pulmonary macrophage function was evaluated by using an in vitro system which allowed direct virus interaction with macrophages and then separate analysis of the steps required for bacterial clearance by macrophages. Infection of macrophages with this virus resulted in the appearance of a hemagglutinating activity on the macrophage surface; expression of this activity was inhibited by amantadine, 2-deoxyglucose, and cycloheximide and by pretreatment of the virus inoculum with ultraviolet light and specific antiserum. Since there was no release of extracellular virus, this growth cycle appeared to be incomplete (abortive). After influenza infection, net ingestion of viable Staphylococcus aureus by macrophage monolayers was unaltered and there was no change in the fraction of the monolayer which ingested cocci over a wide range of bacterial inputs. Influenza-infected macrophages also inactivated intracellular S. aureus at a rate indistinguishable from controls. Therefore, these in vitro studies do not support the hypothesis that the defect in pulmonary antibacterial mechanisms associated with influenza infections results from a direct effect of virus infection on either the phagocytic or bactericidal activity of resident pulmonary macrophages. Images PMID:546791

Nugent, K M; Pesanti, E L

1979-01-01

187

Antiviral, Immunomodulatory, and Free Radical Scavenging Activities of a Protein-Enriched Fraction from the Larvae of the Housefly, Musca domestica  

PubMed Central

In our previous study, protein-enriched fraction (PEF) that was isolated from the larvae of the housefly, Musca domestica L. (Diptera: Muscidae), showed excellent hepatoprotective activity as well as the potential for clinical application in therapy for liver diseases. In this study, antiviral, immunomodulatory, and free radical scavenging activities of PEF were evaluated. The antiviral results demonstrated that PEF inhibited the infection of avian influenza virus H9N2 and had a virucidal effect against the multicapsid nucleopolyhedrovirus of the alfalfa looper, Autographa californica Speyer (Lepidoptera: Noctuidae) in vitro. The mortality of silkworm larve in a PEF treatment group decreased significantly compared with a negative control. PEF showed excellent scavenging activity for 1,1-diphenyl-2-picrylhydrazyl and superoxide anion radicals, which were similar to those of ascorbic acid. The imunomodulatory results suggested that PEF could effectively improve immune function in experimental mice. Our results indicated that PEF could possibly be used for the prophylaxis and treatment of diseases caused by avian influenza virus infection. In addition, PEF with virucidal activity against insect viruses might provide useful for the development of antimicrobial breeding technology for economically important insects. As a natural product from insects, PEF could be a potential source for the discovery of potent antioxidant and immunomodulatory agents. PMID:24735244

Ai, Hui; Wang, Furong; Zhang, Na; Zhang, Lingyao; Lei, Chaoliang

2013-01-01

188

Antiviral, immunomodulatory, and free radical scavenging activities of a protein-enriched fraction from the larvae of the housefly, Musca domestica.  

PubMed

In our previous study, protein-enriched fraction (PEF) that was isolated from the larvae of the housefly, Musca domestica L. (Diptera: Muscidae), showed excellent hepatoprotective activity as well as the potential for clinical application in therapy for liver diseases. In this study, antiviral, immunomodulatory, and free radical scavenging activities of PEF were evaluated. The antiviral results demonstrated that PEF inhibited the infection of avian influenza virus H9N2 and had a virucidal effect against the multicapsid nucleopolyhedrovirus of the alfalfa looper, Autographa californica Speyer (Lepidoptera: Noctuidae) in vitro. The mortality of silkworm larve in a PEF treatment group decreased significantly compared with a negative control. PEF showed excellent scavenging activity for 1,1-diphenyl-2-picrylhydrazyl and superoxide anion radicals, which were similar to those of ascorbic acid. The imunomodulatory results suggested that PEF could effectively improve immune function in experimental mice. Our results indicated that PEF could possibly be used for the prophylaxis and treatment of diseases caused by avian influenza virus infection. In addition, PEF with virucidal activity against insect viruses might provide useful for the development of antimicrobial breeding technology for economically important insects. As a natural product from insects, PEF could be a potential source for the discovery of potent antioxidant and immunomodulatory agents. PMID:24735244

Ai, Hui; Wang, Furong; Zhang, Na; Zhang, Lingyao; Lei, Chaoliang

2013-01-01

189

Nigella sativa seed extract: 1. Enhancement of sheep macrophage immune functions in vitro.  

PubMed

Nigella sativa (N. sativa) seed, Black cumin, immunomodulatory activity has been investigated in human and mice. Little is known about the immunomodulatory effect of Nigella sativa (N. sativa) seed extract on animals' immune cells, specifically, antigen presenting cells such as macrophages. This study focused on the immunomodulatory effect of N. sativa seed extract on sheep macrophage functions in vitro. Sheep peripheral blood monocytes were isolated and derived to macrophages (MDM). The MDM were cultured with N. sativa seed extract and their morphological changes, phagocytic activity, nitric oxide production, and microbicidal activity were investigated. Marked morphological changes were observed in MDM cultured with N. sativa seed extract including cell size enlargement; increase in both cytoplasmic space and cytoplasmic granules. Significant increases in phagocytic activity to Candida albicans yeast and in number of yeast engulfed per individual MDM were observed in cells cultured with seed extract. MDM capacity to produce nitric oxide was higher in the culture media of the seed extract-cultured cells compared to the control. Interestingly, prominent enhancement in MDM microbicidal activity to yeast or bacteria was observed in MDM cultured with N. sativa seed extract confirming the potent immunostimulatory effect of the extract. From this study, it could be concluded that N. sativa seed extract can enhance macrophages' important innate immune functions that could control infectious diseases and regulate adaptive immunity. PMID:23664216

Elmowalid, Gamal; Amar, Ahmad M; Ahmad, Adel Attia M

2013-10-01

190

The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages  

PubMed Central

RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program. PMID:25030696

Daniel, Bence; Hah, Nasun; Horvath, Attila; Czimmerer, Zsolt; Poliska, Szilard; Gyuris, Tibor; Keirsse, Jiri; Gysemans, Conny; Van Ginderachter, Jo A.; Balint, Balint L.; Evans, Ronald M.; Barta, Endre; Nagy, Laszlo

2014-01-01

191

Comparative study of various immunomodulators for macrophage and natural killer cell activation and antiviral efficacy against exotic RNA viruses.  

PubMed

Several immunomodulators were compared for immunomodulatory and antiviral activity in B6C3F1 female mice. Our results demonstrate that murine recombinant gamma interferon (rIFN-G), human recombinant alpha A/D interferon (rIFN-A), ampligen (a polyribonucleotide) and CL246,738 modulate nonspecific immunity and are effective antiviral agents in vivo. Administration of each of these agents 1 day before cell harvest induced high levels of splenic natural killer (NK) cell activity against YAC-1 target cells. rIFN-G was also a potent activator of peritoneal macrophages (M phi), as evidenced by high levels of antitumor activity and changes in ectoenzyme phenotype that is characteristic of tumoricidal M phi. rIFN-A, ampligen and CL246,738 induced moderate to low levels of M phi activation by these criteria. In vivo protection experiments showed that repeated therapeutic treatment with rIFN-A protected mice against i.p. infection with Venezuelan equine encephalitis (an alpha togavirus, VEE), Banzi (a flavivirus) and herpes simplex virus type 2 (HSV-2). Similar treatment with rIFN-G was effective against VEE and HSV-2, but ineffective against Banzi virus. A single prophylactic i.p. dose of ampligen 1 day before virus challenge was very effective against Banzi virus, moderately effective against HSV-2, and ineffective against VEE and Caraparu (a bunyavirus) infection. A single prophylactic oral dose of CL246,738 provided almost complete protection of mice against VEE, Banzi, and HSV-2, and also increased the mean survival time for Caraparu infected mice. Collectively, these results indicate that rIFN-A, r-IFN-G, ampligen and CL246,738 may be useful in prophylactic or early therapeutic treatment of several serious virus infections. Since these agents stimulate NK cells and M phi, their antiviral activity may result, in part, from the alterations they induce in the natural immune system. PMID:3182149

Pinto, A J; Morahan, P S; Brinton, M A

1988-01-01

192

Immunomodulatory activity of analog of muramyl dipeptide and their use as adjunct to chemotherapy of Leishmania donovani in hamster.  

PubMed

In search of a potent immunomodulator to be used as an immunoprophylactic agent and as adjunct to chemotherapy against Leishmania infection, two analogs of muramyl dipeptide, viz. N.Ac-norMur-MeVal-D-isoGln (86/448) and N.AcMur-Acc-D-isoGln (89/729) were evaluated for desired activity. Effect of these peptides on cell mediated and humoral immunity was studied by immunizing the peptide treated mouse with sheep red blood cells (SRBC) and determining HA-titer, plaque forming cells assay and delayed type of hypersensitivity (DTH) response after 4-5 days. Both the peptides stimulated cell mediated immunity (CMI), humoral response as well as macrophage function in terms of super oxide anion (O2-) and nitric oxide (NO) generation. Mitogen induced lymphocyte proliferation and production of IL-2 and INF-gamma increased while that of IL-4 and IL-10 decreased by both the peptides showing a typical Th1 type response. After establishing the immunostimulatory activity, these peptides were evaluated for immunoprophylactic efficacy as well as for use as adjunct to chemotherapy with stibanate (SSG) against Leishmania donovani infection in golden hamster. These peptides were found quite effective in both the modes. In adjunct use the treatment may require lower dose of SSG and thereby reduce the chances of drug toxicity. PMID:15829410

Puri, A; Sahai, R; Haq, W; Zaidi, A; Guru, P Y; Tripathi, L M; Srivastava, V M L

2005-06-01

193

Macrophage Reporter Cell Assay for Screening Immunopharmacological Activity of Cell Wall-Active Antifungals  

PubMed Central

Antifungal exposure can elicit immunological effects that contribute to activity in vivo, but this activity is rarely screened in vitro in a fashion analogous to MIC testing. We used RAW 264.7 murine macrophages that express a secreted embryonic alkaline phosphatase (SEAP) gene induced by transcriptional activation of NF-?B and activator protein 1 (AP-1) to develop a screen for immunopharmacological activity of cell wall-active antifungal agents. Isolates of Candida albicans and Aspergillus fumigatus that conditionally express genes involved in cell wall synthesis were also tested with the reporter macrophages. We found that growth of fungi in subinhibitory concentrations of glucan synthesis inhibitors (caspofungin and enfumafungin A) or repression of the ?-glucan catalytic subunit of glucan synthase, FKS1, increased macrophage NF-?B/AP-1 activation in a dectin-1-dependent manner. This pattern of activation was also transiently observed with repression of chitin synthesis in C. albicans or when yeast cells were incubated in low concentrations of the chitin synthesis inhibitor nikkomycin Z. PMID:24395226

Lewis, Russell E.; Liao, Guangling; Young, Katherine; Douglas, Cameron

2014-01-01

194

Liposomal Cholesterol Delivery Activates the Macrophage Innate Immune Arm To Facilitate Intracellular Leishmania donovani Killing  

PubMed Central

Leishmania donovani causes visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated with L. donovani infection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-?) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T-cell arm. PMID:24478076

Ghosh, June; Guha, Rajan; Das, Shantanabha

2014-01-01

195

Activation of murine dendritic cells and macrophages induced by Salmonella enterica serovar Typhimurium  

PubMed Central

Macrophages and dendritic cells (DCs) are antigen-presenting cells (APCs), and the direct involvement of both cell types in the immune response to Salmonella has been identified. In this study we analysed the phenotypic and functional changes that take place in murine macrophages and DCs in response to live and heat-killed Salmonella enterica serovar Typhimurium. Both types of cell secreted proinflammatory cytokines and nitric oxide (NO) in response to live and heat-killed salmonellae. Bacterial stimulation also resulted in up-regulation of costimulatory molecules on macrophages and DCs. The expression of major histocompatibility complex (MHC) class II molecules by macrophages and DCs was differentially regulated by interferon (IFN)-? and salmonellae. Live and heat-killed salmonellae as well as lipopolysaccharide (LPS) inhibited the up-regulation of MHC class II expression induced by IFN-? on macrophages but not on DCs. Macrophages as well as DCs presented Salmonella-derived antigen to CD4 T cells, although DCs were much more efficient than macrophages at stimulating CD4 T-cell cytokine release. Macrophages are effective in the uptake and killing of bacteria whilst DCs specialize in antigen presentation. This study showed that the viability of salmonellae was not essential for activation of APCs but, unlike live bacteria, prolonged contact with heat-killed bacteria was necessary to obtain maximal expression of the activation markers studied. PMID:16011515

Kalupahana, Ruwani Sagarika; Mastroeni, Pietro; Maskell, Duncan; Blacklaws, Barbara Ann

2005-01-01

196

Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice.  

PubMed

Overnutrition activates a proinflammatory program in macrophages to induce insulin resistance (IR), but its molecular mechanisms remain incompletely understood. Here, we show that saturated fatty acid and lipopolysaccharide, two factors implicated in high-fat diet (HFD)-induced IR, suppress macrophage CGI-58 expression. Macrophage-specific CGI-58 knockout (MaKO) in mice aggravates HFD-induced glucose intolerance and IR, which is associated with augmented systemic/tissue inflammation and proinflammatory activation of adipose tissue macrophages. CGI-58-deficient macrophages exhibit mitochondrial dysfunction due to defective peroxisome proliferator-activated receptor (PPAR)? signaling. Consequently, they overproduce reactive oxygen species (ROS) to potentiate secretion of proinflammatory cytokines by activating NLRP3 inflammasome. Anti-ROS treatment or NLRP3 silencing prevents CGI-58-deficient macrophages from oversecreting proinflammatory cytokines and from inducing proinflammatory signaling and IR in the cocultured fat slices. Anti-ROS treatment also prevents exacerbation of inflammation and IR in HFD-fed MaKO mice. Our data thus establish CGI-58 as a suppressor of overnutrition-induced NLRP3 inflammasome activation in macrophages. PMID:24703845

Miao, Hongming; Ou, Juanjuan; Ma, Yinyan; Guo, Feng; Yang, Zhenggang; Wiggins, Melvin; Liu, Chaohong; Song, Wenxia; Han, Xianlin; Wang, Miao; Cao, Qiang; Chung, Bik-Ho Florence; Yang, Dan; Liang, Houjie; Xue, Bingzhong; Shi, Hang; Gan, Lixia; Yu, Liqing

2014-04-10

197

Fermentation in traditional medicine: the impact of Woodfordia fruticosa flowers on the immunomodulatory activity, and the alcohol and sugar contents of Nimba arishta.  

PubMed

The impact of Woodfordia fruticosa flowers on the immunomodulatory activity, and alcohol and sugar contents of the ayurvedic drug 'Nimba arishta' was investigated by means of model preparations. The use of Woodfordia flowers in model preparations resulted in a substantial increase of the inhibition of both human complement activity and chemiluminescence generated by zymosan-stimulated human polymorphonuclear leukocytes. It was established that the increased biological activity was not due to microbial interference, but to immuno-active constituents released from the Woodfordia flowers. It was also found that the flowers themselves are not the source of alcohol-producing microorganisms. Experiments performed with yeasts isolated from commercial Nimba arishtas showed, in agreement with empirical findings, significantly raised alcohol content upon addition of Woodfordia. An invertase activity exhibited by Woodfordia flowers may be causative of this effect. PMID:8133651

Kroes, B H; van den Berg, A J; Abeysekera, A M; de Silva, K T; Labadie, R P

1993-10-01

198

The inhibitory neurotransmitter glycine modulates macrophage activity by activation of neutral amino acid transporters.  

PubMed

Glycine, an important inhibitory neurotransmitter in the mammalian central nervous system (CNS), has been shown to modulate peripheral immune cell responses. In that respect, glycine levels are increased in several neuroinflammatory disorders, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, we show that glycine modulates macrophage effector functions implicated in CNS inflammation and in other, related inflammatory conditions. We demonstrate that glycine does not affect the production of reactive oxygen species but stimulates myelin phagocytosis and the production of the proinflammatory mediators nitric oxide (NO) and tumor necrosis factor (TNF)-alpha by rat macrophages. These effects of glycine are not mediated by the glycine receptor (GlyR) or by glycine transporters (GlyTs), as neither the GlyR antagonist strychnine nor the antagonist of GlyT1 (ALX5407) reverses the observed effects. In contrast, 2-aminoisobutyric acid, a substrate of neutral amino acid transporters (NAATs), inhibits the glycine-mediated enhancement of myelin phagocytosis as well as of NO and TNF-alpha production. In conclusion, our findings demonstrate that glycine modulates macrophage function through activation of NAATs. Glycine may thereby influence immunological processes in inflammatory diseases involving macrophage activation and demyelination, including MS and related conditions associated with altered glycine levels. PMID:20623529

Carmans, Sofie; Hendriks, Jerome J A; Thewissen, Kristof; Van den Eynden, Jimmy; Stinissen, Piet; Rigo, Jean-Michel; Hellings, Niels

2010-08-15

199

Combination of Alphavirus replicon particle-based vaccination with immunomodulatory antibodies: therapeutic activity in the B16 melanoma mouse model and immune correlates  

PubMed Central

Induction of potent immune responses to self-antigens remains a major challenge in tumor immunology. We have shown that a vaccine based on alphavirus replicon particles (VRP) activates strong cellular and humoral immunity to tyrosinase related protein-2 (TRP2) melanoma antigen, providing prophylactic and therapeutic effects in stringent mouse models. Here we report that the immunogenicity and efficacy of this vaccine is increased in combination with either antagonist anti-CTLA-4 or agonist anti-GITR immunomodulatory monoclonal antibodies (mAbs). In the challenging therapeutic setting, VRP-TRP2 plus anti-GITR or anti-CTLA-4 mAb induced complete tumor regression respectively in 90% and 50% of mice. These mAbs had similar adjuvant effects in priming an adaptive immune response against the vaccine-encoded antigen, augmenting respectively ~4- and 2-fold the TRP2-specific CD8+ T-cell response and circulating Abs, compared to the vaccine alone. Furthermore, while both mAbs increased the frequency of tumor-infiltrating CD8+ T cells, anti-CTLA-4 mAb also increased the quantity of intra-tumor CD4+Foxp3? T cells expressing the negative co-stimulatory molecule programmed death-1 (PD-1). Concurrent GITR expression on these cells suggests that they might be controlled by anti-GITR mAbs, thus potentially explaining their differential accumulation under the two treatment conditions. These findings indicate that combining immunomodulatory mAbs with alphavirus-based anti-cancer vaccines can provide therapeutic anti-tumor immune responses in a stringent mouse model, suggesting potential utility in clinical trials. They also indicate that tumor-infiltrating CD4+Foxp3?PD-1+ T cells may affect the outcome of immunomodulatory treatments. PMID:24795357

Avogadri, Francesca; Zappasodi, Roberta; Yang, Arvin; Budhu, Sadna; Malandro, Nicole; Hirshhorn-Cymerman, Daniel; Tiwari, Shakuntala; Maughan, Maureen F.; Olmsted, Robert; Wolchok, Jedd D; Merghoub, Taha

2015-01-01

200

Apoprotein E is synthesized and secreted by resident and thioglycollate- elicited macrophages but not by pyran copolymer- or bacillus Calmette- Guerin-activated macrophages  

PubMed Central

Macrophages are active secretory cells that display functionally distinct phenotypes that are regulated by inflammation. We have found that apoprotein E (ApoE), a component of plasma lipoproteins, was synthesized and secreted by resident and nonspecifically stimulated macrophages elicited with thioglycollate broth, but not by activated macrophages obtained from mice treated with bacillus Calmette-Guerin, pyran copolymer, whole Corynebacterium parvum, or bacterial endotoxin. ApoE represented approximately 1% of the newly synthesized protein and approximately 10% of secreted protein of resident and thioglycollate- elicited macrophages. ApoE from thioglycollate-elicited macrophages was indistinguishable from ApoE in mouse plasma lipoproteins, as determined by immunoreactivity, peptide mapping, and molecular weight. When specific antibodies were used to localize cell-associated ApoE, strong immunofluorescence was seen in the Golgi region of resident and thioglycollate-elicited macrophages immediately after removal from the peritoneal cavity, as well as after culture for up to 7 d. In contrast, activated macrophages did not synthesize or secrete ApoE to an appreciable extent and had no immunocytochemically detectable intracellular ApoE. When activated macrophages were cultured in medium containing serum, their activated state, as judged by production of H2O2, declined within 48-72 h in parallel with the induction of synthesis and secretion of ApoE and detection of intracellular ApoE by immunofluorescence. During prolonged culture the rate of synthesis and secretion of ApoE increased in both resident and activated macrophages. Therefore, the synthesis and secretion of ApoE may serve as markers for the functional state of macrophages. PMID:6619735

1983-01-01

201

Effect of lipopolysaccharide on thymidine salvage as related to macrophage activation.  

PubMed Central

Lipopolysaccharide (LPS), known as one of the potent activators of macrophages, has inhibitory effects on the proliferation of normal macrophages and macrophage-like cell lines. We report here that LPS dose- and time-dependently suppressed the tritiated thymidine ([3H]TdR) incorporation into the acid-insoluble fraction with a significant inverse correlation to the tumour necrosis factor-alpha (TNF) production in the J774.1 macrophage cell line. Among the three tested enzymes involved in DNA synthesis, only thymidine kinase (TK) activity decreased progressively in parallel with the decline in [3H]TdR incorporation, reaching 97% inhibition within 12 hr of LPS treatment, while changes in the activities of other two enzymes, DNA polymerase alpha and thymidylate synthase (TS), were less significant. On the other hand, LPS inhibited the cell proliferation only incompletely, as judged by 62% inhibition of cell growth at 36 hr. Even in the experiments done in a TdR-free medium, cell growth was inhibited by LPS to the same extent, suggesting that TK was not directly involved in the proliferation of J774 cells. LPS also inhibited the conversion of TdR to thymidine monophosphate (TMP) in murine peritoneal exudate macrophages (PEM). Thus LPS-induced suppression of TdR salvage related to TNF production is common in both normal and neoplastic macrophages, and therefore may be of potential importance in the process of macrophage activation. PMID:7751001

Harada, Y; Nagao, S; Nakamura, M; Okada, F; Tanigawa, Y

1995-01-01

202

Macrophage Activation: Role of Toll-like Receptors, Nitric Oxide, and Nuclear Factor kappa B  

PubMed Central

Macrophages play an important role in host-defense and inflammation. In response to an immune challenge, macrophages become activated and produce proinflammatory mediators that contribute to nonspecific immunity. The mediators released by activated macrophages include: superoxide anion; reactive nitrogen intermediates, such as nitric oxide and peroxynitrite; bioactive lipids; and cytokines. Although essential to the immune response, overproduction of certain macrophage-derived mediators during an immune challenge or inflammatory response can result in tissue injury and cellular death. The present report is focused on understanding some of the molecular mechanisms used by macrophages to produce reactive nitrogen intermediates in response to immunostimulatory agents such as heat shock protein 60 and bacterial lipopolysaccharide. The role of Toll-like receptors and transcription factors such as nuclear factor kappa B (NF?B) in the innate immune response is also described. A basic understanding of the underlying molecular mechanisms responsible for macrophage activation should serve as a foundation for novel drug development aimed at modulating macrophage activity. PMID:17149431

Billack, Blase

2006-01-01

203

Immunomodulatory and anticancer activities of some novel 2-substituted-6-bromo-3-methylthiazolo[3,2-a]benzimidazole derivatives.  

PubMed

Ethyl 6-bromo-3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate 2 was prepared by the ambient temperature bromination of ethyl 3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate 1. The acid hydrazide 4 was obtained by the reaction of ester 2 with hydrazine hydrate. Treatment of compound 4 with benzaldehyde or 2-thiophenaldehyde yielded the corresponding hydrazones 6a and 6b, respectively, while the reaction of acid hydrazide 4 with ethoxymethylene malononitrile (7a) or with ethyl ethoxymethylene cyanoacetate (7b) in refluxing ethanol afforded pyrazole derivatives 9a and 9b, respectively. Taken together, from the biological investigations compounds 9a and 9b were the most significant inhibitors of LPS-stimulated NO generation from Raw murine macrophage 264.7, and, as another result, compounds 2 and 4 had a weak radical scavenging activity against DPPH radicals. Moreover, 2, 4, and 9a had a concomitant strong cytotoxicity against both colon carcinoma cells (HCT-116) and hepatocellular carcinoma cells (Hep-G2) while 9b showed specific cytotoxicity only against colon carcinoma cells. PMID:19340836

Abdel-Aziz, Hatem A; Gamal-Eldeen, Amira M; Hamdy, Nehal A; Fakhr, Issa M I

2009-04-01

204

Induction of classical activation of macrophage in vitro by water soluble chitin  

NASA Astrophysics Data System (ADS)

The purpose of this study is to understand the effect of chitin on macrophage mediated immunity, which is a significant factor to wound healing and tissue regeneration. In this work, water soluble chitin (WSC) was prepared by re-acetylation of chitosan and was treated with the murine RAW 264.7 macrophage cell lines (ATCC TIB-71). WSC induced classical activation in the RAW 264.7 cells, accompanied by the induction of associated genes. The results suggest that WSC is one of the functional chitin molecules that are responsible for the immune response, especially present in macrophage classical activation.

Jeon, Dong-Won; Ahn, Woong Shick; You, Su Jung; Chae, Gue Tae; Shim, Young Bock; Chun, Heung Jae

2012-12-01

205

Tie2 Signaling Cooperates with TNF to Promote the Pro-Inflammatory Activation of Human Macrophages Independently of Macrophage Functional Phenotype  

PubMed Central

Angiopoietin (Ang) -1 and -2 and their receptor Tie2 play critical roles in regulating angiogenic processes during development, homeostasis, tumorigenesis, inflammation and tissue repair. Tie2 signaling is best characterized in endothelial cells, but a subset of human and murine circulating monocytes/macrophages essential to solid tumor formation express Tie2 and display immunosuppressive properties consistent with M2 macrophage polarization. However, we have recently shown that Tie2 is strongly activated in pro-inflammatory macrophages present in rheumatoid arthritis patient synovial tissue. Here we examined the relationship between Tie2 expression and function during human macrophage polarization. Tie2 expression was observed under all polarization conditions, but was highest in IFN-? and IL-10 –differentiated macrophages. While TNF enhanced expression of a common restricted set of genes involved in angiogenesis and inflammation in GM-CSF, IFN-? and IL-10 –differentiated macrophages, expression of multiple chemokines and cytokines, including CXCL3, CXCL5, CXCL8, IL6, and IL12B was further augmented in the presence of Ang-1 and Ang-2, via Tie2 activation of JAK/STAT signaling. Conditioned medium from macrophages stimulated with Ang-1 or Ang-2 in combination with TNF, sustained monocyte recruitment. Our findings suggest a general role for Tie2 in cooperatively promoting the inflammatory activation of macrophages, independently of polarization conditions. PMID:24404127

García, Samuel; Krausz, Sarah; Ambarus, Carmen A.; Fernández, Beatriz Malvar; Hartkamp, Linda M.; van Es, Inge E.; Hamann, Jörg; Baeten, Dominique L.; Tak, Paul P.; Reedquist, Kris A.

2014-01-01

206

Methylthioadenosine Reprograms Macrophage Activation through Adenosine Receptor Stimulation  

PubMed Central

Regulation of inflammation is necessary to balance sufficient pathogen clearance with excessive tissue damage. Central to regulating inflammation is the switch from a pro-inflammatory pathway to an anti-inflammatory pathway. Macrophages are well-positioned to initiate this switch, and as such are the target of multiple therapeutics. One such potential therapeutic is methylthioadenosine (MTA), which inhibits TNF? production following LPS stimulation. We found that MTA could block TNF? production by multiple TLR ligands. Further, it prevented surface expression of CD69 and CD86 and reduced NF-KB signaling. We then determined that the mechanism of this action by MTA is signaling through adenosine A2 receptors. A2 receptors and TLR receptors synergized to promote an anti-inflammatory phenotype, as MTA enhanced LPS tolerance. In contrast, IL-1? production and processing was not affected by MTA exposure. Taken together, these data demonstrate that MTA reprograms TLR activation pathways via adenosine receptors to promote resolution of inflammation. PMID:25117662

Keyel, Peter A.; Romero, Matthew; Wu, Wenbo; Kwak, Daniel H.; Zhu, Qin; Liu, Xinyu; Salter, Russell D.

2014-01-01

207

Methylthioadenosine reprograms macrophage activation through adenosine receptor stimulation.  

PubMed

Regulation of inflammation is necessary to balance sufficient pathogen clearance with excessive tissue damage. Central to regulating inflammation is the switch from a pro-inflammatory pathway to an anti-inflammatory pathway. Macrophages are well-positioned to initiate this switch, and as such are the target of multiple therapeutics. One such potential therapeutic is methylthioadenosine (MTA), which inhibits TNF? production following LPS stimulation. We found that MTA could block TNF? production by multiple TLR ligands. Further, it prevented surface expression of CD69 and CD86 and reduced NF-KB signaling. We then determined that the mechanism of this action by MTA is signaling through adenosine A2 receptors. A2 receptors and TLR receptors synergized to promote an anti-inflammatory phenotype, as MTA enhanced LPS tolerance. In contrast, IL-1? production and processing was not affected by MTA exposure. Taken together, these data demonstrate that MTA reprograms TLR activation pathways via adenosine receptors to promote resolution of inflammation. PMID:25117662

Keyel, Peter A; Romero, Matthew; Wu, Wenbo; Kwak, Daniel H; Zhu, Qin; Liu, Xinyu; Salter, Russell D

2014-01-01

208

Regulation of Macrophage Function by Adenosine  

PubMed Central

Following its release into the extracellular space in response to metabolic disturbances, the endogenous nucleoside adenosine exerts a range of immunomodulatory effects and cells of the mononuclear phagocyte system are among its major targets. Adenosine governs mononuclear phagocyte functions via 4 G-protein–coupled cell membrane receptors, which are denoted A1, A2A, A2B, and A3 receptors. Adenosine promotes osteoclast differentiation via A1 receptors and alters monocyte to dendritic cell differentiation through A2B receptors. Adenosine downregulates classical macrophage activation mainly through A2A receptors. In contrast A2B receptor activation upregulates alternative macrophage activation. Adenosine promotes angiogenesis, which is mediated by inducing the production of vascular endothelial growth factor by mononuclear phagocytes through A2A, A2B, and A3 receptors. By regulating mononuclear phagocyte function adenosine dictates the course of inflammatory and vascular diseases and cancer. PMID:22423038

Haskó, György; Pacher, Pál

2012-01-01

209

Macrophage activation and nitric oxide production by water soluble components of Hericium erinaceum.  

PubMed

Hericium erinaceum is a medicinal and edible mushroom with anti-microbial and anti-cancer activities. To evaluate the immunoregulatory functions of H. erinaceum, we prepared water extract from H. erinaceum (WEHE) and investigated its ability to activate macrophages and to induce nitric oxide (NO) production in macrophages. Rat peritoneal macrophages stimulated with 1 to 100 mug/ml of WEHE for 24, 48, or 72 h produced NO in a time- and dose-dependent manner. Reverse transcription-polymerase chain reaction demonstrated that WEHE augmented the steady-state level of inducible NO synthase (iNOS) mRNA in both the peritoneal macrophages and a murine macrophage cell-line, RAW 264.7. Electrophoretic mobility shift assay showed that WEHE increased DNA binding activity of the transcription factor NF-kappaB, which is responsible for iNOS gene expression. Furthermore, its trans-acting activity was confirmative as determined by in vitro transfection assay using a reporter gene construct, p(NF-kappaB)(3)-CAT, whose expression is solely regulated by the activity of NF-kappaB. Concomitantly with the activation of NF-kappaB, WEHE markedly decreased intracellular IkappaBalpha level as demonstrated by Western blot assay. These results suggested that WEHE induces iNOS gene expression followed by NO production in macrophages via enhancing the activation of transcription factor, NF-kappaB. PMID:16782550

Son, Chang Gue; Shin, Jang Woo; Cho, Jung Hyo; Cho, Chong Kwan; Yun, Cheol-Heui; Chung, Wantae; Han, Seung Hyun

2006-08-01

210

Activation of mouse peritoneal macrophages by monoclonal antibodies to Mac-1 (complement receptor type 3)  

PubMed Central

Several features of activation of mouse peritoneal macrophages were elicited by 1-2-d exposure to submicrogram concentrations of anti-Mac-1 (M1/70), a rat monoclonal antibody that reacts with the alpha chain of complement receptor type 3 (Mac-1). The changes induced included enhanced capacity to secrete H2O2 when triggered with PMA, decreased secretion of proteins, increased expression of Ia antigen and decreased phagocytosis of particles. These changes closely resembled those induced by rIFN-gamma in type, extent, and time course. The concentration of M1/70 IgG resulting in 50% of the maximal activation of macrophage H2O2-releasing capacity averaged 0.18 +/- 0.03 micrograms/ml. This activation was not blocked by anti-FcR mAb, and could be reproduced with M18/2, a mAb against beta chain of Mac-1, suggesting that a direct ligation of Mac-1 with mAb was responsible for the activation. Neither depletion of T cells nor addition of neutralizing Abs to IFN-gamma or TNF-alpha prevented M1/70-mediated macrophage activation. Moreover, F(ab')2 of M1/70, or plating of macrophages on C3bi-coated surfaces, inhibited the activation of macrophages by rIFN-gamma. These findings suggest that Mac-1 (CR3) may play an important role in macrophage activation. PMID:3102677

1987-01-01

211

HIV1 infection of macrophages is dependent on evasion of innate immune cellular activation  

Microsoft Academic Search

Objective: The cellular innate immune response to HIV-1 is poorly characterized. In view of HIV-1 tropism for macrophages, which can be activated via pattern recognition receptorstotriggerantimicrobialdefences,weinvestigatedinnateimmuneresponsesto HIV-1 by monocyte-derived macrophages. Design: In a model of productive HIV-1 infection, cellular innate immune responses to HIV-1 were investigated, at the level of transcription factor activation, specific gene expression and genome-wide transcriptional profiling.

Jhen Tsang; Benjamin M. Chain; Robert F. Miller; Benjamin L. J. Webb; Wendy Barclay; Greg J. Towers; David R. Katz; Mahdad Noursadeghi

2009-01-01

212

Translational Regulation of Specific mRNAs Controls Feedback Inhibition and Survival during Macrophage Activation  

PubMed Central

For a rapid induction and efficient resolution of the inflammatory response, gene expression in cells of the immune system is tightly regulated at the transcriptional and post-transcriptional level. The control of mRNA translation has emerged as an important determinant of protein levels, yet its role in macrophage activation is not well understood. We systematically analyzed the contribution of translational regulation to the early phase of the macrophage response by polysome fractionation from mouse macrophages stimulated with lipopolysaccharide (LPS). Individual mRNAs whose translation is specifically regulated during macrophage activation were identified by microarray analysis. Stimulation with LPS for 1 h caused translational activation of many feedback inhibitors of the inflammatory response including NF-?B inhibitors (Nfkbid, Nfkbiz, Nr4a1, Ier3), a p38 MAPK antagonist (Dusp1) and post-transcriptional suppressors of cytokine expression (Zfp36 and Zc3h12a). Our analysis showed that their translation is repressed in resting and de-repressed in activated macrophages. Quantification of mRNA levels at a high temporal resolution by RNASeq allowed us to define groups with different expression patterns. Thereby, we were able to distinguish mRNAs whose translation is actively regulated from mRNAs whose polysomal shifts are due to changes in mRNA levels. Active up-regulation of translation was associated with a higher content in AU-rich elements (AREs). For one example, Ier3 mRNA, we show that repression in resting cells as well as de-repression after stimulation depends on the ARE. Bone-marrow derived macrophages from Ier3 knockout mice showed reduced survival upon activation, indicating that IER3 induction protects macrophages from LPS-induced cell death. Taken together, our analysis reveals that translational control during macrophage activation is important for cellular survival as well as the expression of anti-inflammatory feedback inhibitors that promote the resolution of inflammation. PMID:24945926

Schott, Johanna; Reitter, Sonja; Philipp, Janine; Haneke, Katharina; Schäfer, Heiner; Stoecklin, Georg

2014-01-01

213

Transcellular regulation of cell respiration by nitric oxide generated by activated macrophages  

Microsoft Academic Search

A macrophage cell line (J774), activated with interferon-? and endotoxin to express the inducible form of NO synthase (iNOS), immediately inhibited the cellular respiration of co-incubated L-929 fibroblasts or non-activated J774 macrophages. The inhibition was potent, rapid and reversible when the NO was removed by adding oxyhaemoglobin or by inhibiting iNOS. Exogenously added NO also rapidly and reversibly inhibited cellular

Guy C Brown; Neale Foxwell; Salvador Moncada

1998-01-01

214

Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis.  

PubMed

Atherosclerosis is a chronic inflammatory disorder of the arterial wall leading to coronary artery disease, stroke, and peripheral arterial disease. Along with the discovery of dipeptidyl peptidase 4 (DPP4) as a therapeutic target in type 2 diabetes, a role for DPP4 in atherosclerosis is emerging. However, until now the expression and role of other DPPs such as DPP8 and DPP9 in atherosclerosis is completely unknown. In the present study, we first investigated DPP expression in human atherosclerotic plaques. DPP4 could only be observed in endothelial cells of plaque neovessels in half of the specimens. In contrast, DPP8 and DPP9 were abundantly present in macrophage-rich regions of plaques. We then focused on DPP expression and function in macrophage differentiation, activation and apoptosis. DPP8/9 was responsible for most of the DPP activity in macrophages. During monocyte to macrophage differentiation, DPP9 was upregulated both in pro-inflammatory M1 (3.7 ± 0.3-fold increase) and anti-inflammatory M2 macrophages (3.7 ± 0.4-fold increase) whereas DPP8 expression remained unchanged. Inhibition of DPP8/9 activity with compound 1G244 reduced activation of M1 macrophages (IL-6 88 ± 16 vs. 146 ± 19 pg/ml; TNF? 3.8 ± 1.0 vs. 6.6 ± 1.9 ng/ml in treated vs. untreated cells), but not of M2 macrophages. Likewise, DPP9 silencing reduced TNF? and IL-6 secretion, pointing to a DPP9-mediated effect of the inhibitor. DPP8/9 inhibition also enhanced macrophage apoptosis (15 ± 4 vs. 7 ± 3 % in untreated cells). Because pro-inflammatory macrophages play a key role in atherogenesis, plaque rupture and subsequent infarction, DPP9 inhibition might provide interesting therapeutic prospects in reducing atherosclerosis and/or in the prevention of plaque rupture. PMID:23608773

Matheeussen, Veerle; Waumans, Yannick; Martinet, Wim; Van Goethem, Sebastiaan; Van der Veken, Pieter; Scharpé, Simon; Augustyns, Koen; De Meyer, Guido R Y; De Meester, Ingrid

2013-05-01

215

Classical and alternative macrophage activation in the lung following ozone-induced oxidative stress  

SciTech Connect

Ozone is a pulmonary irritant known to cause oxidative stress, inflammation and tissue injury. Evidence suggests that macrophages play a role in the pathogenic response; however, their contribution depends on the mediators they encounter in the lung which dictate their function. In these studies we analyzed the effects of ozone-induced oxidative stress on the phenotype of alveolar macrophages (AM). Exposure of rats to ozone (2 ppm, 3 h) resulted in increased expression of 8-hydroxy-2?-deoxyguanosine (8-OHdG), as well as heme oxygenase-1 (HO-1) in AM. Whereas 8-OHdG was maximum at 24 h, expression of HO-1 was biphasic increasing after 3 h and 48–72 h. Cleaved caspase-9 and beclin-1, markers of apoptosis and autophagy, were also induced in AM 24 h post-ozone. This was associated with increased bronchoalveolar lavage protein and cells, as well as matrix metalloproteinase (MMP)-2 and MMP-9, demonstrating alveolar epithelial injury. Ozone intoxication resulted in biphasic activation of the transcription factor, NF?B. This correlated with expression of monocyte chemotactic protein?1, inducible nitric oxide synthase and cyclooxygenase?2, markers of proinflammatory macrophages. Increases in arginase-1, Ym1 and galectin-3 positive anti-inflammatory/wound repair macrophages were also observed in the lung after ozone inhalation, beginning at 24 h (arginase-1, Ym1), and persisting for 72 h (galectin-3). This was associated with increased expression of pro-surfactant protein-C, a marker of Type II cell proliferation and activation, important steps in wound repair. These data suggest that both proinflammatory/cytotoxic and anti-inflammatory/wound repair macrophages are activated early in the response to ozone-induced oxidative stress and tissue injury. -- Highlights: ? Lung macrophages are highly sensitive to ozone induced oxidative stress. ? Ozone induces autophagy and apoptosis in lung macrophages. ? Proinflammatory and wound repair macrophages are activated early after ozone. ? Oxidative stress may contribute to regulating macrophage phenotype and function.

Sunil, Vasanthi R., E-mail: sunilva@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Patel-Vayas, Kinal; Shen, Jianliang [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)] [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ (United States)] [Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)] [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)

2012-09-01

216

Metabolic Characterization of Leishmania major Infection in Activated and Nonactivated Macrophages.  

PubMed Central

Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining 1H NMR spectroscopy with multi- and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies. PMID:22724526

2012-01-01

217

Metabolic characterization of Leishmania major infection in activated and nonactivated macrophages.  

PubMed

Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining 1H NMR spectroscopy with multi- and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies. PMID:22724526

Lamour, Sabrina D; Choi, Beak-San; Keun, Hector C; Müller, Ingrid; Saric, Jasmina

2012-08-01

218

Chitosan-induced phospholipase A2 activation and arachidonic acid mobilization in P388D1 macrophages  

E-print Network

). Collectively, the results of this work establish chitosan as a novel macrophage- activating factor that elicits and macrophages [4]. Histological ˘ndings suggest that these com- pounds stimulate the migration factor, interleu- kin-1 and colony-stimulating factor by macrophages and to induce immunologic adjuvant e

Dennis, Edward A.

219

Regulation of Delayed Prostaglandin Production in Activated P388D1 Macrophages by Group IV Cytosolic and Group V Secretory  

E-print Network

mobilization and prostaglandin E2 (PGE2) production in the macrophage-like cell line P388D1. When a new cloneRegulation of Delayed Prostaglandin Production in Activated P388D1 Macrophages by Group IV of prostaglandins by major immunoinflammatory cells such as macrophages and mast cells usually occur in two phases

Dennis, Edward A.

220

Unfolding the relationship between secreted molecular chaperones and macrophage activation states  

PubMed Central

Over the last 20 years, it has emerged that many molecular chaperones and protein-folding catalysts are secreted from cells and function, somewhat in the manner of cytokines, as pleiotropic signals for a variety of cells, with much attention being focused on the macrophage. During the last decade, it has become clear that macrophages respond to bacterial, protozoal, parasitic and host signals to generate phenotypically distinct states of activation. These activation states have been termed ‘classical’ and ‘alternative’ and represent not a simple bifurcation in response to external signals but a range of cellular phenotypes. From an examination of the literature, the hypothesis is propounded that mammalian molecular chaperones are able to induce a wide variety of alternative macrophage activation states, and this may be a system for relating cellular or tissue stress to appropriate macrophage responses to restore homeostatic equilibrium. PMID:18958583

Henderson, Samantha

2008-01-01

221

Human activated macrophages and hypoxia: a comprehensive review of the literature  

PubMed Central

Macrophages accumulate in poorly vascularised and hypoxic sites including solid tumours, wounds and sites of infection and inflammation where they can be exposed to low levels of oxygen for long periods. Up to date, different studies have shown that a number of transcription factors are activated by hypoxia which in turn activate a broad array of mitogenic, pro-invasive, pro-angiogenic, and pro-metastatic genes. On the other hand, macrophages respond to hypoxia by up-regulating several genes which are chief factors in angiogenesis and tumorigenesis. Therefore, in this review article we focus mainly on the role of macrophages during inflammation and discuss their response to hypoxia by regulating a diverse array of transcription factors. We also review the existing literatures on hypoxia and its cellular and molecular mechanism which mediates macrophages activation. PMID:25691922

Sotoodehnejadnematalahi, Fattah; Burke, Bernard

2014-01-01

222

Construction and expression of a recombinant eukaryotic expression plasmid containing the preS1-preS2-S genes of hepatitis B virus and the granulocyte-macrophage colony stimulating factor gene: A study of its immunomodulatory effects  

PubMed Central

A total of 10–20% of the population remains unresponsive or weakly responsive to hepatitis B vaccine, which is composed of hepatitis B surface antigen HBsAg (S protein). Therefore, it is necessary to develop a hepatitis B vaccine with a better penetrating and responsive rate. In the present study, a plasmid pVAX1-L-GM was constructed and its immunomodulatory effect of as hepatitis B virus (HBV) DNA vaccine was analyzed through the immunization of BALB/c mice. Immune responses were measured after immunization by anti-HBsAg, proliferation of splenocytes, the number of CD4+ and CD8+ molecules, CTL cytotoxicity, cytokines of IFN-? and IL-2 secretion assays. Following the immunization, mice in the pVAX1-L-GM group produced antibody 2 weeks earlier compared to the control plasmid pVAX1 and pVAX1HBsAg groups and antibody levels showed significant differences. Enhanced HBsAg-specific splenocyte proliferation as well as specific cytotoxic activities of splenic CTLs were also detected. Furthermore, pVAX1-L-GM plasmid increased the number of CD4+ and CD8+ molecules on the surface of the spleen T cell and the level of IFN-?, IL-2 secretion. pVAX1-L-GM induced a specific immune response in mice and enhanced the immune effect. Thus, a foundation was laid for developing immunogenicity of a better prevention and treatment of HBV via a hepatitis B vaccine. PMID:24648930

GONG, JUN-YUAN; LIU, XIN; DONG, YAN; ZHOU, TIAN-HONG; LI, JUN-WU

2013-01-01

223

Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability  

PubMed Central

Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14hi??TIMP-3lo rabbit foam cells are more invasive and more prone to apoptosis than MMP-14lo??TIMP-3hi cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction. PMID:25301980

Johnson, Jason L.; Jenkins, Nicholas P.; Huang, Wei-Chun; Sala-Newby, Graciela B.; Scholtes, Vincent P. W.; Moll, Frans L.; Pasterkamp, Gerard; Newby, Andrew C.

2014-01-01

224

Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis  

PubMed Central

Macrophages regulate innate immunity to maintain intestinal homeostasis and play pathological roles in intestinal inflammation. Activation of the epidermal growth factor receptor (EGFR) promotes cellular proliferation, differentiation, survival and wound closure in several cell types. However, the impact of EGFR in macrophages remains unclear. This study was to investigate whether EGFR activation in macrophages regulates cytokine production and intestinal inflammation. We found that EGFR was activated in colonic macrophages in mice with dextran sulfate sodium (DSS)-induced colitis and in patients with ulcerative colitis. DSS-induced acute colitis was ameliorated and recovery from colitis was promoted in Egfrfl/flLysM-Cre mice with myeloid cell-specific deletion of EGFR, compared with LysM-Cre mice. DSS treatment increased IL-10 and TNF levels during the acute phase of colitis, and increased IL-10 but reduced TNF levels during the recovery phase in Egfrfl/flLysM-Cre mice. An anti-IL-10 neutralizing antibody abolished these effects of macrophage-specific EGFR deletion on DSS-induced colitis in Egfrfl/flLysM-Cre mice. LPS stimulated EGFR activation and inhibition of EGFR kinase activity enhanced LPS-stimulated NF-?B activation in RAW 264.7 macrophages. Furthermore, induction of IL-10 production by EGFR kinase-blocked RAW 264.7 cells, in response to LPS plus IFN-?, correlated with decreased TNF production. Thus, although selective deletion of EGFR in macrophages leads to increases in both pro- and anti-inflammatory cytokines in response to inflammatory stimuli, the increase in the IL-10 level plays a role in suppressing pro-inflammatory cytokine production, resulting in protection of mice from intestinal inflammation. These results reveal an integrated response of macrophages regulated by EGFR in intestinal inflammatory disorders. PMID:24391216

Lu, Ning; Wang, Lihong; Cao, Hailong; Liu, Liping; Van Kaer, Luc; Washington, Mary K.; Rosen, Michael J.; Dubé, Philip E.; Wilson, Keith T.; Ren, Xiubao; Hao, Xishan; Polk, D. Brent; Yan, Fang

2014-01-01

225

Augmentation of macrophage growth-stimulating activity of lipids by their peroxidation  

SciTech Connect

Previously, we reported that some kinds of lipids (cholesterol esters, triglycerides, and some negatively charged phospholipids) that are constituents of lipoproteins or cell membranes induce growth of peripheral macrophages in vitro. In this paper, we examined the effect of peroxidation of lipids on their macrophage growth-stimulating activity because lipid peroxidation is observed in many pathological states such as inflammation. When phosphatidylserine, one of the phospholipids with growth-stimulating activity, was peroxidized by UV irradiation, its macrophage growth-stimulating activity was augmented in proportion to the extent of its peroxidation. The activity of phosphatidylethanolamine was also increased by UV irradiation. On the other hand, phosphatidylcholine or highly unsaturated free fatty acids, such as arachidonic acid and eicosapentaenoic acid, did not induce macrophage growth irrespective of whether they were peroxidized. The augmented activity of UV-irradiated phosphatidylserine was not affected by the coexistence of an antioxidant, vitamin E or BHT. These results suggest that some phospholipids included in damaged cells or denatured lipoproteins which are scavenged by macrophages in vivo may induce growth of peripheral macrophages more effectively when they are peroxidized by local pathological processes.

Yui, S.; Yamazaki, M. (Teikyo Univ., Kanagawa (Japan))

1990-02-15

226

Hyper-Inflammation and Skin Destruction Mediated by Rosiglitazone Activation of Macrophages in IL-6 Deficiency  

PubMed Central

Injury initiates recruitment of macrophages to support tissue repair; however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the peroxisome proliferation–activated receptor-? agonist, rosiglitazone (Rosi), a medication recently reintroduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates pro-inflammatory macrophages. This is observed in both IL-6-deficient mice and control wild-type mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6 deficiency in human diseases. IL-6 deficiency when combined with Rosi-mediated upregulation of suppressor of cytokine signaling 3 leads to an altered ratio of nuclear signal transducer and activator of transcription 3/NF-?B that allows hyper-induction of inducible nitric oxide synthase (iNOS). Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6 deficiency. PMID:25184961

Das, Lopa M; Rosenjack, Julie; Au, Liemin; Galle, Pia S; Hansen, Morten B; Cathcart, Martha K; McCormick, Thomas S; Cooper, Kevin D; Silverstein, Roy L; Lu, Kurt Q

2015-01-01

227

Effect of macrophage classical (M1) activation on implant-adherent macrophage interactions with Staphylococcus epidermidis: A murine in vitro model system  

PubMed Central

A model in vitro system was developed for eliciting classical (M1) activation of surface-adherent murine macrophages, which was then used to study the interaction of the M1 macrophages with Staphylococcus epidermidis. Glass substrata were first covalently grafted with a mixture of methoxy- and biotin-terminated silanated polyethylene glycol. Interferon (IFN)-? and/or lipopolysaccharide (LPS), ligands known to induce the highly microbicidal M1 activation state in macrophages, were biotinylated and immobilized by way of a streptavidin intermediate to the biotin-PEG base substratum. Assessment of mouse bone marrow-derived macrophage (BMDM) interleukin (IL)-12(p40) and nitric oxide response to the fabricated surfaces confirmed that the model system achieved activation of adherent macrophage: IFN-?-presenting surfaces primed cells for M1 activation, LPS-presenting surfaces elicited innate activation, and surface presenting a combination of IFN-? and LPS induced M1 activation. The phagocytic and microbicidal capacity of activated, surface-adherent BMDM was evaluated using S. epidermidis, a bacterial species prevalent in implant-associated infections. Results indicate that M1 activation of implant-adherent macrophages trends towards diminishing their phagocytic capacity, but enhances their microbicidal capacity for S. epidermidis. PMID:22581669

Park, Kyung R.; Bryers, James D.

2012-01-01

228

Arginase activity in alternatively activated macrophages protects PI3Kp110? deficient mice from dextran sodium sulfate induced intestinal inflammation.  

PubMed

Alternatively activated or M2 macrophages have been reported to protect mice from intestinal inflammation, but the mechanism of protection has not been elucidated. In this study, we demonstrate that mice deficient in the p110? catalytic subunit activity of class I phosphatidylinositol 3-kinase (PI3Kp110?) have increased clinical disease activity and histological damage during dextran sodium sulfate (DSS) induced colitis. Increased disease severity in PI3Kp110?-deficient mice is dependent on professional phagocytes and correlates with reduced numbers of arginase I+ M2 macrophages in the colon and increased production of inflammatory nitric oxide. We further demonstrate that PI3Kp110?-deficient macrophages are defective in their ability to induce arginase I when skewed to an M2 phenotype with IL-4. Importantly, adoptive transfer of IL-4-treated macrophages derived from WT mice, but not those from PI3Kp110?-deficient mice, protects mice during DSS-induced colitis. Moreover, M2 macrophages mediated protection is lost when mice are cotreated with inhibitors that block arginase activity or during adoptive transfer of arginase I deficient M2 macrophages. Taken together, our data demonstrate that arginase I activity is required for M2 macrophages mediated protection during DSS-induced colitis in PI3Kp110?-deficient mice. PMID:25124254

Weisser, Shelley B; Kozicky, Lisa K; Brugger, Hayley K; Ngoh, Eyler N; Cheung, Bonnie; Jen, Roger; Menzies, Susan C; Samarakoon, Asanga; Murray, Peter J; Lim, C James; Johnson, Pauline; Boucher, Jean-Luc; van Rooijen, Nico; Sly, Laura M

2014-11-01

229

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome  

PubMed Central

Inflammasomes are innate immune sensors that respond to pathogen and damage-associated signals with caspase-1 activation, IL-1? and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the Cryopyrin Associated Periodic Syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1? oversecretion, led to successful treatment with IL-1 blocking agents1. Herein, we report a de novo missense mutation, c.1009A>T, p.Thr337Ser, in the nucleotide-binding domain of inflammasome component NLRC4 (IPAF/CARD12) that causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1? and IL-18, the latter exceeding levels in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in transduced cells and increased production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests novel targets for therapy. PMID:25217959

Canna, Scott W.; de Jesus, Adriana Almeida; Gouni, Sushanth; Brooks, Stephen R.; Marrero, Bernadette; Liu, Yin; DiMattia, Michael A.; Zaal, Kristien J.M.; Montealegre Sanchez, Gina A.; Kim, Hanna; Chapelle, Dawn; Plass, Nicole; Huang, Yan; Villarino, Alejandro V.; Biancotto, Angelique; Fleisher, Thomas A.; Duncan, Joseph A.; O’Shea, John J; Benseler, Susanne; Grom, Alexei; Deng, Zuoming; Laxer, Ronald M; Goldbach-Mansky, Raphaela

2014-01-01

230

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.  

PubMed

Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1? and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1? oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1? and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy. PMID:25217959

Canna, Scott W; de Jesus, Adriana A; Gouni, Sushanth; Brooks, Stephen R; Marrero, Bernadette; Liu, Yin; DiMattia, Michael A; Zaal, Kristien J M; Sanchez, Gina A Montealegre; Kim, Hanna; Chapelle, Dawn; Plass, Nicole; Huang, Yan; Villarino, Alejandro V; Biancotto, Angelique; Fleisher, Thomas A; Duncan, Joseph A; O'Shea, John J; Benseler, Susanne; Grom, Alexei; Deng, Zuoming; Laxer, Ronald M; Goldbach-Mansky, Raphaela

2014-10-01

231

Immunomodulatory Activity of Dietary Fiber: Arabinoxylan and Mixed-Linked Beta-Glucan Isolated from Barley Show Modest Activities in Vitro  

PubMed Central

High intake of dietary fiber is claimed to protect against development of colorectal cancer. Barley is a rich source of dietary fiber, and possible immunomodulatory effects of barley polysaccharides might explain a potential protective effect. Dietary fiber was isolated by extraction and enzyme treatment. A mixed-linked ?-glucan (WSM-TPX, 96.5% ?-glucan, Mw 886 kDa), an arabinoxylan (WUM-BS-LA, 96.4% arabinoxylan, Mw 156 kDa), a mixed-linked ?-glucan rich fraction containing 10% arabinoxylan (WSM-TP) and an arabinoxylan rich fraction containing 30% mixed-linked ?-glucan (WUM-BS) showed no significant effect on IL-8 secretion and proliferation of two intestinal epithelial cell lines, Caco-2 and HT-29, and had no significant effect on the NF-?B activity in the monocytic cell line U937-3?B-LUC. Further enriched arabinoxylan fractions (WUM-BS-LA) from different barley varieties (Tyra, NK96300, SB94897 and CDCGainer) were less active than the mixed-linked ?-glucan rich fractions (WSM-TP and WSM-TPX) in the complement-fixing test. The mixed-linked ?-glucan rich fraction from NK96300 and CDCGainer showed similar activities as the positive control while mixed-linked ?-glucan rich fractions from Tyra and SB94897 were less active. From these results it is concluded that the isolated high molecular weight mixed-linked ?-glucans and arabinoxylans from barley show low immunological responses in selected in vitro test systems and thus possible anti-colon cancer effects of barley dietary fiber cannot be explained by our observations. PMID:21340001

Samuelsen, Anne Berit; Rieder, Anne; Grimmer, Stine; Michaelsen, Terje E.; Knutsen, Svein H.

2011-01-01

232

Activation of Adipose Tissue Macrophages in Obese Mice does not Require Lymphocytes  

PubMed Central

Macrophages which infiltrate adipose tissue and secrete pro-inflammatory cytokines may be responsible for obesity-induced insulin resistance. However, why macrophages migrate into adipose tissue and become activated remains unknown, though some studies suggest this may be regulated by T and B lymphocytes. In the present study, we test whether T and B lymphocytes and NK cells are necessary for the obesity-induced activation of macrophages in adipose tissue. NOD/SCID/IL2-receptor gamma-chain knockout (NSG) mice, which lack mature T and B lymphocytes and NK cells, were made obese by selectively reducing litters and weaning onto a high-fat diet. Mice were then maintained on the diet for 10-11 weeks. Adipose tissue from obese NSG mice had more activated macrophages than non-obese mice. These macrophages were found in “crown like structures” surrounding adipocytes, and expressed higher levels of the inflammatory cytokine TNF?. However, obesity did not impair glucose tolerance in the NSG mice. These studies demonstrate that T and B lymphocytes and NK cells are not necessary for adipose tissue macrophage activation in obese mice. T and B lymphocytes and/or NK cells may be necessary for the development of obesity-induced impaired glucose tolerance. PMID:23754826

Behan, JW; Ehsanipour, EA; Sheng, X; Pramanik, R; Wang, Xingchao; Hsieh, Yao-Te; Kim, Yong-Mi; Mittelman, Steven D.

2012-01-01

233

ROS-Responsive Activatable Photosensitizing Agent for Imaging and Photodynamic Therapy of Activated Macrophages  

PubMed Central

The optical properties of macrophage-targeted theranostic nanoparticles (MacTNP) prepared from a Chlorin e6 (Ce6)-hyaluronic acid (HA) conjugate can be activated by reactive oxygen species (ROS) in macrophage cells. MacTNP are nonfluorescent and nonphototoxic in their native state. However, when treated with ROS, especially peroxynitrite, they become highly fluorescent and phototoxic. In vitro cell studies show that MacTNP emit near-infrared (NIR) fluorescence inside activated macrophages. The NIR fluorescence is quenched in the extracellular environment. MacTNP are nontoxic in macrophages up to a Ce6 concentration of 10 ?M in the absence of light. However, MacTNP become phototoxic upon illumination in a light dose-dependent manner. In particular, significantly higher phototoxic effect is observed in the activated macrophage cells compared to human dermal fibroblasts and non-activated macrophages. The ROS-responsive MacTNP, with their high target-to-background ratio, may have a significant potential in selective NIR fluorescence imaging and in subsequent photodynamic therapy of atherosclerosis with minimum side effects. PMID:24396511

Kim, Hyunjin; Kim, Youngmi; Kim, In-Hoo; Kim, Kyungtae; Choi, Yongdoo

2014-01-01

234

Effect of cinnamon water extract on monocyte-to-macrophage differentiation and scavenger receptor activity  

PubMed Central

Background Water soluble cinnamon extract has been shown to increase insulin sensitivity and modulate macrophage activation, a desirable trait for the management of obesity or atherosclerosis. Our present study investigated whether cinnamon water extract (CWE) may influence the differentiation of monocytes into macrophages and the activity of macrophage scavenger receptors, commonly observed in atherosclerotic lesions. Methods We investigated the effect of CWE on the expression of various surface markers and the uptake of acetylated low density lipoprotein (LDL) in phorbol-12-myristate-13-acetate (PMA)-stimulated THP-1 cells. The protein levels of PMA or macrophage-colony stimulating factor (M-CSF)-stimulated type 1 macrophage scavenger receptor (SRA) were analyzed. Finally, the role of extracellar signal-related kinase (ERK) 1/2 in SRA synthesis and the effect of CWE on PMA-stimulated ERK1/2 were determined. Results CWE inhibited the differentiation of monocyte by decreasing the expression of CD11b, CD36 and SRA and the uptake of acetyl LDL. CWE suppressed the upregulation of SRA by M-CSF and modulated ERK1/2 activity, which was required for PMA-induced SRA synthesis. Conclusions Our results demonstrate that CWE was able to interfere with monocyte differentiation and macrophage scavenger activity, indicating its potential in preventing the development of atherosclerotic lesions. PMID:24602512

2014-01-01

235

Hydroxysafflor yellow A attenuates ischemia/reperfusion-induced liver injury by suppressing macrophage activation.  

PubMed

Hydroxysafflor yellow A (HSYA), a major constituent in the hydrophilic fraction of the safflower plant, can retard the progress of hepatic fibrosis. However, the anti-inflammatory properties and the underlying mechanisms of HSYA on I/R-induced acute liver injury are unknown. Inhibiting macrophage activation is a potential strategy to treat liver ischemia/reperfusion (I/R) injury. In this study, we investigated the therapeutic effect of HSYA on liver I/R injury and the direct effect of HSYA on macrophage activation following inflammatory conditions. The therapeutic effects of HSYA on I/R injury were tested in vivo using a mouse model of segmental (70%) hepatic ischemia. The mechanisms of HSYA were examined in vitro by evaluating migration and the cytokine expression profile of the macrophage cell line RAW264.7 exposed to acute hypoxia and reoxygenation (H/R). Results showed that mice pretreated with HSYA had reduced serum transaminase levels, attenuated inflammation and necrosis, reduced expression of inflammatory cytokines, and less macrophage recruitment following segmental hepatic ischemia. In vitro HSYA pretreated RAW264.7 macrophages displayed reduced migratory response and produced less inflammatory cytokines. In addition, HSYA pretreatment down-regulated the expression of matrix matalloproteinase-9 and reactive oxygen species, and inhibited NF-?B activation and P38 phosphorylation in RAW264.7 cells. Thus, these data suggest that HSYA can reduce I/R-induced acute liver injury by directly attenuating macrophage activation under inflammatory conditions. PMID:24966974

Jiang, Shujun; Shi, Zhen; Li, Changyong; Ma, Chunlei; Bai, Xianyong; Wang, Chaoyun

2014-01-01

236

In vitro cytotoxicity of mouse macrophages activated by coculture with syngeneic sarcoma cells.  

PubMed

Normal resident peritoneal macrophages from C3D2 (C3H/Tif X DBA/2) F1 mice were activated in vitro by culturing with semisyngeneic tumour cells. The tumour cells originated from a methylcholanthrene-induced sarcoma (MC1M) growing in vivo in ascites form. Macrophage-mediated cytotoxicity was evaluated after 5 days of in vitro culture, using five different target cells. Semisyngeneic (L 929), allogeneic (B16 melanoma), and xenogeneic (HeLa) tumour cell lines and normal allogeneic fibroblast cell lines (3T3, 3T6) were tested. The morphology and kinetics of the cytotoxicity reaction were studied by scanning electron microscopy and compared with release of radioactivity from 14C-thymidine-labelled target cells. The activated macrophages were able to kill the semisyngeneic, allogeneic, and xenogeneic tumour cell lines tested under conditions that did not affect normal fibroblasts. The requirement for T cells during activation of the macrophages was also tested. The cytotoxicity decreased markedly when T cells were removed from the macrophage cultures before activation or when macrophages from nude mice were used in the experiments. PMID:6983715

Olstad, R; Kaplan, G; Seljelid, R

1982-11-01

237

Critical role of methylglyoxal and AGE in mycobacteria-induced macrophage apoptosis and activation.  

PubMed

Apoptosis and activation of macrophages play an important role in the host response to mycobacterial infection involving TNF-alpha as a critical autocrine mediator. The underlying mechanisms are still ill-defined. Here, we demonstrate elevated levels of methylglyoxal (MG), a small and reactive molecule that is usually a physiological product of various metabolic pathways, and advanced glycation end products (AGE) during mycobacterial infection of macrophages, leading to apoptosis and activation of macrophages. Moreover, we demonstrate abundant AGE in pulmonary lesions of tuberculosis (TB) patients. Global gene expression profiling of MG-treated macrophages revealed a diverse spectrum of functions induced by MG, including apoptosis and immune response. Our results not only provide first evidence for the involvement of MG and AGE in TB, but also form a basis for novel intervention strategies against infectious diseases in which MG and AGE play critical roles. PMID:17183656

Rachman, Helmy; Kim, Nayoung; Ulrichs, Timo; Baumann, Sven; Pradl, Lydia; Nasser Eddine, Ali; Bild, Matthias; Rother, Marion; Kuban, Ralf-Jürgen; Lee, Jong Seok; Hurwitz, Robert; Brinkmann, Volker; Kosmiadi, George A; Kaufmann, Stefan H E

2006-01-01

238

Critical Role of Methylglyoxal and AGE in Mycobacteria-Induced Macrophage Apoptosis and Activation  

PubMed Central

Apoptosis and activation of macrophages play an important role in the host response to mycobacterial infection involving TNF-? as a critical autocrine mediator. The underlying mechanisms are still ill-defined. Here, we demonstrate elevated levels of methylglyoxal (MG), a small and reactive molecule that is usually a physiological product of various metabolic pathways, and advanced glycation end products (AGE) during mycobacterial infection of macrophages, leading to apoptosis and activation of macrophages. Moreover, we demonstrate abundant AGE in pulmonary lesions of tuberculosis (TB) patients. Global gene expression profiling of MG-treated macrophages revealed a diverse spectrum of functions induced by MG, including apoptosis and immune response. Our results not only provide first evidence for the involvement of MG and AGE in TB, but also form a basis for novel intervention strategies against infectious diseases in which MG and AGE play critical roles. PMID:17183656

Rachman, Helmy; Kim, Nayoung; Ulrichs, Timo; Baumann, Sven; Pradl, Lydia; Eddine, Ali Nasser; Bild, Matthias; Rother, Marion; Kuban, Ralf-Jürgen; Lee, Jong Seok; Hurwitz, Robert; Brinkmann, Volker; Kosmiadi, George A.; Kaufmann, Stefan H.E.

2006-01-01

239

METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages.  

PubMed

Cytokines are involved in many functions of the immune system including initiating, amplifying and resolving immune responses. Through bioinformatics analyses of a comprehensive database of gene expression (BIGE: Body Index of Gene Expression) we observed that a small secreted protein encoded by a poorly characterized gene called meteorin-like (METRNL), is highly expressed in mucosal tissues, skin and activated macrophages. Further studies indicate that Metrnl is produced by Alternatively Activated Macrophages (AAM) and M-CSF cultured bone marrow macrophages (M2-like macrophages). In the skin, METRNL is expressed by resting fibroblasts and IFN?-treated keratinocytes. A screen of human skin-associated diseases showed significant over-expression of METRNL in psoriasis, prurigo nodularis, actinic keratosis and atopic dermatitis. METRNL is also up-regulated in synovial membranes of human rheumatoid arthritis. Taken together, these results indicate that Metrnl represents a novel cytokine, which is likely involved in both innate and acquired immune responses. PMID:25486603

Ushach, Irina; Burkhardt, Amanda M; Martinez, Cynthia; Hevezi, Peter A; Gerber, Peter Arne; Buhren, Bettina Alexandra; Schrumpf, Holger; Valle-Rios, Ricardo; Vazquez, Monica I; Homey, Bernhard; Zlotnik, Albert

2015-02-01

240

Functional activity of monocytes and macrophages in HTLV-1 infected subjects.  

PubMed

The Human T lymphotropic virus type-1 (HTLV-1) infects predominantly T cells, inducing proliferation and lymphocyte activation. Additionally, HTLV-1 infected subjects are more susceptible to other infections caused by other intracellular agents. Monocytes/macrophages are important cells in the defense against intracellular pathogens. Our aims were to determine the frequency of monocytes subsets, expression of co-stimulatory molecules in these cells and to evaluate microbicidal ability and cytokine and chemokine production by macrophages from HTLV-1 infected subjects. Participants were 23 HTLV-1 carriers (HC), 22 HAM/TSP patients and 22 healthy subjects (HS) not infected with HTLV-1. The frequencies of monocyte subsets and expression of co-stimulatory molecules were determined by flow cytometry. Macrophages were infected with L. braziliensis or stimulated with LPS. Microbicidal activity of macrophages was determined by optic microscopy. Cytokines/chemokines from macrophage supernatants were measured by ELISA. HAM/TSP patients showed an increase frequency of intermediate monocytes, but expression of co-stimulatory molecules was similar between the groups. Macrophages from HTLV-1 infected individuals were infected with L. braziliensis at the same ratio than macrophages from HS, and all the groups had the same ability to kill Leishmania parasites. However, macrophages from HTLV-1 infected subjects produced more CXCL9 and CCL5, and less IL-10 than cells from HS. While there was no correlation between IFN-? and cytokine/chemokine production by macrophages, there was a correlation between proviral load and TNF and CXCL10. These data showed a dissociation between the inflammatory response and microbicidal ability of macrophages from HTLV-1 infected subjects. While macrophages ability to kill an intracellular pathogen did not differ among HTLV-1 infected subjects, these cells secreted high amount of chemokines even in unstimulated cultures. Moreover the increasing inflammatory activity of macrophages was similar in HAM/TSP patients and HC and it was related to HTLV-1 proviral load rather than the high IFN-? production observed in these subjects. PMID:25521499

Amorim, Camila F; Souza, Anselmo S; Diniz, Angela G; Carvalho, Natália B; Santos, Silvane B; Carvalho, Edgar M

2014-12-01

241

Functional Activity of Monocytes and Macrophages in HTLV-1 Infected Subjects  

PubMed Central

The Human T lymphotropic virus type-1 (HTLV-1) infects predominantly T cells, inducing proliferation and lymphocyte activation. Additionally, HTLV-1 infected subjects are more susceptible to other infections caused by other intracellular agents. Monocytes/macrophages are important cells in the defense against intracellular pathogens. Our aims were to determine the frequency of monocytes subsets, expression of co-stimulatory molecules in these cells and to evaluate microbicidal ability and cytokine and chemokine production by macrophages from HTLV-1 infected subjects. Participants were 23 HTLV-1 carriers (HC), 22 HAM/TSP patients and 22 healthy subjects (HS) not infected with HTLV-1. The frequencies of monocyte subsets and expression of co-stimulatory molecules were determined by flow cytometry. Macrophages were infected with L. braziliensis or stimulated with LPS. Microbicidal activity of macrophages was determined by optic microscopy. Cytokines/chemokines from macrophage supernatants were measured by ELISA. HAM/TSP patients showed an increase frequency of intermediate monocytes, but expression of co-stimulatory molecules was similar between the groups. Macrophages from HTLV-1 infected individuals were infected with L. braziliensis at the same ratio than macrophages from HS, and all the groups had the same ability to kill Leishmania parasites. However, macrophages from HTLV-1 infected subjects produced more CXCL9 and CCL5, and less IL-10 than cells from HS. While there was no correlation between IFN-? and cytokine/chemokine production by macrophages, there was a correlation between proviral load and TNF and CXCL10. These data showed a dissociation between the inflammatory response and microbicidal ability of macrophages from HTLV-1 infected subjects. While macrophages ability to kill an intracellular pathogen did not differ among HTLV-1 infected subjects, these cells secreted high amount of chemokines even in unstimulated cultures. Moreover the increasing inflammatory activity of macrophages was similar in HAM/TSP patients and HC and it was related to HTLV-1 proviral load rather than the high IFN-? production observed in these subjects. PMID:25521499

Amorim, Camila F.; Souza, Anselmo S.; Diniz, Angela G.; Carvalho, Natália B.; Santos, Silvane B.; Carvalho, Edgar M.

2014-01-01

242

Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation  

PubMed Central

This study aimed to investigate the role of 5-lipoxygenase (5-LO) in acute liver failure (ALF) and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN)/lipopolysaccharide (LPS). Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor), 24?hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (Tbil), and tumor necrosis factor- (TNF-)?. Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8?hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF-? was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition. PMID:24987711

Li, Lu; Liu, Yi-Rong; Li, Jun-Feng; Li, Shan-Shan; Zhang, Dan-Dan; Liu, Shuang; Bai, Li; Zheng, Su-Jun; Duan, Zhong-Ping; Chen, Yu

2014-01-01

243

Plasminogen activator inhibitor-1 regulates infiltration of macrophages into melanoma via phosphorylation of FAK-Tyr?˛?.  

PubMed

Tumor-infiltrating macrophages are potential candidates for cancer immunotherapy. However, the detailed molecular mechanism underlying macrophage infiltration into tumors is poorly understood. Based on our previous finding that plasminogen activator inhibitor-1 (PAI-1) enhances vitronectin-dependent migration of macrophages, we investigated the potential role of PAI-1 in macrophage invasion into melanoma. Experimental evidence obtained from spheroid confrontation assay clearly showed that PAI-1 overexpression significantly enhanced the invasion of RAW 264.7 cells into B16F10 melanoma. We further demonstrated that PAI-1 induces phosphorylation of focal adhesion kinase (FAK) at Tyr(925), which, in turn, mediated the invasion of macrophages into the melanoma. This work further illustrates that low-density lipoprotein receptor related-protein 1 (LRP1) is essential for PAI-1-mediated FAK phosphorylation and macrophage invasion into melanoma. In conclusion, our study demonstrates a novel role of PAI-1 in macrophage invasion into melanoma and provides insights into the underlying molecular mechanism. PMID:25063025

Thapa, Bikash; Koo, Bon-Hun; Kim, Yeon Hyang; Kwon, Hyung-Joo; Kim, Doo-Sik

2014-08-01

244

The contractile response of isolated small pulmonary arteries induced by activated macrophages.  

PubMed

To test whether macrophages can play any role in hypoxic pulmonary vasoconstriction, we tested the in vitro response of rings from small pulmonary arteries to the activation of macrophages by FMLP, a substance stimulating predominantly membrane-bound NADPH oxidase. A small vessel myograph was used to measure the responses of rings from small pulmonary arteries (300-400 microm) isolated from rat lungs. Rings from 5 rats were placed into both chambers of the myograph. The vessels were stabilized for 40 min and then normalized by automatic stretching to a wall tension equivalent to the intravascular pressure 30 mm Hg. At the start of each experiment, vessels were exposed to 80 mM K+ to obtain maximal contractile response, which was used to normalize subsequent contractile responses. 2x10(6) viable macrophages, obtained by peritoneal lavage, were added into one chamber, then 5 microM FMLP was administrated to both chambers and the tension measurement was started. The hydrogen peroxide concentration produced by stimulated macrophages was measured luminometrically. The concentrations of H2O2 in specimens from chambers containing activated macrophages rose from 3.5+/-1.5 nM to 110+/-28 nM within 25 min of stimulation, while FMLP itself didn't increase the H2O2 concentration from the baseline value (4.5+/-3 nM) in samples from control chambers. After FMLP administration, the tension of the vessel rings in the presence of macrophages reached 0.23+/-0.07 of maximal contractile response, it did not change in controls. The addition of ROS scavenger 4-hydroxy-TEMPO blocked the contractile response to the activation of macrophages. We conclude that the activation of macrophages stimulates the contraction of small pulmonary arteries and that this contraction is probably mediated by reactive oxygen species. PMID:24779609

Zaloudíková, M; Herget, J; Vízek, M

2014-01-01

245

Targeting Activated Macrophages Via a Functional Folate Receptor for Potential Treatment of Autoimmune\\/Inflammatory Disorders  

Microsoft Academic Search

\\u000a The folate receptor expressed by activated macrophages associated with chronic inflammation is fully functional in binding\\/internalization\\u000a of high-affinity folate ligands. The recent effort in developing folate-targeted anti-macrophage therapies has yielded some\\u000a encouraging results. However, the challenges lie not so much in finding the right ligand, but rather its multifaceted nature\\u000a in identifying suitable intracellular targets, finding highly potent base drugs,

Yingjuan Lu; Christopher P. Leamon

246

Ultrastructural localization of NADPH-oxidase activity in murine peritoneal macrophages during phagocytosis of Brucella  

Microsoft Academic Search

Summary  The localization of the enzyme NADPH oxidase in mouse peritoneal macrophages unstimulated or after phagocytosis ofBruceila suis was investigated by electron microscopy in normal mice and mice immunized againstB. suis. The enzyme was clearly visualized on mitochondrial cristae, smooth endoplasmic reticulum, and the plasma membrane; its activity\\u000a correlated mainly with the state of the endoplasmic reticulum which itself reflected macrophage

Bernard Gay; Simone Sanchez-Teff; René Caravano

1984-01-01

247

E-NTPDase (ecto-nucleoside triphosphate diphosphohydrolase) of Leishmania amazonensis inhibits macrophage activation.  

PubMed

Leishmania amazonensis, the causal agent of diffuse cutaneous leishmaniasis, is known for its ability to modulate the host immune response. Because a relationship between ectonucleotidase activity and the ability of Leishmania to generate injury in C57BL/6 mice has been demonstrated, in this study we evaluated the involvement of ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) activity of L. amazonensis in the process of infection of J774-macrophages. Our results show that high-activity parasites show increased survival rate in LPS/IFN-?-activated cells, by inhibiting the host-cell NO production. Conversely, inhibition of E-NTPDase activity reduces the parasite survival rates, an effect associated with increased macrophage NO production. E-NTPDase activity generates substrate for the production of extracellular adenosine, which binds to A2B receptors and reduces IL-12 and TNF-? produced by activated macrophages, thus inhibiting NO production. These results indicate that E-NTPDase activity is important for survival of L. amazonensis within macrophages, showing the role of the enzyme in modulating macrophage response and lower NO production, which ultimately favors infection. Our results point to a new mechanism of L. amazonensis infection that may pave the way for the development of new treatments for this neglected disease. PMID:25554487

Gomes, Rodrigo Saar; de Carvalho, Luana Cristina Faria; de Souza Vasconcellos, Raphael; Fietto, Juliana Lopes Rangel; Afonso, Luís Carlos Crocco

2015-04-01

248

Fate of Legionella pneumophila Philadelphia-1 strain in resident, elicited, activated, and immune peritoneal macrophages of guinea pigs.  

PubMed Central

Legionella pneumophila is known to grow intracellularly in resident peritoneal macrophages of guinea pigs. The present study was done to determine what kinds of macrophage stimulants are able to activate guinea pig macrophages to inhibit intracellular growth of the organism. Peritoneal macrophages were harvested from healthy guinea pigs, from guinea pigs injected intraperitoneally with proteose peptone (PP) or thioglycolate medium, from guinea pigs injected intraperitoneally with live Mycobacterium bovis BCG or killed Propionibacterium acnes (Corynebacterium parvum), and from guinea pigs surviving infection with live L. pneumophila. After in vitro phagocytosis, the L. pneumophila CFU in each well were counted on charcoal-yeast extract agar plates. In the macrophages elicited by PP or thioglycolate medium, the organism grew as well as it did in resident macrophages. In BCG-activated and immune macrophages, growth was inhibited almost completely. In P. acnes-activated macrophages, the initial growth of L. pneumophila was inhibited to some extent, but its growth reached the same level as in the resident and PP-induced macrophages after 3 or 4 days of culture. In the lethal challenge experiments in vivo, the superior protection provided by BCG over P. acnes was ascertained and the importance of macrophages in resistance to L. pneumophila was confirmed. Difference of activation by BCG and P. acnes in relation to the inhibition of intracellular growth of L. pneumophila in guinea pig macrophages is discussed. PMID:3308708

Yoshida, S; Mizuguchi, Y; Nikaido, Y; Mitsuyama, M; Nomoto, K

1987-01-01

249

Chaperone-like activity of macrophage migration inhibitory factor  

Microsoft Academic Search

Macrophage migration inhibitory factor is a ubiquitous multifunctional cytokine having diverse immunological and neuroendocrine properties. Although this protein is known to be released into the circulation from the secretory granules of anterior pituitary or directly from immune cells as a consequence of stress, its participation in heat stress-induced aggregation of proteins has not yet been reported. We provide here the

Oxana A. Cherepkova; Elena M. Lyutova; Tatyana B. Eronina; Bella Ya. Gurvits

2006-01-01

250

Immunomodulatory drugs: Oral and systemic adverse effects  

PubMed Central

Objectives: The main objectives are to present the different adverses effects of the immunomodulatory drugs that can impair the quality of life of the immunosupressed patients and study the impact of immunomodualtion on oral diseases. Immunomodulatory drugs have changed the treatment protocols of many diseases where immune functions play a central role, such as rheumatic diseases. Their effect on oral health has not been systematically investigated, however. Study Design: We review current data on the new immunomodulatory drugs from the oral health perspective based on open literature search of the topic. Results: These target specific drugs appear to have less drug interactions than earlier immunomodulating medicines but have nevertheless potential side effects such as activating latent infections. There are some data showing that the new immunomodulatory drugs may also have a role in the treatment of certain oral diseases such as lichen planus or ameliorating symptoms in Sjögren´s syndrome, but the results have not been overly promising. Conclusions: In general, data are sparse of the effect of these new drugs vs. oral diseases and there are no properly powered randomized controlled trials published on this topic. Key words:Immunomodulatory drugs, oral diseases, adverse effects, therapeutic action. PMID:23986016

Mattila, Riikka; Gomez-Font, Rafael; Meurman, Jukka H.

2014-01-01

251

Distinct Roles for IFN Regulatory Factor (IRF)-3 and IRF-7 in the Activation of Antitumor Properties of Human Macrophages  

Microsoft Academic Search

When properly activated, macrophages can be tumoricidal, thus making them attractive additions to standard cancer therapies. To this end, tolerance and activity of human autologous IFN-;-activated macrophages, produced in large scale for clinical use (MAK cells), have been assessed in pilot trials in cancer patients. In the present study, we tested the hypothesis that activation of IFN regulatory factor (IRF)-3

Raphaelle Romieu-Mourez; Mayra Solis; Alessandra Nardin; Delphine Goubau; Veronique Baron-Bodo; Bernard Massie; Margarita Salcedo; John Hiscott

2006-01-01

252

Coculture with intraocular lens material-activated macrophages induces an inflammatory phenotype in lens epithelial cells.  

PubMed

Cataracts are the leading cause of blindness worldwide, requiring surgical implantation of an intraocular lens. Despite evidence of leukocyte ingress into the postoperative lens, few studies have investigated the leukocyte response to intraocular lens materials. A novel coculture model was developed to examine macrophage activation by hydrophilic acrylic (poly(2-hydroxyethyl methacrylate)) and hydrophobic acrylic (polymethylmethacrylate) commercial intraocular lens. The human monocytic cell line THP-1 was differentiated into macrophages and cocultured with human lens epithelial cell line (HLE-B3) with or without an intraocular lens for one, two, four, or six days. Using flow cytometry and confocal microscopy, expression of the macrophage activation marker CD54 (intercellular adhesion molecule-1) and production of reactive oxygen species via the fluorogenic probe 2',7'-dichlorodihydrofluorescein diacetate were examined in macrophages. ?-Smooth muscle actin, a transdifferentiation marker, was characterized in lens epithelial cells. The poly(2-hydroxyethyl methacrylate) intraocular lens prevented adhesion but induced significant macrophage activation (p?activation. Coculture with either intraocular lens increased reactive oxygen species production in macrophages after one day (p?macrophage adherence is not necessary for a strong inflammatory response to an intraocular lens, with hydrophilic surfaces inducing higher activation than hydrophobic surfaces. These findings provide a new method of inquiry into uveal biocompatibility, specifically through the quantification of cell-surface markers of leukocyte activation. PMID:25281645

Pintwala, Robert; Postnikoff, Cameron; Molladavoodi, Sara; Gorbet, Maud

2015-03-01

253

ATP Release from Dying Autophagic Cells and Their Phagocytosis Are Crucial for Inflammasome Activation in Macrophages  

PubMed Central

Pathogen-activated and damage-associated molecular patterns activate the inflammasome in macrophages. We report that mouse macrophages release IL-1? while co-incubated with pro-B (Ba/F3) cells dying, as a result of IL-3 withdrawal, by apoptosis with autophagy, but not when they are co-incubated with living, apoptotic, necrotic or necrostatin-1 treated cells. NALP3-deficient macrophages display reduced IL-1? secretion, which is also inhibited in macrophages deficient in caspase-1 or pre-treated with its inhibitor. This finding demonstrates that the inflammasome is activated during phagocytosis of dying autophagic cells. We show that activation of NALP3 depends on phagocytosis of dying cells, ATP release through pannexin-1 channels of dying autophagic cells, P2X7 purinergic receptor activation, and on consequent potassium efflux. Dying autophagic Ba/F3 cells injected intraperitoneally in mice recruit neutrophils and thereby induce acute inflammation. These findings demonstrate that NALP3 performs key upstream functions in inflammasome activation in mouse macrophages engulfing dying autophagic cells, and that these functions lead to pro-inflammatory responses. PMID:22768222

Ayna, Gizem; Krysko, Dmitri V.; Kaczmarek, Agnieszka; Petrovski, Goran; Vandenabeele, Peter; Fésüs, László

2012-01-01

254

Interleukin-6 signaling promotes alternative macrophage activation to limit obesity-associated insulin resistance and endotoxemia  

PubMed Central

Obesity and insulin resistance are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation, however its role in this context remains controversial. Here, we show that mice with inactivated Il6ra gene in myeloid cells (Il6ra?myel) displayed exaggerated deterioration of glucose homeostasis upon diet-induced obesity due to enhanced insulin resistance. Insulin target tissues showed increased inflammation and a shift in macrophage polarization. IL-6 induced IL-4-receptor expression and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6ra?myel mice were resistant to IL-4-mediated alternative macrophage polarization and exhibited increased susceptibility to LPS-induced endotoxemia. These results reveal IL-6 signaling as an important determinant for alternative macrophage-activation and assign IL-6 an unexpected homeostatic role to limit inflammation. PMID:24681566

Mauer, Jan; Chaurasia, Bhagirath; Goldau, Julia; Vogt, Merly C.; Ruud, Johan; Nguyen, Khoa D.; Theurich, Sebastian; Hausen, A. Christine; Schmitz, Joel; Brönneke, Hella S.; Estevez, Emma; Allen, Tamara L.; Mesaros, Andrea; Partridge, Linda; Febbraio, Mark A.; Chawla, Ajay; Wunderlich, F. Thomas; Brüning, Jens C.

2014-01-01

255

Differential effects of osteopontin on the cytotoxic activity of macrophages from young and old mice.  

PubMed Central

Osteopontin (OPN) is a secreted phosphoprotein found in body fluids (e.g. plasma, urine, milk) and in mineralized tissues. Its expression is increased in many transformed cells and in normal cells exposed to various cytokines. When stimulated with the inflammatory mediators lipopolysaccharide and interferon-gamma, mouse macrophages secrete nitric oxide (NO) as a cytotoxic agent effective against microbial invaders and tumour cells. This report documents (1) that thioglycollate-elicited peritoneal macrophages, activated with the inflammatory mediators, produced less NO and exhibited reduced cytotoxicity towards target cells when they were obtained from old animals than when they were obtained from young animals; and (2) that OPN was able to inhibit both the induced NO synthesis and cytotoxicity, but more effectively in macrophages from the young animals than those from the old animals. This may be due to the observed higher level of OPN expression in macrophages from old animals. Images Figure 1 Figure 2 PMID:8881770

Rollo, E E; Denhardt, D T

1996-01-01

256

Transcriptomic Analysis of Human Polarized Macrophages: More than One Role of Alternative Activation?  

PubMed Central

Background Macrophages are a heterogeneous cell population which in response to the cytokine milieu polarize in either classically activated macrophages (M1) or alternatively activated macrophages (M2). This plasticity makes macrophages essential in regulating inflammation, immune response and tissue remodeling and a novel therapeutic target in inflammatory diseases such as atherosclerosis. The aim of the study was to describe the transcriptomic profiles of differently polarized human macrophages to generate new hypotheses on the biological function of the different macrophage subtypes. Methods and Results Polarization of circulating monocytes/macrophages of blood donors was induced in vitro by IFN-? and LPS (M1), by IL-4 (M2a), and by IL-10 (M2c). Unstimulated cells (RM) served as time controls. Gene expression profile of M1, M2a, M2c and RM was assessed at 6, 12 and 24h after polarization with Whole Human Genome Agilent Microarray technique. When compared to RM, M1 significantly upregulated pathways involved in immunity and inflammation, whereas M2a did the opposite. Conversely, decreased and increased expression of mitochondrial metabolism, consistent with insulin resistant and insulin sensitive patterns, was seen in M1 and M2a, respectively. The time sequence in the expression of some pathways appeared to have some specific bearing on M1 function. Finally, canonical and non-canonical Wnt genes and gene groups, promoting inflammation and tissue remodeling, were upregulated in M2a compared to RM. Conclusion Our data in in vitro polarized human macrophages: 1. confirm and extend known inflammatory and anti-inflammatory gene expression patterns; 2. demonstrate changes in mitochondrial metabolism associated to insulin resistance and insulin sensitivity in M1 and M2a, respectively; 3. highlight the potential relevance of gene expression timing in M1 function; 4. unveil enhanced expression of Wnt pathways in M2a suggesting a potential dual (pro-inflammatory and anti-inflammatory) role of M2a in inflammatory diseases. PMID:25799240

Derlindati, Eleonora; Dei Cas, Alessandra; Montanini, Barbara; Spigoni, Valentina; Curella, Valentina; Aldigeri, Raffaella; Ardigň, Diego; Zavaroni, Ivana; Bonadonna, Riccardo C.

2015-01-01

257

Immunocytochemical localization of latent transforming growth factor-beta1 activation by stimulated macrophages  

NASA Technical Reports Server (NTRS)

Transforming growth factor-beta1 (TGF-beta) is secreted in a latent form consisting of mature TGF-beta noncovalently associated with its amino-terminal propeptide, which is called latency associated peptide (LAP). Biological activity depends upon the release of TGF-beta from the latent complex following extracellular activation, which appears to be the key regulatory mechanism controlling TGF-beta action. We have identified two events associated with latent TGF-beta (LTGF-beta) activation in vivo: increased immunoreactivity of certain antibodies that specifically detect TGF-beta concomitant with decreased immunoreactivity of antibodies to LAP. Macrophages stimulated in vitro with interferon-gamma and lipopolysaccharide reportedly activate LTGF-beta via cell membrane-bound protease activity. We show through dual immunostaining of paraformaldehyde-fixed macrophages that such physiological TGF-beta activation is accompanied by a loss of LAP immunoreactivity with concomitant revelation of TGF-beta epitopes. The induction of TGF-beta immunoreactivity colocalized with immunoreactive betaglycan/RIII in activated macrophages, suggesting that LTGF-beta activation occurs on the cell surface. Confocal microscopy of metabolically active macrophages incubated with antibodies to TGF-beta and betaglycan/RIII prior to fixation supported the localization of activation to the cell surface. The ability to specifically detect and localize LTGF-beta activation provides an important tool for studies of its regulation.

Chong, H.; Vodovotz, Y.; Cox, G. W.; Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

1999-01-01

258

Mechanism of vitamin E inhibition of cyclooxygenase activity in macrophages from old mice: role of peroxynitrite.  

PubMed

Vitamin E inhibits cyclooxygenase activity in macrophages from old mice by reducing peroxynitrite production. PGE(2) is a proinflammatory mediator that has been linked to a variety of age-associated diseases such as cancer, arthritis, and cardiovascular disease. Furthermore in the aged, increased cyclooxygenase (COX)-2-mediated PGE(2) production contributes to decline in T-cell-mediated function. Previously we reported that increased macrophage PGE(2) production in the aged is due to higher COX-2 activity and that supplementation with vitamin E significantly reduced the age-associated increase in macrophage PGE(2) production posttranslationally without changing COX-2 expression. Peroxynitrite, a product of nitric oxide (NO) and superoxide (O(-)(2)), increases the activity of COX without affecting its expression. Thus, we investigated if vitamin E inhibits COX activity through decreasing peroxynitrite formation. Macrophages from old mice had higher PGE(2) levels, COX activity, and NO levels than those from young mice, all of which were significantly reduced by vitamin E. When added individually, inhibitors of NO and O(-)(2) did not significantly reduce COX activity; however, when the inhibitors were combined, COX activity was significantly reduced in macrophages from old mice fed 30 ppm vitamin E. Increasing NO levels alone using SNAP or O(-)(2) levels, using X/XO, had no effect; however, increasing peroxynitrite levels using Sin-1 or X/XO + SNAP significantly increased COX activity in macrophages from old mice fed 500, but not those fed 30 ppm vitamin E. These data strongly suggest that peroxynitrite plays an important role in the vitamin E-induced inhibition of COX activity. These findings have important implications for designing interventions to reverse and/or delay age-associated dysregulation of immune and inflammatory responses and diseases associated with them. PMID:11958951

Beharka, Alison A; Wu, Dayong; Serafini, Mauro; Meydani, Simin Nikbin

2002-03-15

259

Nitroarachidonic acid prevents NADPH oxidase assembly and superoxide radical production in activated macrophages  

PubMed Central

Nitration of arachidonic acid (AA) to nitroarachidonic acid (AANO2) leads to anti-inflammatory intracellular activities during macrophage activation. However, less is known about the capacity of AANO2 to regulate the production of reactive oxygen species (ROS) under pro-inflammatory conditions. One of the immediate responses upon macrophage activation involves the production of superoxide radical (O2·?), due to the NADPH dependent univalent reduction of oxygen to O2·? by the phagocytic NADPH-oxidase isoform (NOX2), being the activity of NOX2 the main source of O2·? in monocytes/macrophages. Since NOX2 and AA pathways are connected, we propose that AANO2can modulate macrophage activation by inhibiting O2·? formation by NOX2. When macrophages were activated in the presence of AANO2, a significant inhibition of NOX2 activity was observed as evaluated by cytochrome c reduction, luminol chemiluminescence, Amplex Red fluorescence and flow cytometry; this process also occurs in physiological mimic conditions within the phagosomes. AANO2 decreased O2·? production in a dose-(IC50= 4.1 ± 1.8 ?M AANO2) and time-dependent manner. The observed inhibition was not due to a decreased phosphorylation of the cytosolic subunits (e.g. p40phox and p47phox), as analyzed by immunoprecipitation and western blot. However, a reduction of the migration to the membrane of p47phox was obtained suggesting that the protective actions involve the prevention of the correct assembly of the active enzyme in the membrane. Finally, the observed in vitro effects were confirmed in an in vivo inflammatory model, where subcutaneous injection of AANO2 was able to decrease NOX2 activity in macrophages from thioglycolate treated mice. PMID:23318789

González-Perilli, Lucía; Álvarez, María Noel; Prolo, Carolina; Radi, Rafael; Rubbo, Homero; Trostchansky, Andrés

2013-01-01

260

IRAK-M Promotes Alternative Macrophage Activation and Fibroproliferation in Bleomycin-Induced Lung Injury.  

PubMed

Idiopathic pulmonary fibrosis is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. Although previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages. Recently, TLR signaling has been identified as a regulator of pulmonary fibrosis. IL-1R-associated kinase-M (IRAK-M), a MyD88-dependent inhibitor of TLR signaling, suppresses deleterious inflammation, but may paradoxically promote fibrogenesis. Mice deficient in IRAK-M (IRAK-M(-/-)) were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with reduced production of IL-13 compared with wild-type (WT) control mice. Bone marrow chimera experiments indicated that IRAK-M expression by bone marrow-derived cells, rather than structural cells, promoted fibrosis. After bleomycin, WT macrophages displayed an alternatively activated phenotype, whereas IRAK-M(-/-) macrophages displayed higher expression of classically activated macrophage markers. Using an in vitro coculture system, macrophages isolated from in vivo bleomycin-challenged WT, but not IRAK-M(-/-), mice promoted increased collagen and ?-smooth muscle actin expression from lung fibroblasts in an IL-13-dependent fashion. Finally, IRAK-M expression is upregulated in peripheral blood cells from idiopathic pulmonary fibrosis patients and correlated with markers of alternative macrophage activation. These data indicate expression of IRAK-M skews lung macrophages toward an alternatively activated profibrotic phenotype, which promotes collagen production, leading to the progression of experimental pulmonary fibrosis. PMID:25595781

Ballinger, Megan N; Newstead, Michael W; Zeng, Xianying; Bhan, Urvashi; Mo, Xiaokui M; Kunkel, Steven L; Moore, Bethany B; Flavell, Richard; Christman, John W; Standiford, Theodore J

2015-02-15

261

Secreted hCLCA1 Is a Signaling Molecule That Activates Airway Macrophages  

PubMed Central

The CLCA gene family produces both secreted and membrane-associated proteins that modulate ion-channel function, drive mucus production and have a poorly understood pleiotropic effect on airway inflammation. The primary up-regulated human CLCA ortholog in airway inflammation is hCLCA1. Here we show that this protein can activate airway macrophages, inducing them to express cytokines and to undertake a pivotal role in airway inflammation. In a U-937 airway macrophage–monocyte cell line, conditioned media from HEK 293 cells heterologously expressing hCLCA1 (with or without fetal bovine serum) increased the levels of pro-inflammatory cytokines (IL-1?, IL-6, TNF-? and IL-8). This effect was independent of the metalloprotease domain of hCLCA1. Primary porcine alveolar macrophages were similarly activated, demonstrating the effect was not cell line dependent. Similarly, immuno-purified hCLCA1 at physiologically relevant concentration of ~100 pg/mL was able to activate macrophages and induce pro-inflammatory response. This cytokine response increased with higher concentration of immuno-purified hCLCA1. These findings demonstrate the ability of hCLCA1 to function as a signaling molecule and activate macrophages, central regulators of airway inflammation. PMID:24349445

Ching, John C. H.; Lobanova, Liubov; Loewen, Matthew E.

2013-01-01

262

Inhibition of ecto-ATPase activities impairs HIV-1 infection of macrophages.  

PubMed

Nucleotides and nucleosides are secreted into extracellular media at different concentrations as a consequence of different physiologic and pathological conditions. Ecto-nucleotidases, enzymes present on the surface of most cells, hydrolyze these extracellular nucleotides and reduce the concentration of them, thus affecting the activation of different nucleotide and nucleoside receptors. Also, ecto-nucleotidases are present in a number of microorganisms and play important roles in host-pathogen interactions. Here, we characterized the ecto-ATPase activities present on the surface of HIV-1 particle and human macrophages as well. We found that the kinetic properties of HIV-1 and macrophage ecto-ATPases are similar, suggesting that the enzyme is the same. This ecto-ATPase activity was increased in macrophages infected in vitro with HIV-1. Using three different non-related ecto-ATPase inhibitors-POM-1, ARL67156 and BG0-we showed that the inhibition of these macrophage and viral ecto-ATPase activities impairs HIV-1 infection. In addition, we also found that elevated extracellular concentrations of ATP inhibit HIV-1 production by infected macrophages. PMID:25577295

Schachter, Julieta; Valcárcel Delgado, Kelly; Barreto-de-Souza, Victor; Bou-Habib, Dumith Chequer; Persechini, Pedro Muanis; Meyer-Fernandes, José Roberto

2015-05-01

263

CIRCRESAHA/2013/301656/R2 Liver X Receptor (LXR) activation stimulates iron export in human alternative macrophages  

E-print Network

atherosclerotic plaques, CD68+MR+ macrophages accumulate oxidized lipids, which activate Liver X Receptors (LXR LXR liver X receptor LXRE LXR response element M1 classically activated macrophages M2 alternativelyCIRCRESAHA/2013/301656/R2 1 Liver X Receptor (LXR) activation stimulates iron export in human

Boyer, Edmond

264

Outer membrane protein A (OmpA) binds to and activates human macrophages.  

PubMed

Outer membrane protein (Omp)A is highly represented and conserved in the Enterobacteriaceae family. Using a recombinant OmpA from Klebsiella pneumoniae (P40), we have analyzed the interaction between OmpA and macrophages. We report that Alexa488-labeled P40 binds (at 4 degrees C) to murine and human macrophages in a dose-dependent manner and is rapidly internalized (at 37 degrees C). No binding or internalization of the Alexa488-labeled glycophorin A control protein is observed under the same conditions. Furthermore, P40 up-regulates the production of IL-1beta, IL-8, IL-10, IL-12, and TNF-alpha by human macrophages and of NO by the RAW 264.7 murine macrophage cell line. P40 also synergizes with IFN-gamma and suboptimal concentrations of LPS to up-regulate the production of these mediators. In conclusion, P40 binds to and activates macrophages. These data suggest that recognition of OmpA by macrophages may be an initiating event in the antibacterial host response. PMID:10946255

Soulas, C; Baussant, T; Aubry, J P; Delneste, Y; Barillat, N; Caron, G; Renno, T; Bonnefoy, J Y; Jeannin, P

2000-09-01

265

Binding and activation of major histocompatibility complex class II-deficient macrophages by staphylococcal exotoxins  

NASA Technical Reports Server (NTRS)

Macrophages from C2D transgenic mice deficient in the expression of major histocompatibility complex (MHC) class II proteins were used to identify binding sites for superantigens distinct from the MHC class II molecule. Iodinated staphylococcal enterotoxins A and B (SEA and SEB) and exfoliative toxins A and B (ETA and ETB) bound to C2D macrophages in a concentration-dependent and competitive manner. All four toxins increased F-actin concentration within 30 s of their addition to C2D macrophages, indicating that signal transduction occurred in response to toxin in the absence of class II MHC. Furthermore, ETA, ETB, SEA, and, to a lesser extent, SEB induced C2D macrophages to produce interleukin 6. Several molecular species on C2D macrophages with molecular masses of 140, 97, 61, 52, 43, and 37 kDa bound SEA in immunoprecipitation experiments. These data indicate the presence of novel, functionally active toxin binding sites on murine macrophages distinct from MHC class II molecules.

Beharka, A. A.; Armstrong, J. W.; Iandolo, J. J.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1994-01-01

266

Immunomodulation of RAW264.7 macrophages by GLIS, a proteopolysaccharide from Ganoderma lucidum.  

PubMed

The immunomodulatory effect of Ganoderma lucidum immunomodulating substance (GLIS) on macrophages has been investigated as part of on-going research into the anti-cancer properties of Ganoderma lucidum. Proliferation of bone marrow macrophages (BMMs) was enhanced by GLIS in a dose-dependent manner. Microscopic examination revealed that numerous GLIS-treated RAW264.7 macrophages were enlarged and formed pseudopodia. Exposure of RAW264.7 macrophages to GLIS resulted in significant increases in NO production, induction of cellular respiratory burst activity, and increased levels of IL-1beta, IL-12p35 and IL-12p40 gene expression. Our data indicate that GLIS activates the immune system by modulating cytokine production. PMID:17524580

Ji, Zhe; Tang, Qingjiu; Zhang, Jinsong; Yang, Yan; Jia, Wei; Pan, Yingjie

2007-07-25

267

Synthetic cationic peptide IDR-1018 modulates human macrophage differentiation.  

PubMed

Macrophages play a critical role in the innate immune response. To respond in a rapid and efficient manner to challenges in the micro-environment, macrophages are able to differentiate towards classically (M1) or alternatively (M2) activated phenotypes. Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defence peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on innate immune cells like monocytes/macrophages. Here we tested the effect of IDR-1018 on macrophage differentiation, a process essential to macrophage function and the immune response. Using transcriptional, protein and systems biology analysis, we observed that differentiation in the presence of IDR-1018 induced a unique signature of immune responses including the production of specific pro and anti-inflammatory mediators, expression of wound healing associated genes, and increased phagocytosis of apoptotic cells. Transcription factor IRF4 appeared to play an important role in promoting this IDR-1018-induced phenotype. The data suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1-M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection. Synthetic peptides like IDR-1018, which act by modulating the immune system, could represent a powerful new class of therapeutics capable of treating the rising number of multidrug resistant infections as well as disorders associated with dysregulated immune responses. PMID:23308112

Pena, Olga M; Afacan, Nicole; Pistolic, Jelena; Chen, Carol; Madera, Laurence; Falsafi, Reza; Fjell, Christopher D; Hancock, Robert E W

2013-01-01

268

Synthetic Cationic Peptide IDR-1018 Modulates Human Macrophage Differentiation  

PubMed Central

Macrophages play a critical role in the innate immune response. To respond in a rapid and efficient manner to challenges in the micro-environment, macrophages are able to differentiate towards classically (M1) or alternatively (M2) activated phenotypes. Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defence peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on innate immune cells like monocytes/macrophages. Here we tested the effect of IDR-1018 on macrophage differentiation, a process essential to macrophage function and the immune response. Using transcriptional, protein and systems biology analysis, we observed that differentiation in the presence of IDR-1018 induced a unique signature of immune responses including the production of specific pro and anti-inflammatory mediators, expression of wound healing associated genes, and increased phagocytosis of apoptotic cells. Transcription factor IRF4 appeared to play an important role in promoting this IDR-1018-induced phenotype. The data suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1–M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection. Synthetic peptides like IDR-1018, which act by modulating the immune system, could represent a powerful new class of therapeutics capable of treating the rising number of multidrug resistant infections as well as disorders associated with dysregulated immune responses. PMID:23308112

Pena, Olga M.; Afacan, Nicole; Pistolic, Jelena; Chen, Carol; Madera, Laurence; Falsafi, Reza; Fjell, Christopher D.; Hancock, Robert E. W.

2013-01-01

269

CD14 Influences Host Immune Responses and Alternative Activation of Macrophages during Schistosoma mansoni Infection  

PubMed Central

Antigen-presenting cell (APC) plasticity is critical for controlling inflammation in metabolic diseases and infections. The roles that pattern recognition receptors (PRRs) play in regulating APC phenotypes are just now being defined. We evaluated the expression of PRRs on APCs in mice infected with the helminth parasite Schistosoma mansoni and observed an upregulation of CD14 expression on macrophages. Schistosome-infected Cd14?/? mice showed significantly increased alternative activation of (M2) macrophages in the livers compared to infected wild-type (wt) mice. In addition, splenocytes from infected Cd14?/? mice exhibited increased production of CD4+-specific interleukin-4 (IL-4), IL-5, and IL-13 and CD4+Foxp3+IL-10+ regulatory T cells compared to cells from infected wt mice. S. mansoni-infected Cd14?/? mice also presented with smaller liver egg granulomas associated with increased collagen deposition compared to granulomas in infected wt mice. The highest expression of CD14 was found on liver macrophages in infected mice. To determine if the Cd14?/? phenotype was in part due to increased M2 macrophages, we adoptively transferred wt macrophages into Cd14?/? mice and normalized the M2 and CD4+ Th cell balance close to that observed in infected wt mice. Finally, we demonstrated that CD14 regulates STAT6 activation, as Cd14?/? mice had increased STAT6 activation in vivo, suggesting that lack of CD14 impacts the IL-4R?-STAT6 pathway, altering macrophage polarization during parasite infection. Collectively, these data identify a previously unrecognized role for CD14 in regulating macrophage plasticity and CD4+ T cell biasing during helminth infection. PMID:24866794

Tundup, Smanla; Srivastava, Leena; Nagy, Tamas

2014-01-01

270

CD14 influences host immune responses and alternative activation of macrophages during Schistosoma mansoni infection.  

PubMed

Antigen-presenting cell (APC) plasticity is critical for controlling inflammation in metabolic diseases and infections. The roles that pattern recognition receptors (PRRs) play in regulating APC phenotypes are just now being defined. We evaluated the expression of PRRs on APCs in mice infected with the helminth parasite Schistosoma mansoni and observed an upregulation of CD14 expression on macrophages. Schistosome-infected Cd14(-/-) mice showed significantly increased alternative activation of (M2) macrophages in the livers compared to infected wild-type (wt) mice. In addition, splenocytes from infected Cd14(-/-) mice exhibited increased production of CD4(+)-specific interleukin-4 (IL-4), IL-5, and IL-13 and CD4(+)Foxp3(+)IL-10(+) regulatory T cells compared to cells from infected wt mice. S. mansoni-infected Cd14(-/-) mice also presented with smaller liver egg granulomas associated with increased collagen deposition compared to granulomas in infected wt mice. The highest expression of CD14 was found on liver macrophages in infected mice. To determine if the Cd14(-/-) phenotype was in part due to increased M2 macrophages, we adoptively transferred wt macrophages into Cd14(-/-) mice and normalized the M2 and CD4(+) Th cell balance close to that observed in infected wt mice. Finally, we demonstrated that CD14 regulates STAT6 activation, as Cd14(-/-) mice had increased STAT6 activation in vivo, suggesting that lack of CD14 impacts the IL-4R?-STAT6 pathway, altering macrophage polarization during parasite infection. Collectively, these data identify a previously unrecognized role for CD14 in regulating macrophage plasticity and CD4(+) T cell biasing during helminth infection. PMID:24866794

Tundup, Smanla; Srivastava, Leena; Nagy, Tamas; Harn, Donald

2014-08-01

271

A light-activated theranostic nanoagent for targeted macrophage ablation in inflammatory atherosclerosis.  

PubMed

The synthesis and utility of a multimodal theranostic nanoagent based upon magnetofluorescent nanoparticles for the treatment of inflammatory atherosclerosis is described. These particles are modified with near-infrared fluorophores and light-activated therapeutic moieties, which allow for the optical determination of agent localization and phototoxic activation at spectrally distinct wavelengths. The resulting agent is readily taken up by murine macrophages in vitro and is highly phototoxic, with an LD(50) of 430 pM. Intravenous administration results in the localization of the nanoagent within macrophage-rich atherosclerotic lesions that can be imaged by intravital fluorescence microscopy. Irradiation of the atheroma with 650 nm light activates the therapeutic component and results in eradication of inflammatory macrophages, which may induce lesion stabilization. Importantly, these agents display limited skin photosensitivity, are highly efficacious, and provide an integrated imaging and therapeutic nanoplatform for atherosclerosis. PMID:20721949

McCarthy, Jason R; Korngold, Ethan; Weissleder, Ralph; Jaffer, Farouc A

2010-09-20

272

INTERLEUKIN-4- AND INTERLEUKIN-13-MEDIATED ALTERNATIVELY ACTIVATED MACROPHAGES: ROLES IN HOMEOSTASIS AND DISEASE  

PubMed Central

The macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair. PMID:23298208

Van Dyken, Steven J.; Locksley, Richard M.

2013-01-01

273

Aging Enhances the Production of Reactive Oxygen Species and Bactericidal Activity in Peritoneal Macrophages by Upregulating Classical Activation Pathways  

SciTech Connect

Maintenance of macrophages in their basal state and their rapid activation in response to pathogen detection are central to the innate immune system, acting to limit nonspecific oxidative damage and promote pathogen killing following infection. To identify possible age-related alterations in macrophage function, we have assayed the function of peritoneal macrophages from young (3?4 months) and aged (14?15 months) Balb/c mice. In agreement with prior suggestions, we observe age-dependent increases in the extent of recruitment of macrophages into the peritoneum, as well as ex vivo functional changes involving enhanced nitric oxide production under resting conditions that contribute to a reduction in the time needed for full activation of senescent macrophages following exposure to lipopolysaccharides (LPS). Further, we observe enhanced bactericidal activity following Salmonella uptake by macrophages isolated from aged Balb/c mice in comparison with those isolated from young animals. Pathways responsible for observed phenotypic changes were interrogated using tandem mass spectrometry, which identified age-dependent increases in levels of proteins linked to immune cell pathways under basal conditions and following LPS activation. Immune pathways upregulated in macrophages isolated from aged mice include proteins critical to the formation of the immunoproteasome. Detection of these latter proteins is dramatically enhanced following LPS exposure for macrophages isolated from aged animals; in comparison, the identification of immunoproteasome subunits is insensitive to LPS exposure for macrophages isolated from young animals. Consistent with observed global changes in the proteome, quantitative proteomic measurements indicate that there are age-dependent abundance changes involving specific proteins linked to immune cell function under basal conditions. LPS exposure selectively increases the levels of many proteins involved in immune cell function in aged Balb/c mice. Collectively, these results indicate that macrophages isolated from old mice are in a preactivated state that enhances their sensitivities to LPS exposure. The hyper-responsive activation of macrophages in aged animals may act to minimize infection by general bacterial threats that arise due to age-dependent declines in adaptive immunity. However, this hypersensitivity and the associated increase in the level of formation of reactive oxygen species are likely to contribute to observed age-dependent increases in the level of oxidative damage that underlie many diseases of the elderly.

Smallwood, Heather S.; Lopez-Ferrer, Daniel; Squier, Thomas C.

2011-10-07

274

Allergens as immunomodulatory proteins: the cat dander protein Fel d 1 enhances TLR activation by lipid ligands.  

PubMed

Allergic responses can be triggered by structurally diverse allergens. Most allergens are proteins, yet extensive research has not revealed how they initiate the allergic response and why the myriad of other inhaled proteins do not. Among these allergens, the cat secretoglobulin protein Fel d 1 is a major allergen and is responsible for severe allergic responses. In this study, we show that similar to the mite dust allergen Der p 2, Fel d 1 substantially enhances signaling through the innate receptors TLR4 and TLR2. In contrast to Der p 2, however, Fel d 1 does not act by mimicking the TLR4 coreceptor MD2 and is not able to bind stably to the TLR4/MD2 complex in vitro. Fel d 1 does, however, bind to the TLR4 agonist LPS, suggesting that a lipid transfer mechanism may be involved in the Fel d 1 enhancement of TLR signaling. We also show that the dog allergen Can f 6, a member of a distinct class of lipocalin allergens, has very similar properties to Fel d 1. We propose that Fel d 1 and Can f 6 belong to a group of allergen immunomodulatory proteins that enhance innate immune signaling and promote airway hypersensitivity reactions in diseases such as asthma. PMID:23878318

Herre, Jurgen; Grönlund, Hans; Brooks, Heather; Hopkins, Lee; Waggoner, Lisa; Murton, Ben; Gangloff, Monique; Opaleye, Olaniyi; Chilvers, Edwin R; Fitzgerald, Kate; Gay, Nick; Monie, Tom; Bryant, Clare

2013-08-15

275

Differential activation of transcription factors NF-?B and AP1 in rat liver macrophages  

Microsoft Academic Search

Liver macrophages (Kupffer cells) respond to many stimulations with the production of bioactive substances including cytokines, eicosanoids, and inorganic radicals. In this study the activation of transcription factors by substances inducing cytokine gene expression or superoxide formation in rat Kupffer cells was examined. Using primary cultures of rat Kupffer cells the role of NF-?B and activator protein 1 (AP-1) in

Thuy-Anh Tran-Thi; Karl Decker; Patrick A. Baeuerle

1995-01-01

276

Restricted cytosolic growth of Francisella tularensis subsp. tularensis by IFN-? activation of macrophages  

PubMed Central

The intracellular bacterium Francisella tularensis ensures its survival and proliferation within phagocytes of the infected host through phagosomal escape and cytosolic replication, to cause the disease tularemia. The cytokine interferon-? (IFN-?) is important in controlling primary infections in vivo, and in vitro intracellular proliferation of Francisella in macrophages, but its actual effects on the intracellular cycle of the bacterium are ambiguous. Here, we have performed an extensive analysis of the intracellular fate of the virulent F. tularensis subsp. tularensis strain Schu S4 in primary IFN-?-activated murine and human macrophages to understand how this cytokine controls Francisella proliferation. In both murine bone marrow-derived macrophages (muBMMs) and human blood monocyte-derived macrophages (MDMs), IFN-? controlled bacterial proliferation. Schu S4 growth inhibition was not due to a defect in phagosomal escape, since bacteria disrupted their phagosomes with indistinguishable kinetics in both muBMMs and MDMs, regardless of their activation state. Rather, IFN-? activation restricted cytosolic replication of Schu S4 in a manner independent of reactive oxygen or nitrogen species. Hence, IFN-? induces phagocyte NADPH oxidase Phox- and inducible nitric oxide synthase (iNOS)-independent cytosolic effector mechanisms that restrict growth of virulent Francisella in macrophages. PMID:19926654

Edwards, Jessica A.; Rockx-Brouwer, Dedeke; Nair, Vinod; Celli, Jean

2010-01-01

277

Macrophage stimulating protein: purification, partial amino acid sequence, and cellular activity  

PubMed Central

Macrophage stimulating protein (MSP) was purified to homogeneity from human blood plasma by selection of biologically active fractions obtained by sequential immunoaffinity and high pressure liquid ion exchange chromatography. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis the molecular mass of MSP was 70 kilodaltons (kD); under reducing conditions two gel bands were seen, at 47 and 22 kD. The disulfide-linked two-chain structure of MSP was confirmed by separation of reduced and alkylated MSP chains. A computer search comparison of six partial sequences of MSP digests showed that MSP has not been recorded in data banks of protein sequences. Two MSP fragments had greater than 80% identity in overlaps of 12-16 residues to sequences in the protein family that includes human prothrombin, plasminogen, and hepatocyte growth factor. The concentration of purified MSP required for half-maximal biological activity was the order of 10(-10) M. In addition to making mouse resident peritoneal macrophages responses to chemoattractants, MSP caused the appearance of long cytoplasmic processes and pinocytic vesicles in freshly plated macrophages. MSP also caused phagocytosis via the C3b receptor, CR1. Whereas resident peritoneal macrophages bind but do not ingest sheep erythrocytes opsonized with IgM anti-Forssman antibody and mouse C3b, addition of MSP caused ingestion. Thus, MSP causes direct or indirect activation of two receptors of the mouse resident peritoneal macrophage, CR1 and the C5a receptor. PMID:1827141

1991-01-01

278

Folic acid-functionalized human serum albumin nanocapsules for targeted drug delivery to chronically activated macrophages.  

PubMed

Activated synovial macrophages play a key role in Rheumatoid Arthritis (RA). Recent studies have shown that folate receptor beta (FR?) is specifically expressed by activated macrophages. Therefore a folate-based nanodevice would provide the possibility of delivering therapeutic agents to activated macrophages without affecting normal cells and tissues. This study shows for the first time the sonochemical preparation of HSA nanocapsules avoiding toxic cross linking chemicals and emulsifiers used in other methods. Production of HSA nanocapsules was optimized leading to a diameter of 443.5 ± 9.0 nm and a narrow size distribution indicated by a polydispersity index (PDI) of 0.066 ± 0.080. Nanocapsules were surface modified with folic acid (FA) and the FA content was determined to be 0.38 and 6.42 molecules FA per molecule HSA, depending on the surplus of FA employed. Dynamic light scattering was used to determine size, PDI and zetapotential of the produced nanocapsules before and after surface modification. FA distribution on the surface of HSA nanocapsules was localized three-dimensionally after fluorescence labeling using confocal laser scanning microscopy (CLSM). Furthermore, specific binding and internalization of HSA nanocapsules by FR?-positive and FR?-negative macrophages, obtained from human peripheral blood mononuclear cells, was demonstrated by flow cytometry. FR?-expressing macrophages showed an increased binding for FA-modified capsules compared with those without FA. PMID:22374516

Rollett, Alexandra; Reiter, Tamara; Nogueira, Patricia; Cardinale, Massimiliano; Loureiro, Ana; Gomes, Andreia; Cavaco-Paulo, Artur; Moreira, Alexandra; Carmo, Alexandre M; Guebitz, Georg M

2012-05-10

279

Anti-inflammatory Activity and Mechanism of Surfactin in Lipopolysaccharide-Activated Macrophages.  

PubMed

Surfactin is primarily produced by Bacillus natto TK-1 and is one of the most powerful biosurfactants. It consists of a heptapeptide interlinked with a ?-hydroxy fatty acid. Because of its special structure, surfactin shows broad biological effects, including anti-tumour, anti-microbial and anti-mycoplasma activities. It also has potential anti-inflammatory activity; however, the anti-inflammatory mechanism of surfactin has not been explored. In this study, we investigated the anti-inflammatory mechanism of surfactin in lipopolysaccharide (LPS)-stimulated macrophages. Surfactin exhibited an anti-inflammatory effect without cytotoxicity at certain concentrations, and the lipopolysaccharide (LPS)-stimulated cells appeared normal after surfactin treatment. Surfactin significantly inhibited the increased expression of IFN-?, IL-6, iNOS and nitric oxide (NO). TLR4 is the critical receptor for LPS; therefore, the TLR4 signal transduction pathway is the primary pathway that mediates LPS-induced inflammation. The results show that surfactin downregulated the LPS-induced TLR4 protein expression of macrophages and indicated that the surfactin-mediated signal pathway was involved in with TLR4. The subsequent studies demonstrated that surfactin exhibited anti-inflammatory effects by attenuating the activation of nuclear factor-?B (NF-?B), which is involved in the nuclear factor-?B (NF-?B) cell signalling pathways. These results suggest that surfactin may be a new therapeutic agent for inflammation. PMID:25331175

Zhang, Yuanyuan; Liu, Chuan; Dong, Bin; Ma, Xiaolei; Hou, Lihua; Cao, Xiaohong; Wang, Chunling

2015-04-01

280

Extracellular cytolysis by activated macrophages and granulocytes. II. Hydrogen peroxide as a mediator of cytotoxicity  

PubMed Central

When deprived of oxygen, Bacille Calmette-Guerin (BCG)-activated macrophages no longer lysed P388 lymphoma cells. Both H2O2 release and cytotoxicity by BCG-activated macrophages and by granulocytes triggered with phorbol myristate acetate (PMA) were markedly inhibited when the glucose concentration in the medium was reduced to 0.03 mM or less, or if glucose were replaced with galactose. Catalase abolished PMA- triggered cytotoxicity by both types of effector cells, whereas superoxide dismutase had no effect. Ferricytochrome C reduced the cytotoxicity of BCG-activated macrophages, an effect which was largely reversed by superoxide dismutase. 10 drugs, thought to quench singlet oxygen and/or scavenge hydroxyl radical, did not affect cytotoxicity in this system. Neither azide nor cyanide reduced cytolysis, but there was marked inhibition by lactoperoxidase and iodide. This suggested that cytotoxicity was not dependent upon myeloperoxidase, and that lactoperoxidase may have diverted H2O2 from the oxidation of target cells to oxidation of substances in serum. Mouse erythrocytes, although sensitive targets, interfered with the cytolysis of lymphoma cells, probably by competition for H2O2. Starch particles with covalently bound glucose oxidase resembled macrophages in their spatial relation to the target cells and in the flux of H2O2 they generated from their surface, but were not expected to produce any other potentially toxic products. Such particles lysed lymphoma cells, and the lysis was prevented by catalase. Neither arginase nor thymidine appeared to be involved in cytolysis by BCG-activated macrophages under the conditions used. These findings demonstrated that release of H2O2 was both necessary and sufficient for cytolysis by BCG-activated macrophages and by granulocytes when pharmacologically triggered. PMID:216763

1979-01-01

281

Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells.  

PubMed

Swift and regulated clearance of apoptotic cells prevents the accumulation of cell remnants in injured tissues and contributes to the shift of macrophages towards alternatively activated reparatory cells that sustain wound healing. Environmental signals, most of which are unknown, in turn control the efficiency of the clearance of apoptotic cells and as such determine whether tissues eventually heal. In this study we show that vessel-associated stem cells (mesoangioblasts) specifically modulate the expression of genes involved in the clearance of apoptotic cells and in macrophage alternative activation, including those of scavenger receptors and of molecules that bridge dying cells and phagocytes. Mesoangioblasts, but not immortalized myoblasts or neural precursor cells, enhance CD163 membrane expression in vitro as assessed by flow cytometry, indicating that the effect is specific. Mesoangioblasts transplanted in acutely or chronically injured skeletal muscles determine the expansion of the population of CD163(+) infiltrating macrophages and increase the extent of CD163 expression. Conversely, macrophages challenged with mesoangioblasts engulf significantly better apoptotic cells in vitro. Collectively, the data reveal a feed-forward loop between macrophages and vessel-associated stem cells, which has implications for the skeletal muscle homeostatic response to sterile injury and for diseases in which homeostasis is jeopardized, including muscle dystrophies and inflammatory myopathies. PMID:24749786

Bosurgi, L; Brunelli, S; Rigamonti, E; Monno, A; Manfredi, A A; Rovere-Querini, P

2015-01-01

282

Rat Macrophage C-Type Lectin Is an Activating Receptor Expressed by Phagocytic Cells  

PubMed Central

Macrophage C-type lectin (MCL) is a membrane surface receptor encoded by the Antigen Presenting Lectin-like gene Complex (APLEC). We generated a mouse monoclonal antibody for the study of this receptor in the rat. We demonstrate that rat MCL is expressed on blood monocytes and neutrophils, as well as on several tissue macrophage populations, including alveolar and peritoneal cavity macrophages. We also demonstrate MCL expression on a subset of resident spleen macrophages. Immunohistochemistry analysis of the spleen showed staining specifically in the marginal zone and red pulp. Exposure to pro-inflammatory mediators or to yeast cell wall extract (zymosan) increased surface MCL expression on peritoneal macrophages. We characterized a rat myeloid cell line, RMW, which expresses high levels of MCL. We found that MCL co-immunoprecipitated with the activating adaptor protein Fc?RI? in these cells. Moreover, beads coated with anti-MCL antibody increased phagocytosis in the RMW cells. Together, these observations indicate that rat MCL is a receptor that activates phagocytosis in myeloid cells under inflammatory conditions. PMID:23468983

Lobato-Pascual, Ana; Saether, Per Christian; Dahle, Maria K.; Gaustad, Peter; Dissen, Erik; Fossum, Sigbjřrn; Daws, Michael R.

2013-01-01

283

TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells  

PubMed Central

Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, since in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN+CD16+ macrophages and CD1b+DC-SIGN? dendritic cells. DC-SIGN+ phagocytic macrophages were expanded by TLR-mediated upregulation of IL-15/IL-15R. CD1b+ dendritic cells were expanded by TLR-mediated upregulation of GM-CSF/GM-CSFR, promoted T cell activation and secreted proinflammatory cytokines. While DC-SIGN+ macrophages were detected in lesions of all leprosy patients, CD1b+ dendritic cells were not detected in patients with the progressive lepromatous form, except during reversal reactions in which bacilli were cleared by Th1 responses. In T-lep lesions, DC-SIGN+ cells were positive for macrophage markers, but negative for dendritic cell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cells appears critically to influence effective host defenses in human infectious disease. PMID:15880118

Krutzik, Stephan R.; Tan, Belinda; Li, Huiying; Ochoa, Maria Teresa; Liu, Philip T.; Sharfstein, Sarah E.; Graeber, Thomas G.; Sieling, Peter A.; Liu, Yong-Jun; Rea, Thomas H.; Bloom, Barry R.; Modlin, Robert L.

2005-01-01

284

Regulation of macrophage activation and human immunodeficiency virus production by invasive Salmonella strains.  

PubMed Central

Salmonellae possess the ability to adhere to and invade macrophages and in so doing trigger a number of intracellular events that are associated with cellular activation. As an initial approach to defining the mechanisms by which invasive salmonellae alter macrophage function, we have explored the impact of Salmonella infection on the production of human immunodeficiency virus (HIV) in U1 cells, a promonocytic cell line latently infected with the virus. Infection of U1 cells with a pathogenic strain of Salmonella enteritidis resulted in a marked induction of macrophage activation and HIV production. The stimulatory effect of salmonellae was mediated by signals other than lipopolysaccharide. Salmonella mutants with specific defects in invasion or intracellular survival were markedly less effective in the induction of HIV production. In contrast to S. enteritidis, strains of Yersinia enterocolitica, Legionella pneumophila, and Escherichia coli did not induce HIV production. However, all of these bacteria induced comparable levels of gene expression mediated by the HIV long terminal repeat. The results of this study are consistent with the notion that invasive salmonellae possess the ability to activate the macrophage by at least one mechanism that is not shared with several other species of gram-negative bacteria. Furthermore, the expression of this unique property is maximal with Salmonella strains that are not only invasive but also capable of prolonged survival within the macrophage. Our results indicate that the U1 cell line may be a very useful model system with which to examine the biochemical pathways by which internalized salmonellae modulate the activation state of the macrophage. PMID:7729890

Mizel, S B; Kucera, L S; Richardson, S H; Ciacci, F; Iyer, N P

1995-01-01

285

The Intestinal Microbiota Are Necessary for Stressor-Induced Enhancement of Splenic Macrophage Microbicidal Activity  

PubMed Central

The indigenous microbiota impact mucosal, as well as systemic, immune responses, but whether the microbiota are involved in stressor-induced immunomodulation has not been thoroughly tested. A well characterized murine stressor, called social disruption (SDR), was used to study whether the microbiota are involved in stressor-induced enhancement of macrophage reactivity. Exposure to the SDR stressor enhanced the ability of splenic macrophages to produce microbicidal mediators (e.g., inducible nitric oxide synthase (iNOS), superoxide anion, and peroxynitrite) and to kill target Escherichia coli. Exposure to the SDR stressor also increased cytokine production by LPS-stimulated splenic macrophages. These effects, however, were impacted by the microbiota. Microbicidal activity and cytokine mRNA in splenic macrophages from Swiss Webster germfree mice that lack any commensal microbiota were not enhanced by exposure to the SDR stressor. However, when germfree mice were conventionalized by colonizing them with microbiota from CD-1 conventional donor mice, exposure to the SDR stressor again increased microbicidal activity and cytokine mRNA. In follow up experiments, immunocompetent conventional CD-1 mice were treated with a cocktail of antibiotics to disrupt the intestinal microbiota. While exposure to the SDR stressor enhanced splenic macrophage microbicidal activity and cytokine production in vehicle-treated mice, treatment with antibiotics attenuated the SDR stressor-induced increases in splenic macrophage reactivity. Treatment with antibiotics also prevented the stressor-induced increase in circulating levels of bacterial peptidoglycan, suggesting that translocation of microbiota-derived peptidoglycan into the body primes the innate immune system for enhanced activity. This study demonstrates that the microbiota play a crucial role in stressor-induced immunoenhancement. PMID:22100833

Allen, Rebecca G.; Lafuse, William P.; Galley, Jeffrey D.; Ali, Mohamed M.; Ahmer, Brian M. M.; Bailey, Michael T.

2011-01-01

286

Serum factors, cell membrane CD14, and beta2 integrins are not required for activation of bovine macrophages by lipopolysaccharide.  

PubMed Central

The role of serum factors such as lipopolysaccharide (LPS)-binding protein (LBP) and of macrophage-expressed CD14 and beta2 integrins in the activation of bovine macrophages by LPS was investigated. Macrophage activation was determined by measuring tumor necrosis factor production, NO generation, and upregulation of procoagulant activity by LPS (Escherichia coli O55:B5) at concentrations of 100 pg/ml to 100 ng/ml. The 50% effective dose for LPS was 1 order of magnitude higher than that for activating human macrophages. Macrophages were activated by LPS in the presence of serum or in the presence of albumin demonstrated to be free of LBP. The capacity to react to LPS in the absence of LBP was not due to the acquisition of LBP during a previous culture in serum. It was then established which CD14-specific antibodies block LPS binding to monocytes. Among the CD14-specific antibodies recognizing bovine mononuclear phagocytes (60bca, 3C10, My4, CAM36, VPM65, CMRF31, and TUK4), the first four blocked the binding of LPS-fluorescein isothiocyanate to bovine monocytes at low concentrations. Anti-CD14 antibodies did not block LPS-mediated activation of bovine bone marrow-derived macrophages, monocyte-derived macrophages, and alveolar macrophages. This was observed in experiments in which anti-CD14 concentrations exceeded the 50% inhibitory dose by >30-fold (3C10 and My4) or >300-fold (60bca), as defined in the binding assay described above. Monocyte-derived macrophages from an animal deficient in beta2 integrins and control macrophages were activated by similar concentrations of LPS, suggesting that beta2 integrins are not important bovine LPS receptors. Thus, in bovine macrophages, LPS recognition pathways which are independent of exogenous LBP, of membrane-expressed CD14, and of beta2 integrins may exist. PMID:9284122

Jungi, T W; Sager, H; Adler, H; Brcic, M; Pfister, H

1997-01-01

287

Cholesterol loading in macrophages stimulates formation of ER-derived vesicles with elevated ACAT1 activity  

PubMed Central

ACAT1 is normally a resident enzyme in the endoplasmic reticulum (ER). We previously showed that treating macrophages with denatured LDL causes a large increase in ER-derived, ACAT1-positive vesicles. Here, we isolated ER membranes and ER-derived vesicles to examine their ACAT enzyme activity in vitro. The results showed that when macrophages are grown under normal conditions, ACAT1 is located in high density ER membrane; its enzymatic activity is relatively low. Loading macrophages with cholesterol did not increase the total cellular ACAT1 protein content significantly but caused more ACAT1 to appear in ER-derived vesicles. These vesicles exhibit lower density and are associated with markers of both ER and the trans-Golgi network. When normalized with equal ACAT1 protein mass, the enzymatic activities of ACAT1 in ER-derived vesicles were 3-fold higher than those present in ER membrane. Results using reconstituted ACAT enzyme assay showed that the increase in enzyme activity in ER-derived vesicles is not due to an increase in the cholesterol content associated with these vesicles. Overall, our results show that macrophages cope with cholesterol loading by using a novel mechanism: they produce more ER-derived vesicles with elevated ACAT1 enzyme activity without having to produce more ACAT1 protein. PMID:20460577

Sakashita, Naomi; Chang, Catherine C. Y.; Lei, Xiaofeng; Fujiwara, Yukio; Takeya, Motohiro; Chang, Ta-Yuan

2010-01-01

288

Complement activation by the alternative pathway and macrophage enzyme secretion in the pathogenesis of chronic inflammation.  

PubMed Central

A number of stimuli known to induce acid hydrolase secretion from cultured macrophages were examined for their ability to activate C3 via the alternative pathway of the complement system. Loss of haemolytically active C3 was checked in normal and C4-deficient guinea-pig serum. For comparison the interactions of cultured macrophages with other agents well known as potent activators of the alternative pathway of the complement system have been investigated. As judged by their activity in these assays, group A streptococcal cell walls, different carrageenan preparations, dental plaque and Actinomyces viscosus were all capable of initiating the alternative pathway but differed with respect to their potency and their ability to inhibit C3 turnover at high concentrations. Zymosan, some carrageenans, polyanethol sulphonate, and Corynebacterium parvum all induce the release of hydrolytic enzymes from macrophages in culture, even in the absence of serum in the medium. The release is time- and dose-dependent and is not associated with loss of the cytoplasmic enzyme lactate dehydrogenase or any other sign of cell death. The parallelism between the capacity of several agents to activate the complement system via the alternative pathway and to induce inflammatory responses in vivo and selective lysosoma enzyme secretion from cultures of macrophages is discussed. PMID:328387

Schorlemmer, H U; Bitter-Suermann, D; Allison, A C

1977-01-01

289

Inhibition of p38 MAP kinase during cellular activation results in IFN-gamma-dependent augmentation of IL-12 production by human monocytes/macrophages.  

PubMed

Interleukin-12 (IL-12) is a key immunomodulatory cytokine produced by antigen-presenting cells that promotes cellular immunity and enables the generation of protective immunity against intracellular pathogens and tumours. Therefore, modulation of IL-12 activity is a primary immunotherapeutic goal. However, little is known about its regulation. Signalling via p38 MAPK has been implicated in the control of inflammatory responses and is therefore a potential therapeutic target. We have used the highly selective p38 MAPK inhibitor (SB203580) to examine the effect of this pathway on the production of IL-12. Surprisingly, we found that SB203580 strongly up-regulated LPS induced IL-12p40 at the protein (intracellular and secreted) and mRNA levels in PBMC cultures. The effect on IL-12 was apparent using both T cell-independent and T cell-dependent stimuli but not in unstimulated cultures, indicating that activation signals are required. Furthermore, the production of IFN-gamma by T cells is crucial as production was not increased in LPS-stimulated, purified adherent monocytes/macrophages without the addition of exogenous IFN-gamma. These results provide evidence that p38 MAPK has an unexpected suppressive effect on IL-12p40 gene transcription, and suggests interplay between p38 MAPK- and IFN-gamma -mediated signals in the regulation of IL-12 production by monocytes/macrophages. Furthermore, the importance of IL-12 as a key immunoregulatory cytokine suggests that the clinical application of pyrinidyl imidazole inhibitors, such as SB203580, may need to be reassessed. PMID:11472427

Marriott, J B; Clarke, I A; Dalgleish, A G

2001-07-01

290

Pneumolysin activates macrophage lysosomal membrane permeabilization and executes apoptosis by distinct mechanisms without membrane pore formation.  

PubMed

Intracellular killing of Streptococcus pneumoniae is complemented by induction of macrophage apoptosis. Here, we show that the toxin pneumolysin (PLY) contributes both to lysosomal/phagolysosomal membrane permeabilization (LMP), an upstream event programing susceptibility to apoptosis, and to apoptosis execution via a mitochondrial pathway, through distinct mechanisms. PLY is necessary but not sufficient for the maximal induction of LMP and apoptosis. PLY's ability to induce both LMP and apoptosis is independent of its ability to form cytolytic pores and requires only the first three domains of PLY. LMP involves TLR (Toll-like receptor) but not NLRP3/ASC (nucleotide-binding oligomerization domain [Nod]-like receptor family, pyrin domain-containing protein 3/apoptosis-associated speck-like protein containing a caspase recruitment domain) signaling and is part of a PLY-dependent but phagocytosis-independent host response that includes the production of cytokines, including interleukin-1 beta (IL-1?). LMP involves progressive and selective permeability to 40-kDa but not to 250-kDa fluorescein isothiocyanate (FITC)-labeled dextran, as PLY accumulates in the cytoplasm. In contrast, the PLY-dependent execution of apoptosis requires phagocytosis and is part of a host response to intracellular bacteria that also includes NO generation. In cells challenged with PLY-deficient bacteria, reconstitution of LMP using the lysomotrophic detergent LeuLeuOMe favored cell necrosis whereas PLY reconstituted apoptosis. The results suggest that PLY contributes to macrophage activation and cytokine production but also engages LMP. Following bacterial phagocytosis, PLY triggers apoptosis and prevents macrophage necrosis as a component of a broad-based antimicrobial strategy. This illustrates how a key virulence factor can become the focus of a multilayered and coordinated innate response by macrophages, optimizing pathogen clearance and limiting inflammation. Importance: Streptococcus pneumoniae, the commonest cause of bacterial pneumonia, expresses the toxin pneumolysin, which can make holes in cell surfaces, causing tissue damage. Macrophages, resident immune cells essential for responses to bacteria in tissues, activate a program of cell suicide called apoptosis, maximizing bacterial clearance and limiting harmful inflammation. We examined pneumolysin's role in activating this response. We demonstrate that pneumolysin did not directly form holes in cells to trigger apoptosis and show that pneumolysin has two distinct roles which require only part of the molecule. Pneumolysin and other bacterial factors released by bacteria that have not been eaten by macrophages activate macrophages to release inflammatory factors but also make the cell compartment containing ingested bacteria leaky. Once inside the cell, pneumolysin ensures that the bacteria activate macrophage apoptosis, rather than necrosis, enhancing bacterial killing and limiting inflammation. This dual response to pneumolysin is critical for an effective immune response to S. pneumoniae. PMID:25293758

Bewley, Martin A; Naughton, Michael; Preston, Julie; Mitchell, Andrea; Holmes, Ashleigh; Marriott, Helen M; Read, Robert C; Mitchell, Timothy J; Whyte, Moira K B; Dockrell, David H

2014-01-01

291

Transgenic expression of salmon delta-5 and delta-6 desaturase in zebrafish muscle inhibits the growth of Vibrio alginolyticus and affects fish immunomodulatory activity.  

PubMed

Marine fish are an important nutritional source for highly polyunsaturated fatty acids (PUFAs). PUFA biosynthesis requires the following key enzymes: delta-4 (?-4) desaturase, delta-5 (?-5) desaturase, delta-6 (?-6) desaturase, delta-5 (?-5) elongase, and delta-6 (?-6) elongase. The effect of overexpressing delta-5 desaturase and/or delta-6 desaturase in zebrafish muscle has not previously been reported. Herein, we investigated the effects of these proteins on antibacterial and immunomodulatory activity in transgenic zebrafish infected with Vibrio alginolyticus. Overexpression of delta-5 and delta-6 desaturase enhanced antibacterial activity at 4 and 12 h after injection of bacteria into muscle, as compared to controls. Furthermore, expression of immune-related genes (IL-1?, IL-22, and TNF-?) was observed to be altered in transgenic fish after 4 h of bacterial infection, resulting in a significant decrease in the inflammatory response, as compared to control fish. These results demonstrate that muscle-specific expression of transgenic desaturases in zebrafish not only enhance PUFA production, but also enhance antibacterial and anti-inflammatory activity. Overall, these results identify delta-5 and delta-6 desaturase as novel candidate genes for use in aquaculture, to enhance both disease resistance and fish oil production. PMID:24811009

Wang, Yi-Da; Peng, Kuan-Chieh; Wu, Jen-Leih; Chen, Jyh-Yih

2014-08-01

292

The Role of Macrophage Derived Urokinase Plasminogen Activator in Myocardial Infarct Repair  

PubMed Central

Cardiac plasmin activity is increased following myocardial ischemia. To test the hypothesis that macrophage-derived uPA is a key mediator of repair following myocardial infarction we performed myocardial infarction on mice with macrophage specific over-expression of uPA (SR-uPA mice). SR-uPA+/0 mice and wild-type littermates were sacrificed at 5 days or 4 weeks after infarction and cardiac content of macrophages, collagen, and myofibroblasts was quantified. Cardiac function and dimensions were assessed by echocardiography at baseline and at 4 weeks post-infarction. At 4 weeks after myocardial infarction, macrophage counts were increased in SR-uPA+/0 mice in the infarct (13.1 vs. 4.9 %, P < 0.001) and distant uninfarcted regions (5.9 vs. 2.4%, P < 0.001). Infarct scar was thicker in SR-uPA+/0 mice (0.54 ± 0.03mm vs. 0.45 ± 0.03mm, P <0.05) and infarct cardiac collagen content was increased (72.4 ± 3.3% vs. 63.0 ± 3.6%, P < 0.06). Functionally, these changes resulted in mildly improved fractional shortening in SR-uPA+/o mice compared to controls (24.6 ±1.68 vs. 19.8 ± 1.3% P = 0.03). At 5 days after infarction there was increased collagen content in the scar without increases in macrophages or myofibroblasts. To understand the mechanisms by which macrophage derived uPA increases collagen, cardiac fibroblasts were treated with macrophage conditioned medium or plasmin and expression of ColI?1 measured by qPCR. Conditioned media from SR-uPA+/o or plasmin-treated nontransgenic macrophages but not plasmin alone increased collagen expression in isolated cardiac fibroblasts. We hypothesize that plasmin generation in the heart in response to injury may induce activation of macrophages to a profibrotic phenotype to allow rapid formation of collagenous scar. PMID:20380835

Minami, Elina; Castellani, Chiara; Malchodi, Laura; Deem, Jennifer; Bertko, Kate; Meznarich, Jessica; Dishmon, Monja; Murry, Charles E.; Stempien-Otero, April

2011-01-01

293

Immunoregulation by macrophages II. Separation of mouse peritoneal macrophages having tumoricidal and bactericidal activities and those secreting PGE and interleukin I  

SciTech Connect

Macrophage subpopulations having bactericidal or tumoricidal activities and secreting interleukin I (IL1) or prostaglandin E (PGE) were identified through primary or secondary infection with Salmonella enteritidis and separated by sedimentation velocity. Bactericidal activity was measured by (3H)-thymidine release from Listeria monocytogenes and tumoricidal activity by 51Cr-release from C-4 fibrosarcoma or P815 mastocytoma cells. Macrophages with bactericidal activity were distinguished from those with tumoricidal activity a) during secondary infection when cytolytic activity occurred only at days 1-4 post injection and bactericidal activity remained high throughout and b) after sedimentation velocity separation. Cytolysis was consistently greatest among adherent cells of low sedimentation velocity, whereas cells with bactericidal activity increased in size during the infection. Tumour cytostasis (inhibition and promotion of (3H)-thymidine uptake) differed from cytolysis in that the former was more prolonged during infection and was also detected among large cells. Secretion of immunoregulatory molecules PGE and IL1 occurred maximally among different macrophage subpopulations separated by sedimentation velocity and depending on the type of stimulus used in vitro. There was an inverse correlation between IL1 production and PGE production after stimulation with C3-zymosan or lipopolysaccharide (LPS). The development of immunity during infection may therefore be dependent upon the relative proportions of effector and regulatory macrophage subpopulations and the selective effects of environmental stimuli on these functions.

Hopper, K.E.; Cahill, J.M.

1983-06-01

294

Phenotypic activation and pharmacological outcomes of spontaneously differentiated human monocyte-derived macrophages.  

PubMed

Macrophage activation has been observed in vivo under physiological and pathological conditions, and may represent an attractive target for pharmacological modulation. This study tested the hypothesis that human blood-derived macrophages generated in vitro in the absence of specific macrophage growth factors respond flexibly to activation stimuli and pharmacological treatment. Monocytes were differentiated to macrophages for 7 days in culture in RPMI 1640 with 10% FCS. The resulting population showed predominance of the M2 over M1 phenotype as measured by flow cytometry and the expression of M1 vs. M2 markers was not mutually exclusive. Activation with LPS/IFN-? for 48h significantly increased the fraction of surface CD68-expressing cells, the CD14(+)/CD16(-)/CD68(+) subset and cell-bound TNF-? levels, whereas expression of the CC chemokine receptor (CCR)-2 was unchanged. Expression of the M2 markers CD206, CD163 and CX3CR1 was down-regulated following M1 activation compared with resting and after pre-exposure to M2-triggers. By contrast, alternative activation with IL-4/IL-13 for 48h did not increase M2 markers, while CD206 up-regulation was observed after 7 days. Both activation signals induced changes in gene expression profiles as shown by Q-PCR. Treatment with 100nM dexamethasone enhanced the M2 morphotype and CD163 expression while preventing LPS/IFN-?-induced CD163 down-regulation. After 1-week dexamethasone treatment, virtually all cells acquired a CD163(+)/CD206(+)/CX3CR1(+) M2 phenotype. Therefore, these protocols appear to be useful to perform screens of pharmacological agents targeting human macrophage activation. PMID:25582402

Tedesco, Serena; Bolego, Chiara; Toniolo, Alice; Nassi, Alberto; Fadini, Gian Paolo; Locati, Massimo; Cignarella, Andrea

2015-05-01

295

Activating Transcription Factor 4 Promotes Angiogenesis of Breast Cancer through Enhanced Macrophage Recruitment  

PubMed Central

Angiogenesis plays an important role in the progression of tumor. Besides being regulated by tumor cells per se, tumor angiogenesis is also influenced by stromal cells in tumor microenvironment (TME), for example, tumor associated macrophages (TAMs). Activating transcription factor 4 (ATF4), a member of the ATF/CREB family, has been reported to be related to tumor angiogenesis. In this study, we found that exogenous overexpression of ATF4 in mouse breast cancer cells promotes tumor growth via increasing tumor microvascular density. However, ATF4 overexpression failed to increase the expression level of a series of proangiogenic factors including vascular endothelial growth factor A (VEGFA) in tumor cells in this model. Thus, we further investigated the infiltration of proangiogenic macrophages in tumor tissues and found that ATF4-overexpressing tumors could recruit more macrophages via secretion of macrophage colony stimulating factor (M-CSF). Overall, we concluded that exogenous overexpression of ATF4 in breast cancer cells may facilitate the recruitment of macrophages into tumor tissues and promote tumor angiogenesis and tumor growth indirectly.

Wang, Lina; Tong, Lingling; He, Ningning; Chen, Yanan; Liu, Yanhua; Wu, Zhongjun; Sun, Peiqing; Xiang, Rong; Ren, Guosheng

2015-01-01

296

Class A scavenger receptor activation inhibits endoplasmic reticulum stress-induced autophagy in macrophage.  

PubMed

Macrophage death in advanced atherosclerosis promotes plaque necrosis and destabilization. Involvement of autophagy in bulk degradation of cellular components has been recognized recently as an important mechanism for cell survival under endoplasmic reticulum (ER) stress. We previously found that the engagement of class A scavenger receptor (SR-A) triggered JNK-dependent apoptosis in ER-stressed macrophages. However, pro-apoptotic mechanisms mediated by SR-A are not fully understood. Therefore, we sought to see if SR-A mediated apoptosis was associated with autophagy in macrophages. Here, we showed that fucoidan inhibited microtubule-associated protein light chain 3-phospholipid conjugates (LC3-II) formation as well as the number of autophagosomes under ER stress. The inhibition of LC3-II formation was paralleled by the activation of the mTOR pathway, and the inhibition of mTOR allowed LC3-II induction in macrophages treated with thapsigargin plus fucoidan. Furthermore, apoptosis induced by fucoidan was prevented under ER stress by the mTOR inhibitor. We propose that fucoidan, a SR-A agonist, may contribute to macrophage apoptosis during ER stress by inhibiting autophagy. PMID:25013404

Huang, Hanpeng; Li, Xiaoyu; Zhuang, Yan; Li, Nan; Zhu, Xudong; Hu, Jin; Ben, Jingjing; Yang, Qing; Bai, Hui; Chen, Qi

2014-05-01

297

Escherichia coli and Candida albicans Induced Macrophage Extracellular Trap-Like Structures with Limited Microbicidal Activity  

PubMed Central

The formation of extracellular traps (ETs) has recently been recognized as a novel defense mechanism in several types of innate immune cells. It has been suggested that these structures are toxic to microbes and contribute significantly to killing several pathogens. However, the role of ETs formed by macrophages (METs) in defense against microbes remains little known. In this study, we demonstrated that a subset of murine J774A.1 macrophage cell line (8% to 17%) and peritoneal macrophages (8.5% to 15%) form METs-like structures (METs-LS) in response to Escherichia coli and Candida albicans challenge. We found only a portion of murine METs-LS, which are released by dying macrophages, showed detectable killing effects on trapped E. coli but not C. albicans. Fluorescence and scanning electron microscopy analyses revealed that, in vitro, both microorganisms were entrapped in J774A.1 METs-LS composed of DNA and microbicidal proteins such as histone, myeloperoxidase and lysozyme. DNA components of both nucleus and mitochondrion origins were detectable in these structures. Additionally, METs-LS formation occurred independently of ROS produced by NADPH oxidase, and this process did not result in cell lysis. In summary, our results emphasized that microbes induced METs-LS in murine macrophage cells and that the microbicidal activity of these METs-LS differs greatly. We propose the function of METs-LS is to contain invading microbes at the infection site, thereby preventing the systemic diffusion of them, rather than significantly killing them. PMID:24587206

Liao, Chengshui; Liu, Xiaolei; Du, Jing; Shi, Haining; Wang, Xuelin; Bai, Xue; Peng, Peng; Yu, Lu; Wang, Feng; Zhao, Ying; Liu, Mingyuan

2014-01-01

298

Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma  

PubMed Central

Background The mechanisms by which viruses cause asthma exacerbations are not precisely known. Previously, we showed that, in ovalbumin (OVA)-sensitized and -challenged mice with allergic airway inflammation, rhinovirus (RV) infection increases type 2 cytokine production from alternatively-activated (M2) airway macrophages, enhancing eosinophilic inflammation and airways hyperresponsiveness. In this paper, we tested the hypothesis that IL-4 signaling determines the state of macrophage activation and pattern of RV-induced exacerbation in mice with allergic airways disease. Methods Eight week-old wild type or IL-4 receptor knockout (IL-4R KO) mice were sensitized and challenged with OVA and inoculated with RV1B or sham HeLa cell lysate. Results In contrast to OVA-treated wild-type mice with both neutrophilic and eosinophilic airway inflammation, OVA-treated IL-4R KO mice showed increased neutrophilic inflammation with few eosinophils in the airways. Like wild-type mice, IL-4R KO mice showed OVA-induced airway hyperreactivity which was further exacerbated by RV. There was a shift in lung cytokines from a type 2-predominant response to a type 1 response, including production of IL-12p40 and TNF-?. IL-17A was also increased. RV infection of OVA-treated IL-4R KO mice further increased neutrophilic inflammation. Bronchoalveolar macrophages showed an M1 polarization pattern and ex vivo RV infection increased macrophage production of TNF-?, IFN-? and IL-12p40. Finally, lung cells from OVA-treated IL-4R KO mice showed reduced CD206+ CD301+ M2 macrophages, decreased IL-13 and increased TNF-? and IL-17A production by F4/80+, CD11b+?macrophages. Conclusions OVA-treated IL-4R KO mice show neutrophilic airway inflammation constituting a model of allergic, type 1 cytokine-driven neutrophilic asthma. In the absence of IL-4/IL-13 signaling, RV infection of OVA-treated mice increased type 1 cytokine and IL-17A production from conventionally-activated macrophages, augmenting neutrophilic rather than eosinophilic inflammation. In mice with allergic airways inflammation, IL-4R signaling determines macrophage activation state and the response to subsequent RV infection. PMID:24907978

2014-01-01

299

Immunomodulatory Effects of Triphala and its Individual Constituents: A Review  

PubMed Central

The role of plant extracts and Ayurvedic polyherbal preparations in treating various ailments has been acknowledged since time immemorial. Studies based on the effect of these extracts in treatment of different diseases have also been well documented. Indian medicinal literature also emphasizes the synergistic effect of polyherbal drugs in restoring and rejuvenating immune system. This review focuses on the immunomodulatory potential of the polyherbal preparation, Triphala and its three constituents, Terminalia bellerica, Terminalia chebula and Emblica officinalis. The role of Triphala and its extract has been emphasized in stimulating neutrophil function. Under stress condition such as noise, Triphala significantly prevents elevation of IL-4 levels as well as corrects decreased IL-2 and IFN-? levels. Under the condition of inflammatory stress its immunosuppressive activity is attributed to its inhibitory action on complement system, humoral immunity, cell mediated immunity and mitogen-induced T-lymphocyte proliferation. The aqueous and alcoholic extracts of the individual constituents reportedly enhance especially the macrophage activation due to their free radical scavenging activity and the ability to neutralize reactive oxygen species. This study thus concludes the use of Triphala and its three individual constituents as potential immunostimulants and/or immunosuppressants further suggests them to be a better alternative for allopathic immunomodulators. PMID:25593379

Belapurkar, Pranoti; Goyal, Pragya; Tiwari-Barua, Preeti

2014-01-01

300

Immunomodulatory effects of triphala and its individual constituents: a review.  

PubMed

The role of plant extracts and Ayurvedic polyherbal preparations in treating various ailments has been acknowledged since time immemorial. Studies based on the effect of these extracts in treatment of different diseases have also been well documented. Indian medicinal literature also emphasizes the synergistic effect of polyherbal drugs in restoring and rejuvenating immune system. This review focuses on the immunomodulatory potential of the polyherbal preparation, Triphala and its three constituents, Terminalia bellerica, Terminalia chebula and Emblica officinalis. The role of Triphala and its extract has been emphasized in stimulating neutrophil function. Under stress condition such as noise, Triphala significantly prevents elevation of IL-4 levels as well as corrects decreased IL-2 and IFN-? levels. Under the condition of inflammatory stress its immunosuppressive activity is attributed to its inhibitory action on complement system, humoral immunity, cell mediated immunity and mitogen-induced T-lymphocyte proliferation. The aqueous and alcoholic extracts of the individual constituents reportedly enhance especially the macrophage activation due to their free radical scavenging activity and the ability to neutralize reactive oxygen species. This study thus concludes the use of Triphala and its three individual constituents as potential immunostimulants and/or immunosuppressants further suggests them to be a better alternative for allopathic immunomodulators. PMID:25593379

Belapurkar, Pranoti; Goyal, Pragya; Tiwari-Barua, Preeti

2014-01-01

301

Estradiol Promotes M1-like Macrophage Activation through Cadherin-11 To Aggravate Temporomandibular Joint Inflammation in Rats.  

PubMed

Macrophages play a major role in joint inflammation. Estrogen is involved in rheumatoid arthritis and temporomandibular disorders. However, the underlying mechanism is still unclear. This study was done to verify and test how estrogen affects M1/M2-like macrophage polarization and then contributes to joint inflammation. Female rats were ovariectomized and treated with increasing doses of 17?-estradiol for 10 d and then intra-articularly injected with CFA to induce temporomandibular joint (TMJ) inflammation. The polarization of macrophages and expression of cadherin-11 was evaluated at 24 h after the induction of TMJ inflammation and after blocking cadherin-11 or estrogen receptors. NR8383 macrophages were treated with estradiol and TNF-?, with or without blocking cadherin-11 or estrogen receptors, to evaluate the expression of the M1/M2-like macrophage-associated genes. We found that estradiol increased the infiltration of macrophages with a proinflammatory M1-like predominant profile in the synovium of inflamed TMJ. In addition, estradiol dose-dependently upregulated the expressions of the M1-associated proinflammatory factor inducible NO synthase (iNOS) but repressed the expressions of the M2-associated genes IL-10 and arginase in NR8383 macrophages. Furthermore, estradiol mainly promoted cadherin-11 expression in M1-like macrophages of inflamed TMJ. By contrast, blockage of cadherin-11 concurrently reversed estradiol-potentiated M1-like macrophage activation and TMJ inflammation, as well as reversed TNF-?-induced induction of inducible NO synthase and NO in NR8383 macrophages. The blocking of estrogen receptors reversed estradiol-potentiated M1-like macrophage activation and cadherin-11 expression. These results suggested that estradiol could promote M1-like macrophage activation through cadherin-11 to aggravate the acute inflammation of TMJs. PMID:25681337

Kou, Xiao-Xing; Li, Chen-Shuang; He, Dan-Qing; Wang, Xue-Dong; Hao, Ting; Meng, Zhen; Zhou, Yan-Heng; Gan, Ye-Hua

2015-03-15

302

Modular analysis of bioinformatics demonstrates a critical role for NF-?B in macrophage activation.  

PubMed

To achieve the goal of identifying the gene groups that regulated macrophage activation, a total of 925 differentially expressed genes of activated macrophages were found at the intersection of the three series (GSE5099-1, GSE5099-2, and GSE18686) from the Gene Expression Omnibus (GEO) database, and a sub-network was constructed based on the protein-protein interaction (PPI) network. Four communities (K?=?3) were identified from the sub-network using the CFinder software. Community 1 was considered as the gene group of interest base on the heat map. GO-BP and KEGG enrichment analysis with the DAVID software showed that the functions of the 14 genes in community 1 were mainly related to the NF-?B pathway. A network was constructed using the Cytoscape software. The diagram showed that STAT1, NFKBIA, NFKAIB, JUN, and RELA were the key genes in the regulation of macrophage activation. Among these genes, RELA (NF-?B P65) was an important member of the NF-?B family, while NFKBIA (I?B?) and NFKAIB (I?B?) were the inhibitory factors of NF-?B. Small molecules capable of regulating these five genes were identified via the CMap software, and a network diagram was generated using the Cytoscape software to provide a reference for the development of new drugs that regulate macrophage activation. PMID:24577727

Zhang, Yingmei; Wang, Yingmei; Lu, Ming; Qiao, Xin; Sun, Bei; Zhang, Weihui; Xue, Dongbo

2014-08-01

303

Kdo2Lipid A of Escherichia coli, a defined endotoxin that activates macrophages via TLR-4  

Microsoft Academic Search

The LIPID MAPS Consortium (www.lipidmaps. org) is developing comprehensive procedures for identify- ing all lipids of the macrophage, following activation by endotoxin. The goal is to quantify temporal and spatial changes in lipids that occur with cellular metabolism and to develop bioinformatic approaches that establish dynamic lipid networks. To achieve these aims, an endotoxin of the highest possible analytical specification

Christian R. H. Raetz; Teresa A. Garrett; C. Michael Reynolds; Walter A. Shaw; Jeff D. Moore; Dale C. Smith; Anthony A. Ribeiro; Robert C. Murphy; Richard J. Ulevitch; Colleen Fearns; Donna Reichart; Christopher K. Glass; Chris Benner; Shankar Subramaniam; Richard Harkewicz; Rebecca C. Bowers-Gentry; Matthew W. Buczynski; Jennifer A. Cooper; Raymond A. Deems; Edward A. Dennis

2006-01-01

304

ARE MACROPHAGES ACTIVATED AND INDUCE PULMONARY INJURY BY INTRACELLULARLY BIOAVAILABLE IRON?  

EPA Science Inventory

ARE MACROPHAGES ACTIVATED AND INDUCE PULMONARY INJURY BY INTRACELLULARLY BIOAVAILABLE IRON? UP Kodavanti1, MCJ Schladweiler1, S Becker2, DL Costa1, P Mayer3, A Ziesenis3, WG Kreyling3, 1ETD, 2HSDivision, NHEERL, USEPA, Research Triangle Park, NC, USA, and 3GSF, Inhalation Biology...

305

An essential regulatory role for macrophage migration inhibitory factor in T-cell activation.  

PubMed Central

The protein known as macrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered and was described 30 years ago to be a T-cell-derived factor that inhibited the random migration of macrophages in vitro. A much broader role for MIF has emerged recently as a result of studies that have demonstrated it to be released from the anterior pituitary gland in vivo. MIF also is the first protein that has been identified to be secreted from monocytes/macrophages upon glucocorticoid stimulation. Once released, MIF acts to "override" or counter-regulate the suppressive effects of glucocorticoids on macrophage cytokine production. We report herein that MIF plays an important regulatory role in the activation of T cells induced by mitogenic or antigenic stimuli. Activated T cells produce MIF and neutralizing anti-MIF antibodies inhibit T-cell proliferation and interleukin 2 production in vitro, and suppress antigen-driven T-cell activation and antibody production in vivo. T cells also release MIF in response to glucocorticoid stimulation and MIF acts to override glucocorticoid inhibition of T-cell proliferation and interleukin 2 and interferon gamma production. These studies indicate that MIF acts in concert with glucocorticoids to control T-cell activation and assign a previously unsuspected but critical role for MIF in antigen-specific immune responses. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8755565

Bacher, M; Metz, C N; Calandra, T; Mayer, K; Chesney, J; Lohoff, M; Gemsa, D; Donnelly, T; Bucala, R

1996-01-01

306

T-cell hybridoma-produced lymphokine that activates macrophages to suppress intracellular growth of Histoplasma capsulatum.  

PubMed Central

Supernatants from concanavalin A-stimulated T-cell hybridomas activated macrophages to suppress the intracellular growth of Histoplasma capsulatum and to kill tumor cells. The supernatants had high interferon activity and were pH 2 sensitive and heat resistant. Gamma interferon is suggested to be among the active substances in the supernatants. Neither alpha interferon nor beta interferon activated macrophages for the Histoplasma growth inhibitory activity. PMID:6197379

Wu-Hsieh, B; Zlotnik, A; Howard, D H

1984-01-01

307

Expression and secretion of type. beta. transforming growth factor by activated human macrophages  

Microsoft Academic Search

Alveolar macrophages activated with concanavalin A and peripheral blood monocytes activated with lipopolysaccharide secrete type ..beta.. transforming growth factor (TGF-..beta..). There is minimal TGF-..beta.. secretion in unactivated monocytes, even though TGF-..beta.. mRNA is expressed in these cells at a level similar to that in activated, lipopolysaccharide-treated cultures. U937 lymphoma cells, which have momocytic characteristics, also express mRNA for TGF-..beta... Freshly

R. K. Assoian; B. E. Fleurdelys; H. C. Stevenson; P. J. Miller; D. K. Madtes; E. W. Raines; R. Ross; M. B. Sporn

1987-01-01

308

Nitric oxide synthase activity is inducible in rat, but not rabbit alveolar macrophages, with a concomitant reduction in arginase activity  

Microsoft Academic Search

Alveolar macrophages were obtained by broncho-alveolar lavage of isolated rat and rabbit lungs and cultured (2.5 × 106 cells\\/dish) for 18 h in the absence or presence of bacterial lipopolysaccharides (LPS) alone or in combination with cytokines. Thereafter, accumulation of 3H-citrulline (NO synthase activity) and 3H-ornithine (arginase activity) were determined.

Claudia Hey; Ignaz Wessler; Kurt Racké

1995-01-01

309

TLR9 and TLR7/8 activation induces formation of keratic precipitates and giant macrophages in the mouse cornea.  

PubMed

Macrophage adherence to the inner corneal surface and formation of MGCs in the stroma are common signs of chronic inflammation following corneal infection. To determine whether macrophage adherence (known clinically as KPs) and giant cell formation were specific to innate immune activation via particular TLR ligands, macrophage activation was examined in a murine model of TLR-mediated corneal inflammation. The corneal epithelium was debrided and highly purified TLR ligands were topically applied once to the cornea of TLR7(-/-), TLR9(-/-), Cx3cr1(gfp/+), CD11c(eYFP), and IL-4(-/-) mice. At 1 week post-treatment macrophage activation and phenotype was evaluated in the cornea. Treatment with TLR2, TLR3, TLR4, and TLR5 ligands caused an increase in the number of activated stromal macrophages in the central cornea at 1 week post-treatment. However, treatment with TLR9 ligand CpG-ODN and the TLR7/8 ligand R848/Resiquimod led to an accumulation of macrophages on the corneal endothelium and formation of multinucleated giant macrophages in the corneal stroma. We suggest that giant cell formation, which is a characteristic feature of granuloma formation in many tissues, may be a unique feature of TLR9- and TLR7/8-mediated macrophage activation. PMID:25416814

Chinnery, Holly R; Leong, Cheng Mee; Chen, Weisan; Forrester, John V; McMenamin, Paul G

2015-01-01

310

Use of folate-conjugated imaging agents to target alternatively activated macrophages in a murine model of asthma.  

PubMed

Pro-inflammatory macrophages play a prominent role in such autoimmune diseases as rheumatoid arthritis, Crohn's disease, psoriasis, sarcoidosis, and atherosclerosis. Because pro-inflammatory macrophages have also been shown to overexpress a receptor for the vitamin folic acid (i.e., folate receptor beta; FR-?), folate-linked drugs have been explored for use in imaging and treatment of these same diseases. To determine whether allergic inflammatory disorders might be similarly targeted with folate-linked drugs, we have examined the characteristics of macrophages that are prominent in the pathogenesis of asthma. We report here that macrophages from the lungs of mice with experimental allergic asthma express FR-?. We further document that these FR-?(+) macrophages coexpress markers of alternatively activated (M2-type) macrophages, including the mannose receptor and arginase-1. Finally, we demonstrate that folate-conjugated fluorescent dyes and radioimaging agents can be specifically targeted to these asthmatic lung macrophages, with little uptake by macrophages present in healthy lung tissue. These data suggest strategies for the development of novel diagnostic agents for the imaging of asthma and other diseases involving alternatively activated macrophages. PMID:23641923

Shen, Jiayin; Chelvam, Venkatesh; Cresswell, Gregory; Low, Philip S

2013-05-01

311

A2B Adenosine Receptors Prevent Insulin Resistance by Inhibiting Adipose Tissue Inflammation via Maintaining Alternative Macrophage Activation  

PubMed Central

Obesity causes increased classical and decreased alternative macrophage activation, which in turn cause insulin resistance in target organs. Because A2B adenosine receptors (ARs) are important regulators of macrophage activation, we examined the role of A2B ARs in adipose tissue inflammation and insulin resistance. A2B AR deletion impaired glucose and lipid metabolism in mice fed chow but not a high-fat diet, which was paralleled by dysregulation of the adipokine system, and increased classical macrophage activation and inhibited alternative macrophage activation. The expression of alternative macrophage activation–specific transcriptions factors, including CCAAT/enhancer-binding protein-?, interferon regulatory factor 4, and peroxisome proliferator–activated receptor-?, was decreased in adipose tissue of A2B AR–deficient mice. Furthermore, in in vitro studies, we found that stimulation of A2B ARs suppressed free fatty acid–induced deleterious inflammatory and metabolic activation of macrophages. Moreover, AR activation upregulated the interleukin-4–induced expression of CCAAT/enhancer-binding protein-?, interferon regulatory factor 4, and peroxisome proliferator–activated receptor-? in macrophages. Altogether, our results indicate that therapeutic strategies targeting A2B ARs hold promise for preventing adipose tissue inflammation and insulin resistance. PMID:24194503

Csóka, Balázs; Koscsó, Balázs; Tör?, Gábor; Kókai, Endre; Virág, László; Németh, Zoltán H.; Pacher, Pál; Bai, Péter; Haskó, György

2014-01-01

312

Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype*  

PubMed Central

Despite the known anti-inflammatory effect of amniotic membrane, its action mechanism remains largely unknown. HC-HA complex (HC-HA) purified from human amniotic membrane consists of high molecular weight hyaluronic acid (HA) covalently linked to the heavy chain (HC) 1 of inter-?-trypsin inhibitor. In this study, we show that soluble HC-HA also contained pentraxin 3 and induced the apoptosis of both formyl-Met-Leu-Phe or LPS-activated neutrophils and LPS-activated macrophages while not affecting the resting cells. This enhanced apoptosis was caused by the inhibition of cell adhesion, spreading, and proliferation caused by HC-HA binding of LPS-activated macrophages and preventing adhesion to the plastic surface. Preferentially, soluble HC-HA promoted phagocytosis of apoptotic neutrophils in resting macrophages, whereas immobilized HC-HA promoted phagocytosis in LPS-activated macrophages. Upon concomitant LPS stimulation, immobilized HC-HA but not HA polarized macrophages toward the M2 phenotype by down-regulating IRF5 protein and preventing its nuclear localization and by down-regulating IL-12, TNF-?, and NO synthase 2. Additionally, IL-10, TGF-?1, peroxisome proliferator-activated receptor ?, LIGHT (TNF superfamily 14), and sphingosine kinase-1 were up-regulated, and such M2 polarization was dependent on TLR ligation. Collectively, these data suggest that HC-HA is a unique matrix component different from HA and uses multiple mechanisms to suppress M1 while promoting M2 phenotype. This anti-inflammatory action of HC-HA is highly desirable to promote wound healing in diseases heightened by unsuccessful transition from M1 to M2 phenotypes. PMID:23878196

He, Hua; Zhang, Suzhen; Tighe, Sean; Son, Ji; Tseng, Scheffer C. G.

2013-01-01

313

Mechanism of macrophage activation induced by polysaccharide from Cordyceps militaris culture broth.  

PubMed

Mushroom-derived polysaccharides have been shown to stimulate immune responses. Our previous report showed that the novel polysaccharide PLCM isolated from the culture broth of Cordyceps militaris could induce nitric oxide production in the murine macrophage-like cell line RAW264.7. In this study, we show that PLCM enhances immunostimulatory activities such as the release of toxic molecules (nitric oxide and reactive oxygen species), secretion of the cytokine tumor necrosis factor (TNF)-?, and phagocytic uptake in RAW264.7 macrophages. In addition, all the specific inhibitors against the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-?B) (SN50, BAY11-7082, PD98059, SP600125 and SB203580) markedly suppressed the nitric oxide production and phagocytic uptake induced by PLCM. Moreover, antibodies specific to the extracellular domain of Toll-like receptor-2, Toll-like receptor-4 or the macrophage receptor Dectin-1 significantly attenuated PLCM-induced secretion of TNF-?. Our results indicate that the C. militaris polysaccharide activates macrophages through the MAPKs and NF-?B signaling pathways via Toll-like receptor 2, Toll-like receptor 4, and Dectin-1. PMID:25662684

Lee, Jong Seok; Kwon, Duck Soo; Lee, Ki Rim; Park, Jun Myoung; Ha, Suk-Jin; Hong, Eock Kee

2015-04-20

314

Modulation of Macrophage Activities in Proliferation, Lysosome, and Phagosome by the Nonspecific Immunostimulator, Mica  

PubMed Central

It was reported that the aluminosilicate material mica activated macrophages and showed its immunostimulating effects. However, the mechanisms by which it exerts these effects are unclear. To address this, we evaluated the effects of mica fine particles (MFP, 804.1 ± 0.02 nm) on the murine macrophage cell line, RAW 264.7. Specifically, RAW 264.7 cells were treated with 100 and 500 ?g/mL MFP and their proliferative response was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Changes in global gene expression upon MFP treatment for 12 and 48 h were also determined using microarrays. Following the MFP treatment, RAW 264.7 cells showed a low level of proliferation compared to nontreated cells (p < 0.01). There was a change in an expression level of 1,128 genes after 48 h treatment. Specifically, genes associated with the cell cycle, DNA replication, and pyrimidine and purine metabolisms, were down-regulated in cells treated with MFP, which resulted in reduction of cell proliferation. MFP treatment also up-regulated genes associated with lysosome and phagosome function, which are both required for macrophage activities. We speculate that activation of macrophages by mica is in part derived from up-regulation of these pathways. PMID:25668030

Jung, Myunghwan; Shin, Min-Kyoung; Jung, Yeon-Kwon; Yoo, Han Sang

2015-01-01

315

Membrane ruffles capture C3bi-opsonized particles in activated macrophages.  

PubMed

A widespread belief in phagocyte biology is that FcgammaR-mediated phagocytosis utilizes membrane pseudopods, whereas Mac-1-mediated phagocytosis does not involve elaborate plasma membrane extensions. Here we report that dynamic membrane ruffles in activated macrophages promote binding of C3bi-opsonized particles. We identify these ruffles as components of the macropinocytosis machinery in both PMA- and LPS-stimulated macrophages. C3bi-particle capture is facilitated by enrichment of high-affinity Mac-1 and the integrin-regulating protein talin in membrane ruffles. Membrane ruffle formation and C3bi-particle binding are cytoskeleton dependent events, having a strong requirement for F-actin and microtubules (MTs). MT disruption blunts ruffle formation and PMA- and LPS-induced up-regulation of surface Mac-1 expression. Furthermore, the MT motor, kinesin participates in ruffle formation implicating a requirement for intracellular membrane delivery to active membrane regions during Mac-1-mediated phagocytosis. We observed colocalization of Rab11-positive vesicles with CLIP-170, a MT plus-end binding protein, at sites of particle adherence using TIRF imaging. Rab11 has been implicated in recycling endosome dynamics and mutant Rab11 expression inhibits both membrane ruffle formation and C3bi-sRBC adherence to macrophages. Collectively these findings represent a novel membrane ruffle "capture" mechanism for C3bi-particle binding during Mac-1-mediated phagocytosis. Importantly, this work also demonstrates a strong functional link between integrin activation, macropinocytosis and phagocytosis in macrophages. PMID:18768756

Patel, Prerna C; Harrison, Rene E

2008-11-01

316

Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages.  

PubMed

Obesity is frequently associated with an infiltration of macrophages into adipose tissue. Adipocyte dysfunction causes a phenotypic switch of macrophages from an alternatively activated M2-like phenotype towards a proinflammatory M1 phenotype. The cross talk between adipocytes and infiltrating immune cells, in particular macrophages, is thought to contribute to local and eventually systemic inflammation. Here, we tested the phenotypic impact of a lack of adipocytes on the inflammatory status of macrophages. We took advantage of the fat apoptosis through targeted activation of caspase-8 (FAT-ATTAC) mouse model that allows for the inducible system-wide elimination of adipocytes through a proapoptotic mechanism and followed the degree and type of inflammatory response upon ablation of live adipocytes. Analysis of depots 2 wk after elimination of adipocytes resulted in markedly reduced levels of adipose tissue and a robust down-regulation of circulating adipokines. Quantitative PCR and immunohistochemistry on epididymal and inguinal fat depots revealed an increase of the macrophage markers F4/80 and CD11c. Using polychromatic flow cytometry, we observed an up-regulation of alternatively activated M2 macrophage markers (CD206 and CD301) on the majority of F4/80 positive cells. Apoptosis of adipocytes is sufficient to initiate a large influx of macrophages into the remnant fat pads. However, these macrophages are alternatively activated, antiinflammatory M2 macrophages and not M1 cells. We conclude that adipocyte death is sufficient to initiate macrophage infiltration, and live adipocytes are required to initiate and/or sustain a proinflammatory response within the infiltrating macrophages in adipose tissue. PMID:21693678

Fischer-Posovszky, Pamela; Wang, Qiong A; Asterholm, Ingrid Wernstedt; Rutkowski, Joseph M; Scherer, Philipp E

2011-08-01

317

Targeted Deletion of Adipocytes by Apoptosis Leads to Adipose Tissue Recruitment of Alternatively Activated M2 Macrophages  

PubMed Central

Obesity is frequently associated with an infiltration of macrophages into adipose tissue. Adipocyte dysfunction causes a phenotypic switch of macrophages from an alternatively activated M2-like phenotype towards a proinflammatory M1 phenotype. The cross talk between adipocytes and infiltrating immune cells, in particular macrophages, is thought to contribute to local and eventually systemic inflammation. Here, we tested the phenotypic impact of a lack of adipocytes on the inflammatory status of macrophages. We took advantage of the fat apoptosis through targeted activation of caspase-8 (FAT-ATTAC) mouse model that allows for the inducible system-wide elimination of adipocytes through a proapoptotic mechanism and followed the degree and type of inflammatory response upon ablation of live adipocytes. Analysis of depots 2 wk after elimination of adipocytes resulted in markedly reduced levels of adipose tissue and a robust down-regulation of circulating adipokines. Quantitative PCR and immunohistochemistry on epididymal and inguinal fat depots revealed an increase of the macrophage markers F4/80 and CD11c. Using polychromatic flow cytometry, we observed an up-regulation of alternatively activated M2 macrophage markers (CD206 and CD301) on the majority of F4/80 positive cells. Apoptosis of adipocytes is sufficient to initiate a large influx of macrophages into the remnant fat pads. However, these macrophages are alternatively activated, antiinflammatory M2 macrophages and not M1 cells. We conclude that adipocyte death is sufficient to initiate macrophage infiltration, and live adipocytes are required to initiate and/or sustain a proinflammatory response within the infiltrating macrophages in adipose tissue. PMID:21693678

Fischer-Posovszky, Pamela; Wang, Qiong A.; Asterholm, Ingrid Wernstedt; Rutkowski, Joseph M.

2011-01-01

318

In vitro anti-inflammatory activity of Phlebodium decumanum. Modulation of tumor necrosis factor and soluble TNF receptors  

Microsoft Academic Search

The immunomodulatory activity of a standardized water soluble fraction of the fern Phlebodium decumanum (EXPLY-37®) previously shown to have “in vivo” anti-inflammatory activity was analyzed “in vitro”. This extract inhibited tumor necrosis factor (TNF) production by macrophages activated with lipopolysaccharide (LPS) or LPS plus interferon (IFN)-?. In contrast, nitric oxide (NO) and interleukin (IL)-1? production were not affected in the

Carmen Punzón; Antonio Alcaide; Manuel Fresno

2003-01-01

319

Myeloid-derived tissue-type plasminogen activator promotes macrophage motility through FAK, Rac1, and NF-?B pathways.  

PubMed

Macrophage accumulation is one of the hallmarks of progressive kidney disease. Tissue-type plasminogen activator (tPA) is known to promote macrophage infiltration and renal inflammation during chronic kidney injury. However, the underlying mechanism remains largely unknown. We examined the role of tPA in macrophage motility in vivo by tracking fluorescence-labeled bone marrow-derived macrophages, and found that tPA-deficient mice had markedly fewer infiltrating fluorescence-labeled macrophages than the wild-type (WT) mice. Experiments in bone marrow chimeric mice further demonstrated that myeloid cells are the main source of endogenous tPA that promotes macrophage migration. In vitro studies showed that tPA promoted macrophage motility through its CD11b-mediated protease-independent function; and focal adhesion kinase (FAK), Rac-1, and NF-?B were indispensable to tPA-induced macrophage migration as either infection of FAK dominant-negative adenovirus or treatment with a Rac-1-specific inhibitor or NF-?B inhibitor abolished the effect of tPA. Moreover, ectopic FAK mimicked tPA and induced macrophage motility. tPA also activated migratory signaling in vivo. The accumulation of phospho-FAK-positive CD11b macrophages in the obstructed kidneys from WT mice was clearly attenuated in tPA knockout mice, which also displayed lower Rac-1 activity than their WT counterparts. Therefore, our results indicate that myeloid-derived tPA promotes macrophage migration through a novel signaling cascade involving FAK, Rac-1, and NF-?B. PMID:25131752

Lin, Ling; Jin, Yang; Mars, Wendy M; Reeves, W Brian; Hu, Kebin

2014-10-01

320

Stat1 combines signals derived from IFN-gamma and LPS receptors during macrophage activation.  

PubMed Central

Complete activation of macrophages during immune responses results from stimulation with the activating cytokine interferon-gamma (IFN-gamma) and a second stimulus, usually a microbial product. Bacterial infection of macrophages, or treatment with bacterial lipopolysaccharide (LPS), resulted in rapid Stat1 phosphorylation on Ser727 (S727) independently of concomitant tyrosine phosphorylation. IFN-gamma also caused rapid phosphorylation of S727. In both situations, S727 phosphorylation was reduced by pre-treatment of cells with the serine kinase inhibitor H7. When macrophages were treated sequentially or simultaneously with LPS and IFN-gamma, the pool of molecules phosphorylated on both Tyr701 (Y701) and S727 was strongly increased. Consistently, Stat1-dependent transcription in response to IFN-gamma was significantly enhanced if the cells were pre-treated with bacterial LPS. The relative amount of S727-phosphorylated Stat1 in the non-tyrosine phosphorylated fraction was considerably smaller than that in the tyrosine-phosphorylated fraction. No evidence was found for an effect of S727 phosphorylation on the phosphorylation of Y701 by IFN-gamma. Thus, serine and tyrosine phosphorylation of Stat1 are caused independently of each other, but the serine kinase may recognize tyrosine-phosphorylated Stat1 preferentially in the course of an IFN-gamma response. The data suggest Stat1 to be a convergence point for immunological stimuli in a macrophage proinflammatory response. PMID:9649436

Kovarik, P; Stoiber, D; Novy, M; Decker, T

1998-01-01

321

Quercetin-3-O-glucuronide induces ABCA1 expression by LXR? activation in murine macrophages  

SciTech Connect

Highlights: •The major circulating quercetin metabolite (Q3GA) activated LXR?. •Q3GA induced ABCA1 via LXR? activation in macrophages. •Nelumbo nucifera leaf extracts contained quercetin glycosides. •N. nucifera leaf extract feeding elevated HDLC in mice. -- Abstract: Reverse cholesterol transport (RCT) removes excess cholesterol from macrophages to prevent atherosclerosis. ATP-binding cassette, subfamily A, member 1 (ABCA1) is a crucial cholesterol transporter involved in RCT to produce high density lipoprotein-cholesterol (HDLC), and is transcriptionally regulated by liver X receptor alpha (LXR?), a nuclear receptor. Quercetin is a widely distributed flavonoid in edible plants which prevented atherosclerosis in an animal model. We found that quercetin-3-O-glucuronide (Q3GA), a major quercetin metabolite after absorption from the digestive tract, enhanced ABCA1 expression, in vitro, via LXR? in macrophages. In addition, leaf extracts of a traditional Asian edible plant, Nelumbo nucifera (NNE), which contained abundant amounts of quercetin glycosides, significantly elevated plasma HDLC in mice. We are the first to present experimental evidence that Q3GA induced ABCA1 in macrophages, and to provide an alternative explanation to previous studies on arteriosclerosis prevention by quercetin.

Ohara, Kazuaki, E-mail: Kazuaki_Ohara@kirin.co.jp [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)] [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan); Wakabayashi, Hideyuki [Laboratory for New Product Development, Kirin Beverage Company Limited, 1-17-1 Namamugi, Tsurumi-ku, Yokohama 230-8628 (Japan)] [Laboratory for New Product Development, Kirin Beverage Company Limited, 1-17-1 Namamugi, Tsurumi-ku, Yokohama 230-8628 (Japan); Taniguchi, Yoshimasa [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)] [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan); Shindo, Kazutoshi [Department of Food and Nutrition, Japan Women’s University, 2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681 (Japan)] [Department of Food and Nutrition, Japan Women’s University, 2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681 (Japan); Yajima, Hiroaki [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)] [Research Laboratories for Health Science and Food Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan); Yoshida, Aruto [Central Laboratories for Key Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)] [Central Laboratories for Key Technologies, Kirin Company Limited, 1-13-5 Fukuura, Kanazawa-ku, Yokohama 236-0004 (Japan)

2013-11-29

322

Anti-tumor and macrophage activation induced by alkali-extracted polysaccharide from Pleurotus ostreatus.  

PubMed

Pleurotus ostreatus is popularly consumed as traditional medicine and health food for enhancing immune function in China. Polysaccharides from mushroom have been demonstrated to possess a wide range of health beneficial properties. This study was carried out to elucidate the immunomodulating effects and molecular mechanism involved in the in vivo and in vitro anti-tumor activities of alkali-extracted polysaccharide (WPOP-N1) from the fruiting bodies of P. ostreatus. The results showed that WPOP-N1 significantly inhibited the tumor growth of Sarcoma 180 tumor-bearing mice, and markedly increased the secretion level of TNF-? in serum. In addition, WPOP-N1 enhanced the phagocytic capability of peritoneal macrophages in vitro. Furthermore, the secretion of TNF-? and NO and the amount of TNF-? and iNOS transcript were increased significantly when the peritoneal macrophages were exposed to WPOP-N1. Meanwhile, Western blot analysis revealed that the stimulation of peritoneal macrophages by WPOP-N1 induced the phosphorylation of p65 and a marked decrease of I?B expression. These results suggest that WPOP-N1 could activate macrophages through NF-?B signaling pathway, and the anti-tumor effects of WPOP-N1 can be achieved by its immunostimulating property. PMID:24942990

Kong, Fanli; Li, Feng-E; He, Zhongmei; Jiang, Yong; Hao, Ruoyi; Sun, Xin; Tong, Haibin

2014-08-01

323

Toxoplasma gondii infection of activated J774-A1 macrophages causes inducible nitric oxide synthase degradation by the proteasome pathway.  

PubMed

Classically activated macrophages produce nitric oxide (NO), which is a potent microbicidal agent. NO production is catalyzed by inducible nitric oxide synthase (iNOS), which uses arginine as substrate producing NO and citruline. However, it has been demonstrated that NO production is inhibited after macrophage infection of Toxoplasma gondii, the agent of toxoplasmosis, due to iNOS degradation. Three possible iNOS degradation pathways have been described in activated macrophages: proteasome, calpain and lysosomal. To identify the iNOS degradation pathway after T. gondii infection, J774-A1 macrophage cell line was activated with lipopolysaccharide and interferon-gamma for 24 h, treated with the following inhibitors, lactacystin (proteasome), calpeptin (calpain), or concanamycin A (lysosomal), and infected with the parasite. NO production and iNOS expression were evaluated after 2 and 6 h of infection. iNOS was degraded in J774-A1 macrophages infected with T. gondii. However, treatment with lactacystin maintained iNOS expression in J774-A1 macrophages infected for 2 h by T. gondii, and after 6 h iNOS was localized in aggresomes. iNOS was degraded after parasite infection of J774-A1 macrophages treated with calpeptin or concanamycin A. NO production confirmed iNOS expression profiles. These results indicate that T. gondii infection of J774-A1 macrophages caused iNOS degradation by the proteasome pathway. PMID:24845536

Padrăo, Juliana da Cruz; Cabral, Gabriel Rabello de Abreu; da Silva, Maria de Fátima Sarro; Seabra, Sergio Henrique; DaMatta, Renato Augusto

2014-10-01

324

Glucans exhibit weak antioxidant activity, but stimulate macrophage free radical activity.  

PubMed

Polymeric carbohydrates have been reported to modulate inflammatory responses in vitro and in vivo. Previous reports suggest that certain carbohydrate polymers, such as (1-->3)-beta-D-glucans, may possess free radical scavenging activity. If glucans are free radical scavengers then it might explain, in part, the ability of these ligands to modulate inflammatory responses. The present study examined the free radical scavenging activity of a variety of carbohydrate polymers and the effect of the polymers on free radical levels in a murine macrophage cell line. All of the carbohydrates exhibited concentration dependent antioxidant effects (EC(50) range = 807 to 43 microg/ml). However, the antioxidant activity for the carbohydrates was modest in comparison with PDTC (EC(50) = 0.13 microg/ml) and the carbohydrate concentration required for antioxidant activity was high (x EC(50) = 283 microg/ml). The antioxidant ability of the polymers was greater (p < .05) than their monosaccharide constituents, i.e., dextrose EC(50) = 807 vs. glucan sulfate EC(50) = 43 microg/ml. Coincubation of glucans with murine J774a.1 cells increased free radical levels when compared to controls. Therefore, the weak free radical scavenging activity of glucan polymers cannot explain their modulatory effect on inflammatory responses in tissue culture and/or disease models of inflammation. PMID:11182295

Tsiapali, E; Whaley, S; Kalbfleisch, J; Ensley, H E; Browder, I W; Williams, D L

2001-02-15

325

Classical and Alternative Macrophage Activation in the Lung following Ozone-induced Oxidative Stress  

PubMed Central

Ozone is a pulmonary irritant known to cause oxidative stress, inflammation and tissue injury. Evidence suggests that macrophages play a role in the pathogenic response; however, their contribution depends on the mediators they encounter in the lung which dictate their function. In these studies we analyzed the effects of ozone-induced oxidative stress on the phenotype of alveolar macrophages (AM). Exposure of rats to ozone (2 ppm, 3 h) resulted in increased expression of 8-hydroxy-2?-deoxyguanosine (8-OHdG), as well as heme oxygenase-1 (HO-1) in AM. Whereas 8-OHdG was maximum at 24 h, expression of HO-1 was biphasic increasing after 3 h and 48–72 h. Cleaved caspase-9 and beclin-1, markers of apoptosis and autophagy, were also induced in AM 24 h post-ozone. This was associated with increased bronchoalveolar lavage protein and cells, as well as matrix metalloproteinase (MMP)-2 and MMP-9, demonstrating alveolar epithelial injury. Ozone intoxication resulted in biphasic activation of the transcription factor, NF?B. This correlated with expression of monocyte chemotactic protein -1, inducible nitric oxide synthase and cyclooxygenase -2, markers of proinflammatory macrophages. Increases in arginase-1, Ym1 and galectin-3 positive anti-inflammatory/wound repair macrophages were also observed in the lung after ozone inhalation, beginning at 24 h (arginase-1, Ym1), and persisting for 72 h (galectin-3). This was associated with increased expression of pro-surfactant protein-C, a marker of Type II cell proliferation and activation, important steps in wound repair. These data suggest that both proinflammatory/cytotoxic and anti-inflammatory/wound repair macrophages are activated early in the response to ozone-induced oxidative stress and tissue injury. PMID:22727909

Sunil, Vasanthi R.; Patel-Vayas, Kinal; Shen, Jianliang; Laskin, Jeffrey D.; Laskin, Debra L.

2012-01-01

326

Induction of Alternatively Activated Macrophages Enhances Pathogenesis during Severe Acute Respiratory Syndrome Coronavirus Infection  

PubMed Central

Infection with severe acute respiratory syndrome coronavirus (SARS-CoV) causes acute lung injury (ALI) that often leads to severe lung disease. A mouse model of acute SARS-CoV infection has been helpful in understanding the host response to infection; however, there are still unanswered questions concerning SARS-CoV pathogenesis. We have shown that STAT1 plays an important role in the severity of SARS-CoV pathogenesis and that it is independent of the role of STAT1 in interferon signaling. Mice lacking STAT1 have greater weight loss, severe lung pathology with pre-pulmonary-fibrosis-like lesions, and an altered immune response following infection with SARS-CoV. We hypothesized that STAT1 plays a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome. To test this, we created bone marrow chimeras and cell-type-specific knockouts of STAT1 to identify which cell type(s) is critical to protection from severe lung disease after SARS-CoV infection. Bone marrow chimera experiments demonstrated that hematopoietic cells are responsible for the pathogenesis in STAT1?/? mice, and because of an induction of alternatively activated (AA) macrophages after infection, we hypothesized that the AA macrophages were critical for disease severity. Mice with STAT1 in either monocytes and macrophages (LysM/STAT1) or ciliated lung epithelial cells (FoxJ1/STAT1) deleted were created. Following infection, LysM/STAT1 mice display severe lung pathology, while FoxJ1/STAT1 mice display normal lung pathology. We hypothesized that AA macrophages were responsible for this STAT1-dependent pathology and therefore created STAT1/STAT6?/? double-knockout mice. STAT6 is essential for the development of AA macrophages. Infection of the double-knockout mice displayed a lack of lung disease and prefibrotic lesions, suggesting that AA macrophage production may be the cause of STAT1-dependent lung disease. We propose that the control of AA macrophages by STAT1 is critical to regulating immune pathologies and for protection from long-term progression to fibrotic lung disease in a mouse model of SARS-CoV infection. PMID:23015710

Page, Carly; Goicochea, Lindsay; Matthews, Krystal; Zhang, Yong; Klover, Peter; Holtzman, Michael J.; Hennighausen, Lothar

2012-01-01

327

In vivo and in vitro immunomodulatory potential of swertiamarin isolated from Enicostema axillare (Lam.) A. Raynal that acts as an anti-inflammatory agent.  

PubMed

Swertiamarin is a secoiridoid glycoside found in Enicostema axillare (Lam) A. Raynal, a medicinal plant used as a depurative in the Indian system of traditional medicine. The present study evaluated the immunomodulatory activity of isolated swertiamarin. In vivo immunomodulatory activity of swertiamarin (2, 5, and 10 mg/kg b.w.) was evaluated in a model of sheep red blood cells (SRBC) by assessing its effect on organ weight, hemagglutinating antibody titer (HA), plaque-forming cells (PFC), quantitative hemolysis of SRBC, and delayed type hypersensitivity (DTH). In vitro immunomodulatory potential was studied on isolated splenocytes, neutrophils, and peritoneal macrophages. In silico immunomodulatory effects were evaluated by docking of swertiamarin on proinflammatory cytokines to confirm its potential. In in vivo studies, the animals treated with swertiamarin showed a significant (P ? 0.05) increase in antibody titer, plaque-forming cells, and also in weight of the thymus and spleen. A decreased response to DTH reaction was recorded with the treatment of swertiamarin. In in vitro studies, treatment with swertiamarin modulated the messenger RNA (mRNA) and protein expression of IFN-?, IL-10, and IL-4 significantly (P ? 0.05) and also favored Th2-mediated response on concanavalin A (Con A)-induced splenocytes. The compound inhibited the release of free radicals significantly (P ? 0.05) in phytohemagglutinin (PHA)-induced neutrophils and also ameliorated the mRNA and protein expression of proinflammatory cytokines (TNF-?, IL-1?, and IL-6) in lipopolysaccharide (LPS)-induced macrophages. In in silico, the best docked pose of swertiamarin with the target proteins (TNF-?, IL-1?, and IL-6) was confirmed that swertiamarin acted as an anti-inflammatory mediator. PMID:24736879

Saravanan, S; Pandikumar, P; Prakash Babu, N; Hairul Islam, V I; Thirugnanasambantham, K; Gabriel Paulraj, M; Balakrishna, K; Ignacimuthu, S

2014-10-01

328

Production of lymphocyte-activating factors by mouse macrophages during aging and under the effect of short peptides.  

PubMed

Age-specific characteristics of production of lymphocyte-activating factor by mouse peritoneal macrophages and modulation of this production by short synthetic peptides (Vilon, Epithalon, and Cortagen) were studied. The production of lymphocyte-activating factors by macrophages stimulated with lipopolysaccharides in vitro was lower in old animals. The opposite modulating effects of short peptides on the production of lymphocyte-activating factors by resident and lipopolysaccharide-stimulated macrophages in young and old mice were demonstrated for the first time. This is a possible mechanism of immune system dysfunction during aging, which opens new vistas for its correction with short synthetic peptides. PMID:17426849

Gumen, A V; Kozinets, I A; Shanin, S N; Malinin, V V; Rybakina, E G

2006-09-01

329

Mefloquine and Its Enantiomers Are Active against Mycobacterium tuberculosis In Vitro and in Macrophages  

PubMed Central

Objective. Tuberculosis is a serious problem of public health. The increase on the number of clinical cases of tuberculosis infected with multidrug resistant (MDR) M. tuberculosis calls for the development of novel therapy. Design. We investigated the effect of mefloquine and two enantiomers, (+)erythro-mefloquine and (+)threo-mefloquine against M. tuberculosis strains in the environment resembling the aspects of the granuloma environment and in macrophages. Results. The results suggest that mefloquine (racemic mixture) and (+)erythro-mefloquine have bactericidal activity against M. tuberculosis strains both in acidic, low oxygen tension and in macrophages. The activity, however, was impaired under increased osmolarity. Conclusion. Identification of the target for mefloquine in the pathogen will allow for the development of novel drugs with antituberculosis activity. PMID:25580293

Bermudez, Luiz E.; Meek, Laura

2014-01-01

330

Production of lymphocyte-activating factors by mouse macrophages during aging and under the effect of short peptides  

Microsoft Academic Search

Age-specific characteristics of production of lymphocyte-activating factor by mouse peritoneal macrophages and modulation\\u000a of this production by short synthetic peptides (Vilon, Epithalon, and Cortagen) were studied. The production of lymphocyte-activating\\u000a factors by macrophages stimulated with lipopolysaccharides in vitro was lower in old animals. The opposite modulating effects of short peptides on the production of lymphocyte-activating factors\\u000a by resident and lipopolysaccharide-stimulated

A. V. Gumen; I. A. Kozinets; S. N. Shanin; V. V. Malinin; E. G. Rybakina

2006-01-01

331

Anti-tumor activity of fucoidan is mediated by nitric oxide released from macrophages.  

PubMed

Fucoidan, a sulfated polysaccharide, has significant cytotoxic activity against tumor cells; however, the mechanism(s) of this action remains poorly understood. The present study was designed to determine the in vitro and in vivo effects of fucoidan and their molecular mechanisms. Fucoidan from Cladosiphon okamuranus Tokida cultivated in Okinawa, Japan, delayed tumor growth in Sarcoma 180 (S-180)-bearing mice. However, it failed to inhibit S-180 cell growth in vitro. Activated macrophages are known to have anti-tumor effects. Murine RAW264.7 macrophages stimulated with fucoidan exerted cytotoxicity towards S-180 cells in vitro. This cytotoxicity was associated with nitric oxide (NO) production. Both cytocidal effect and NO production were significantly inhibited by L-NAME, an inhibitor of NO synthase (NOS). Furthermore, activation of nuclear factor-?B was a key step in the transcriptional activation of the inducible NOS gene. Taken together, our results indicate that the anti-tumor activity of fucoidan on S-180 cells is mediated through increased NO production by fucoidan-stimulated macrophages via nuclear factor-?B-dependent signaling pathway. PMID:21874230

Takeda, Kaori; Tomimori, Koh; Kimura, Ryuichiro; Ishikawa, Chie; Nowling, Tamara K; Mori, Naoki

2012-01-01

332

Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation.  

PubMed

Macrophage dysfunction and inflammasome activation have been implicated in the pathogenesis of diabetes and its complications. Prolonged inflammation and impaired healing are hallmarks of the diabetic response to tissue injury, and excessive inflammasome activation has been associated in these phenotypes. However, the mechanisms that regulate the inflammasome in response to lipid metabolic and inflammatory stress are incompletely understood. We have shown previously that IL-1? secretion is induced in primary macrophages exposed to the dietary saturated fatty acid palmitate in combination with LPS. In this study, we sought to unravel the mechanisms underlying the activation of this lipotoxic inflammasome. We demonstrate that palmitate-loaded primary macrophages challenged with LPS activate the NLRP3 inflammasome through a mechanism that involves the lysosome. Interestingly, the lysosome was involved in both the regulation of pro-IL-1? levels and its subsequent cleavage/release. The lysosomal protease cathepsin B was required for IL-1? release but not pro-IL-1? production. In contrast, disrupting lysosomal calcium regulation decreased IL-1? release by reducing pro-IL-1? levels. The calcium pathway involved the calcium-activated phosphatase calcineurin, which stabilized IL-1? mRNA. Our findings provide evidence that the lysosome plays a key role in both the priming and assembly phases of the lipostoxic inflammasome. These findings have potential relevance to the hyperinflammatory phenotypes observed in diabetics during tissue damage or infection and identify lysosomes and calcineurin as potential therapeutic targets. PMID:24532802

Weber, Kassandra; Schilling, Joel D

2014-03-28

333

Morphologic changes in alveolar macrophages in response to UVEC-activated pulmonary Type II epithelial cells.  

PubMed

We hypothesize that Type II epithelial cells, which line the distal airspaces of the lung, are early responders to invading pathogens and release a signal, which activates and alters the phenotype and phagocytosis properties of alveolar macrophages even at a distance. The T(7) cell line is a conditionally immortalized murine Type II epithelial cell line developed in our laboratory. Using an in vitro transwell model we have previously shown that UV-irradiated Escherichia coli (UVEC)-stimulated T(7) cells cultured in the lower transwell chamber, release a diffusible signal which activates MH-S cells (immortalized murine alveolar macrophages) cultured in the upper transwell chamber, to produce nitric oxide. Using scanning electron microscopy, we show that MH-S cells activated in this manner exhibit increased cell surface ruffling, numerous long filopodia, increased lamellipodia and cell flattening. DynaBead uptake studies show that these morphologic changes are accompanied by increased phagocytosis. These findings indicate that a diffusible signal released at a distance by UVEC-stimulated Type II epithelial cells initiates changes in morphology and phagocytosis reflective of macrophage activation concomitant with the functional activation we previously reported. PMID:15885728

Farberman, M M; Demello, D E; Hoffmann, J W; Ryerse, J S

2005-06-01

334

Lysosomes Integrate Metabolic-Inflammatory Cross-talk in Primary Macrophage Inflammasome Activation*  

PubMed Central

Macrophage dysfunction and inflammasome activation have been implicated in the pathogenesis of diabetes and its complications. Prolonged inflammation and impaired healing are hallmarks of the diabetic response to tissue injury, and excessive inflammasome activation has been associated in these phenotypes. However, the mechanisms that regulate the inflammasome in response to lipid metabolic and inflammatory stress are incompletely understood. We have shown previously that IL-1? secretion is induced in primary macrophages exposed to the dietary saturated fatty acid palmitate in combination with LPS. In this study, we sought to unravel the mechanisms underlying the activation of this lipotoxic inflammasome. We demonstrate that palmitate-loaded primary macrophages challenged with LPS activate the NLRP3 inflammasome through a mechanism that involves the lysosome. Interestingly, the lysosome was involved in both the regulation of pro-IL-1? levels and its subsequent cleavage/release. The lysosomal protease cathepsin B was required for IL-1? release but not pro-IL-1? production. In contrast, disrupting lysosomal calcium regulation decreased IL-1? release by reducing pro-IL-1? levels. The calcium pathway involved the calcium-activated phosphatase calcineurin, which stabilized IL-1? mRNA. Our findings provide evidence that the lysosome plays a key role in both the priming and assembly phases of the lipostoxic inflammasome. These findings have potential relevance to the hyperinflammatory phenotypes observed in diabetics during tissue damage or infection and identify lysosomes and calcineurin as potential therapeutic targets. PMID:24532802

Weber, Kassandra; Schilling, Joel D.

2014-01-01

335

Stimulation of lymphocyte anti-melanoma activity by co-cultured macrophages activated by complex homeopathic medication  

PubMed Central

Background Melanoma is the most aggressive form of skin cancer, and the most rapidly expanding cancer in terms of worldwide incidence. Chemotherapeutic approaches to treat melanoma have been uniformly disappointing. A Brazilian complex homeopathic medication (CHM), used as an immune modulator, has been recommended for patients with depressed immune systems. Previous studies in mice have demonstrated that the CHM activates macrophages, induces an increase in the number of leukocytes and improves the murine response against Sarcoma-180. Methods Here we studied the interaction of mouse lymph node lymphocytes, co-cultured in vitro with macrophages in the presence or absence of the CHM, with B16F10 melanoma cells. Results Lymphocytes co-cultured with macrophages in the presence of the CHM had greater anti-melanoma activity, reducing melanoma cell density and increasing the number of lysed tumor cells. There was also a higher proportion of activated (CD25+) lymphocytes with increased viability. Overall, lymphocytes activated by treatment destroyed growing cancer cells more effectively than control lymphocytes. Conclusion Co-culture of macrophages with lymphocytes in the presence of the CHM enhanced the anti-cancer performance of lymphocytes against a very aggressive lineage of melanoma cells. These results suggest that non-toxic therapies using CHMs are a promising alternative approach to the treatment of melanomas. In addition, they are attractive combination-therapy candidates, which may enhance the efficacy of conventional medicines by improving the immune response against tumor cells. PMID:19698142

2009-01-01

336

? 1-4 mannobiose enhances Salmonella-killing activity and activates innate immune responses in chicken macrophages.  

PubMed

Salmonella spp. is one of the major causes of food-borne illness in humans, and Salmonella enteritidis (SE) infection in commercial poultry is a world-wide problem. Here we have investigated the in vitro immune-modulating effects of ? 1-4 mannobiose (MNB), which was previously found to prevent SE infection in vivo in chickens, using chicken macrophage (MQ-MCSU) cells. Treatment of MQ-NCSU cells with MNB dose-dependently increased both phagocytic activity and Salmonella-killing activity of macrophages, with the highest reduction in SE viability observed at a concentration of 40 ?g/ml at 48 h post-infection. Likewise, both hydrogen peroxide (H(2)O(2)) and nitric oxide (NO) production were increased in a dose-dependent manner by MNB. Gene expression analysis of MNB-treated macrophages revealed significant increases in the expression of iNOS, NOX-1, IFN-?, NRAMP1, and LITAF, genes critical for host defense and antimicrobial activity, when compared to untreated cells. This data confirms that MNB possesses potent innate immune-modulating activities and can up-regulate antibacterial defenses in chicken macrophages. PMID:21067819

Ibuki, Masahisa; Kovacs-Nolan, Jennifer; Fukui, Kensuke; Kanatani, Hiroyuki; Mine, Yoshinori

2011-02-15

337

Ionizing Radiation Induces Macrophage Foam Cell Formation and Aggregation Through JNK-Dependent Activation of CD36 Scavenger Receptors  

SciTech Connect

Purpose: Irradiated arteries of cancer patients can be associated with atherosclerosis-like lesions containing cholesterol-laden macrophages (foam cells). Endothelial cell damage by irradiation does not completely explain the foam cell formation. We investigated the possible underlying mechanisms for ionizing radiation (IR)-induced foam cell formation. Methods and Materials: Human peripheral blood monocytes were activated by macrophage colony-stimulating factor and then treated with varying doses of IR in vitro in the absence of endothelial cells. Scavenger receptor expression and foam cell formation of IR-treated macrophages were investigated in the presence or absence of oxidized low-density lipoprotein. We also assessed the importance of mitogen-activated protein kinase activity in the macrophage colony-stimulating factor-activated human monocytes (macrophages) for the foam cell formation. Results: We found that IR treatment of macrophage colony-stimulating factor-activated human peripheral blood monocytes resulted in the enhanced expression of CD36 scavenger receptors and that cholesterol accumulated in the irradiated macrophages with resultant foam cell formation in the presence of oxidized low-density lipoprotein. Furthermore, when cultured on collagen gels, human macrophages formed large foam cell aggregates in response to IR. Antibodies against CD36 inhibited the IR-induced foam cell formation and aggregation, indicating that the IR-induced foam cell formation and the subsequent aggregation are dependent on functional CD36. In addition, we found that IR of human macrophages resulted in c-Jun N-terminal kinase activation and that c-Jun N-terminal kinase inhibition suppressed IR-induced CD36 expression and the subsequent foam cell formation and aggregation. Conclusion: Taken together, these results suggest that IR-induced foam cell formation is mediated by c-Jun N-terminal kinase-dependent CD36 activation.

Katayama, Ikuo; Hotokezaka, Yuka [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan); Matsuyama, Toshifumi [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan); Sumi, Tadateru [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan); Nakamura, Takashi [Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, Nagasaki (Japan)], E-mail: taku@nagasaki-u.ac.jp

2008-03-01

338

Immunomodulatory effect of Moringa oleifera Lam. extract on cyclophosphamide induced toxicity in mice.  

PubMed

Immunomodulatory effect of ethanolic extract (50%) of M. oleifera leaves (MOE) has been studied in normal and immunosuppressed mice models. Different doses of MOE i.e. 125, 250 and 500 mg/kg body weight of mice were administered orally for 15 days. Cyclophosphamide at a dose of 30 mg/kg body weight was administered orally for the next 3 days. On day 16 and 19, hematological parameters like white blood cell (WBC) count, red blood cell (RBC) count, haemoglobin level (Hb), percent neutrophils and organ weight were recorded. Effect of MOE on phagocytic activity of mice macrophages was determined by carbon clearance test. MOE showed significant dose dependent increase in WBC, percent neutrophils, weight of thymus and spleen along with phagocytic index in normal and immunosuppressed mice. The results indicate that MOE significantly reduced cyclophosphamide induced immunosuppression by stimulating both cellular and humoral immunity. PMID:21117458

Gupta, Anamika; Gautam, Manish K; Singh, Rahul K; Kumar, M Vijay; Rao, Ch V; Goel, R K; Anupurba, Shampa

2010-11-01

339

Antimicrobial and immunomodulatory properties of PGLa-AM1, CPF-AM1, and magainin-AM1: potent activity against oral pathogens.  

PubMed

Cationic amphipathic ?-helical peptides are intensively studied classes of host defence peptides (HDPs). Three peptides, peptide glycine-leucine-amide (PGLa-AM1), caerulein-precursor fragment (CPF-AM1) and magainin-AM1, originally isolated from norepinephrine-stimulated skin secretions of the African volcano frog Xenopus amieti (Pipidae), were studied for their antimicrobial and immunomodulatory activities against oral and respiratory pathogens. Minimal effective concentrations (MECs), determined by radial diffusion assay, were generally lower than minimal inhibitory concentrations (MICs) determined by microbroth dilution. PGLa-AM1 and CPF-AM1 were particularly active against Streptococcus mutans and all three peptides were effective against Fusobacterium nucleatum, whereas Enterococcus faecalis and Candida albicans proved to be relatively resistant micro-organisms. A type strain of Pseudomonas aeruginosa was shown to be more susceptible than the clinical isolate studied. PGLa-AM1 displayed the greatest propensity to bind lipopolysaccharide (LPS) from Escherichia coli, P. aeruginosa and Porphyromonas gingivalis. All three peptides showed less binding to P. gingivalis LPS than to LPS from the other species studied. Oral fibroblast viability was unaffected by 50 ?M peptide treatments. Production of the pro-inflammatory cytokine IL-8 by oral fibroblasts was significantly increased following treatment with 1 or 10 ?M magainin-AM1 but not following treatment with PGLa-AM1 or CPF-AM1. In conclusion, as well as possessing potent antimicrobial actions, the X. amieti peptides bound to LPS from three human pathogens and had no effect on oral fibroblast viability. CPF-AM1 and PGLa-AM1 show promise as templates for the design of novel analogues for the treatment of oral and dental diseases associated with bacteria or fungi. PMID:25447193

McLean, Denise T F; McCrudden, Maelíosa T C; Linden, Gerard J; Irwin, Christopher R; Conlon, J Michael; Lundy, Fionnuala T

2014-11-01

340

The Pro-Inflammatory Cytokine, Interleukin-6, Enhances the Polarization of Alternatively Activated Macrophages  

PubMed Central

Macrophages are important innate immune cells that are associated with two distinct phenotypes: a pro-inflammatory (or classically activated) subset with prototypic macrophage functions such as inflammatory cytokine production and bactericidal activity, and an anti-inflammatory (or alternatively activated (AAM)) subset linked with wound healing and tissue repair processes. In this study, we examined the effect of interlukein-6 on human and murine macrophage polarization. The results indicate that despite being commonly associated with pro-inflammatory functions and being implicated in the pathogenesis/pathophysiology of numerous inflammatory diseases, interleukin-6 can enhance the polarization of AAMs, based on increased expression of hallmark markers: arginase-1, Ym1 and CD206; this effect required the AAM differentiating cytokines, IL-4 and IL-13. Co-treatment of AAMs with IL-6 resulted in spontaneous release of IL-10, suppressed LPS-induced nitric oxide production and inhibited cytokine production by activated CD4+ T cells – immunoregulatory features not observed in the ‘parent’ IL-4+IL-13-induced AAM. The effect of IL-6 required signal transducer and activator of transcription (STAT)-3, was partially dependent on up-regulation of the IL4R? chain, and was independent of autocrine IL-10. In the presence of IFN?, IL-6 promoted the production of IL-1? and TNF? suggesting that this cytokine can enhance the phenotype to which a macrophage has committed. This finding may explain the pleiotrophic nature of IL-6, where it is associated with the perpetuation and enhancement of disease in inflammatory situations, but is also necessary for resolution of inflammation and adequate wound healing to occur in others. Thus, the potential benefit of IL-6 in promoting an AAM, with its’ anti-inflammatory and wound healing ability, may need to be considered in immunotherapies aimed at in vivo modulation or inhibition of IL-6. PMID:24736635

Fernando, Maria Ruweka; Reyes, Jose Luis; Iannuzzi, Jordan; Leung, Gabriella; McKay, Derek Mark

2014-01-01

341

Analysis of the transcriptional networks underpinning the activation of murine macrophages by inflammatory mediators  

PubMed Central

Macrophages respond to the TLR4 agonist LPS with a sequential transcriptional cascade controlled by a complex regulatory network of signaling pathways and transcription factors. At least two distinct pathways are currently known to be engaged by TLR4 and are distinguished by their dependence on the adaptor molecule MyD88. We have used gene expression microarrays to define the effects of each of three variables—LPS dose, LPS versus IFN-? and -?, and genetic background—on the transcriptional response of mouse BMDMs. Analysis of correlation networks generated from the data has identified subnetworks or modules within the macrophage transcriptional network that are activated selectively by these variables. We have identified mouse strain-specific signatures, including a module enriched for SLE susceptibility candidates. In the modules of genes unique to different treatments, we found a module of genes induced by type-I IFN but not by LPS treatment, suggesting another layer of complexity in the LPS-TLR4 signaling feedback control. We also observe that the activation of the complement system, in common with the known activation of MHC class 2 genes, is reliant on IFN-? signaling. Taken together, these data further highlight the exquisite nature of the regulatory systems that control macrophage activation, their likely relevance to disease resistance/susceptibility, and the appropriate response of these cells to proinflammatory stimuli. PMID:24721704

Raza, Sobia; Barnett, Mark W.; Barnett-Itzhaki, Zohar; Amit, Ido; Hume, David A.; Freeman, Tom C.

2014-01-01

342

Immunostimulating activity of maysin isolated from corn silk in murine RAW 264.7 macrophages.  

PubMed

Corn silk (CS) has long been consumed as a traditional herb in Korea. Maysin is a major flavonoid of CS. The effects of maysin on macrophage activation were evaluated, using the murine macrophage RAW 264.7 cells. Maysin was isolated from CS by methanol extraction, and preparative C18 reverse phase column chromatography. Maysin was nontoxic up to 100 ?g/ml, and dose-dependently increased TNF-? secretion and iNOS production by 11.2- and 4.2-fold, respectively, compared to untreated control. The activation and subsequent nuclear translocation of NF-?B was substantially enhanced upon treatment with maysin (1-100 ?g/ml). Maysin also stimulated the phosphorylation of Akt and MAPKs (ERK, JNK). These results indicated that maysin activates macrophages to secrete TNF-? and induce iNOS expression, via the activation of the Akt, NF-?B and MAPKs signaling pathways. These results suggest for the first time that maysin can be a new immunomodulator, enhancing the early innate immunity. PMID:24286330

Lee, Jisun; Kim, Sun-Lim; Lee, Seul; Chung, Mi Ja; Park, Yong Il

2014-07-01

343

Nitric oxide increases susceptibility of toll-like receptor-activated macrophages to spreading Listeria monocytogenes  

PubMed Central

SUMMARY Toll-like receptor (TLR) stimulation activates macrophages to resist intracellular pathogens. Yet, the intracellular bacterium Listeria monocytogenes (Lm) causes lethal infections in spite of innate immune cell activation. Lm uses direct cell-cell spread to disseminate within its host. Here, we have shown that TLR-activated macrophages killed cell-free Lm but failed to prevent infection by spreading Lm. Instead, TLR signals increased the efficiency of Lm spread from “donor” to “recipient” macrophages. This enhancement required nitric oxide (NO) production by nitric oxide synthase-2 (NOS2). NO increased Lm escape from secondary vacuoles in recipient cells and delayed maturation of phagosomes containing membrane-like particles that mimic Lm-containing pseudopods. NO also promoted Lm spread during systemic in vivo infection, as inhibition of NOS2 with 1400W reduced spread-dependent Lm burdens in mouse livers. These findings reveal a mechanism by which pathogens capable of cell-cell spread can avoid the consequences of innate immune cell activation by TLR stimuli. PMID:22542147

Cole, Caroline; Thomas, Stacey; Filak, Holly; Henson, Peter M.; Lenz, Laurel L.

2012-01-01

344

Immunostimulating activity of maysin isolated from corn silk in murine RAW 264.7 macrophages  

PubMed Central

Corn silk (CS) has long been consumed as a traditional herb in Korea. Maysin is a major flavonoid of CS. The effects of maysin on macrophage activation were evaluated, using the murine macrophage RAW 264.7 cells. Maysin was isolated from CS by methanol extraction, and preparative C18 reverse phase column chromatography. Maysin was nontoxic up to 100 ?g/ml, and dose-dependently increased TNF-? secretion and iNOS production by 11.2- and 4.2-fold, respectively, compared to untreated control. The activation and subsequent nuclear translocation of NF-?B was substantially enhanced upon treatment with maysin (1-100 ?g/ml). Maysin also stimulated the phosphorylation of Akt and MAPKs (ERK, JNK). These results indicated that maysin activates macrophages to secrete TNF-? and induce iNOS expression, via the activation of the Akt, NF-?B and MAPKs signaling pathways. These results suggest for the first time that maysin can be a new immunomodulator, enhancing the early innate immunity. [BMB Reports 2014; 47(7): 382-387] PMID:24286330

Lee, Jisun; Kim, Sun-Lim; Lee, Seul; Chung, Mi Ja; Park, Yong Il

2014-01-01

345

A non-peptidic cathepsin S activity-based probe for noninvasive optical imaging of tumor-associated macrophages  

PubMed Central

SUMMARY Macrophage infiltration into tumors has been correlated with poor clinical outcome in multiple cancer types. Therefore, new tools to image tumor-associated macrophages could be valuable for diagnosis and prognosis of cancer. Herein we describe the synthesis and characterization of a cathepsin S-directed, quenched activity-based probe (qABP), BMV083. This probe makes use of an optimized non-peptidic scaffold leading to enhanced in vivo properties relative to previously reported peptide-based probes. In a syngeneic breast cancer model, BMV083 provides high tumor specific fluorescence that can be visualized using noninvasive optical imaging methods. Furthermore, analysis of probe labeled cells demonstrates that the probe primarily targets macrophages with an M2 phenotype. Thus, BMV083 is a potential valuable new in vivo reporter for tumor-associated macrophages that could greatly facilitate the future studies of macrophage function in the process of tumorigenesis. PMID:22633413

Verdoes, Martijn; Edgington, Laura E.; Scheeren, Ferenc; Leyva, Melissa; Blum, Galia; Weiskopf, Kipp; Bachmann, Michael H.; Ellman, Jonathan A.; Bogyo, Matthew

2012-01-01

346

LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPAR? ligand synthesis.  

PubMed

Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract. Here we report that LRH-1 is expressed in macrophages and induced by the Th2 cytokine IL-13 via a mechanism involving STAT6. We show that loss-of-function of LRH-1 in macrophages impedes IL-13-induced macrophage polarization due to impaired generation of 15-HETE PPAR? ligands. The incapacity to generate 15-HETE metabolites is at least partially caused by the compromised regulation of CYP1A1 and CYP1B1. Mice with LRH-1-deficient macrophages are, furthermore, highly susceptible to gastrointestinal and systemic Candida albicans infection. Altogether, these results identify LRH-1 as a critical component of the anti-inflammatory and fungicidal response of alternatively activated macrophages that acts upstream from the IL-13-induced 15-HETE/PPAR? axis. PMID:25873311

Lefčvre, Lise; Authier, Hélčne; Stein, Sokrates; Majorel, Clarisse; Couderc, Bettina; Dardenne, Christophe; Eddine, Mohamad Ala; Meunier, Etienne; Bernad, José; Valentin, Alexis; Pipy, Bernard; Schoonjans, Kristina; Coste, Agnčs

2015-01-01

347

[The clinical assessment of macrophage functional activity in patients with protracted dysentery and its correction with lysozyme and vitamin E].  

PubMed

Prospects for the correction of disturbances in the macrophagal system with a combination of lysozyme and vitamin E in patients with a protracted course of dysentery caused by Shigella flexneri 1b were studied. The phagocytic activity of macrophages (PAM) was found to be suppressed as early as at the beginning of the disease. Out of 38 persons repeatedly found to release shigellae 24 were administered polychemotherapy. PAM indices in patients treated with lysozyme and tocopherol acetate were likely to normalize, this being indicative of the positive effect of these preparations on the functional activity of the macrophagal system. PMID:1301666

Iushchuk, N D; Ziuzin, V A; Frolov, V M; Peresadin, N A

1992-01-01

348

ELECTROSTATIC CHARGE ON NANO-PARTICLES ACTIVATES CNS MACROPHAGES (MICROGLIA).  

EPA Science Inventory

Nanometer size particles carry free radical activity on their surface and can produce oxidative stress (OS)-mediated damage upon impact to target cells. The initiating event of phage cell activation (i.e., the oxidative burst) is unknown, although many proximal events have been i...

349

YC-1 potentiates cAMP-induced CREB activation and nitric oxide production in alveolar macrophages  

SciTech Connect

Alveolar macrophages play significant roles in the pathogenesis of several inflammatory lung diseases. Increases in exhaled nitric oxide (NO) are well documented to reflect disease severity in the airway. In this study, we investigated the effect of 3-(5?-hydroxymethyl-2?-furyl)-1-benzyl indazole (YC-1), a known activator of soluble guanylyl cyclase, on prostaglandin (PG)E{sub 1} (a stable PGE{sub 2} analogue) and forskolin (a adenylate cyclase activator) induced NO production and inducible NO synthase (iNOS) expression in rat alveolar macrophages (NR8383). YC-1 did not directly cause NO production or iNOS expression, but drastically potentiated PGE{sub 1}- or forskolin-induced NO production and iNOS expression in NR8383 alveolar macrophages. Combination treatment with YC-1 and PGE{sub 1} significantly increased phosphorylation of the cAMP response element-binding protein (CREB), but not nuclear factor (NF)-?B activation. The combined effect on NO production, iNOS expression, and CREB phosphorylation was reversed by a protein kinase (PK)A inhibitor (H89), suggesting that the potentiating functions were mediated through a cAMP/PKA signaling pathway. Consistent with this, cAMP analogues, but not the cGMP analogue, caused NO release, iNOS expression, and CREB activation. YC-1 treatment induced an increase in PGE{sub 1}-induced cAMP formation, which occurred through the inhibition of cAMP-specific phosphodiesterase (PDE) activity. Furthermore, the combination of rolipram (an inhibitor of PDE4), but not milronone (an inhibitor of PDE3), and PGE{sub 1} also triggered NO production and iNOS expression. In summary, YC-1 potentiates PGE{sub 1}-induced NO production and iNOS expression in alveolar macrophages through inhibition of cAMP PDE activity and activation of the cAMP/PKA/CREB signaling pathway. Highlights: ? YC-1 potentiated PGE1-induced iNOS expression in alveolar macrophages. ? The combination of YC-1 and PGE1 increased CREB but not NF?B activation. ? The combined effects were reversed by H89. ? The combination of rolipram and PGE1 triggered NO production and iNOS expression. ? Effect of YC-1 occurred through inhibition of cAMP-specific PDE.

Hwang, Tsong-Long, E-mail: htl@mail.cgu.edu.tw [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China) [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China); Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan (China); Tang, Ming-Chi [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China)] [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China); Kuo, Liang-Mou [Department of General Surgery, Chang Gung Memorial Hospital at Chia-Yi, Taiwan (China)] [Department of General Surgery, Chang Gung Memorial Hospital at Chia-Yi, Taiwan (China); Chang, Wen-De; Chung, Pei-Jen; Chang, Ya-Wen; Fang, Yao-Ching [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China)] [Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan (China)

2012-04-15

350

Naloxone Treatment Prevents Prenatal Stress Effects on Peritoneal Macrophage Activity in Mice Offspring  

Microsoft Academic Search

The present study analyzed the effects of maternal stress (PS) and\\/or naloxone treatment on the activity of peritoneal macrophage in male and female Swiss mice offspring. Pregnant female rats received a daily footshock (0.2 mA) and\\/or a naloxone injection from gestational day 15 to 19. Experiments were performed on postnatal day 30 on male and female pups. The following results

Evelise S. M. Fonseca; Monica Sakai; Maria Isabel R. Carvalho-Freitas; Joăo Palermo Neto

2005-01-01

351

Macrophage uptake and recycling of ascorbic acid: Response to activation by lipopolysaccharide  

Microsoft Academic Search

To test whether ascorbic acid might be involved in the antioxidant defenses of inflammatory cells, we studied ascorbate uptake and recycling by quiescent and lipopolysaccharide–activated RAW264.7 murine macrophages. These cells concentrated ascorbate 100-fold in overnight culture, achieving steady-state concentrations of more than 10 mM at extracellular concentrations of 20–100 ?M. This steep gradient was generated by high-affinity sodium-dependent ascorbate transport.

James M. May; Junjun Huang; Zhi-chao Qu

2005-01-01

352

Normal Autophagic Activity in Macrophages from Mice Lacking G?i3, AGS3, or RGS19  

PubMed Central

In macrophages autophagy assists antigen presentation, affects cytokine release, and promotes intracellular pathogen elimination. In some cells autophagy is modulated by a signaling pathway that employs G?i3, Activator of G-protein Signaling-3 (AGS3/GPSM1), and Regulator of G-protein Signaling 19 (RGS19). As macrophages express each of these proteins, we tested their importance in regulating macrophage autophagy. We assessed LC3 processing and the formation of LC3 puncta in bone marrow derived macrophages prepared from wild type, Gnai3-/-, Gpsm1-/-, or Rgs19-/- mice following amino acid starvation or Nigericin treatment. In addition, we evaluated rapamycin-induced autophagic proteolysis rates by long-lived protein degradation assays and anti-autophagic action after rapamycin induction in wild type, Gnai3-/-, and Gpsm1-/- macrophages. In similar assays we compared macrophages treated or not with pertussis toxin, an inhibitor of GPCR (G-protein couple receptor) triggered G?i nucleotide exchange. Despite previous findings, the level of basal autophagy, autophagic induction, autophagic flux, autophagic degradation and the anti-autophagic action in macrophages that lacked G?i3, AGS3, or RGS19; or had been treated with pertussis toxin, were similar to controls. These results indicate that while G?i signaling may impact autophagy in some cell types it does not in macrophages. PMID:24312373

Vural, Ali; McQuiston, Travis J.; Blumer, Joe B.; Park, Chung; Hwang, Il-Young; Williams-Bey, Yolanda; Shi, Chong-Shan; Ma, Dzwokai Zach; Kehrl, John H.

2013-01-01

353

Macrophages from the synovium of active rheumatoid arthritis exhibit an activin A-dependent pro-inflammatory profile.  

PubMed

Rheumatoid arthritis (RA) is a chronic inflammatory disease whose pathogenesis and severity correlates with the presence of macrophage-derived pro-inflammatory cytokines within the inflamed synovium. Macrophage-derived cytokines fuel the pathological processes in RA and are targets of clinically successful therapies. However, although macrophage polarization determines cytokine production, the polarization state of macrophages in RA joints remains poorly defined. To dissect the molecular basis for the tissue-damaging effects of macrophages in RA joints, we undertook the phenotypic and transcriptomic characterization of ex vivo isolated CD14(+) RA synovial fluid (RA-SF) macrophages. Flow cytometry and gene profiling indicated that RA-SF macrophages express pro-inflammatory polarization markers (MMP12, EGLN3, CCR2), lack expression of markers associated with homeostatic and anti-inflammatory polarization (IGF1, HTR2B) and exhibit a transcriptomic profile that resembles the activin A-dependent gene signature of pro-inflammatory in vitro-generated macrophages. In fact, high levels of Smad-activating activin A were found in RA-SF and, accordingly, the Smad signalling pathway was activated in ex vivo-isolated RA-SF macrophages. In vitro experiments on monocytes and macrophages indicated that RA-SF promoted the acquisition of pro-inflammatory markers (INHBA, MMP12, EGLN3, CCR2) but led to a significant reduction in the expression of genes associated with homeostasis and inflammation resolution (FOLR2, SERPINB2, IGF1, CD36), thus confirming the pro-inflammatory polarization ability of RA-SF. Importantly, the macrophage-polarizing ability of RA-SF was inhibited by an anti-activin A-neutralizing antibody, thus demonstrating that activin A mediates the pro-inflammatory macrophage-polarizing ability of RA-SF. Moreover, and in line with these findings, multicolour immunofluorescence evidenced that macrophages within RA synovial membranes (RA-SM) also express pro-inflammatory polarization markers whose expression is activin A-dependent. Altogether, our results demonstrate that macrophages from RA synovial fluids and membranes exhibit an MMP12(+) EGLN3(+) CCR2(+) pro-inflammatory polarization state whose acquisition is partly dependent on activin A from the synovial fluid. PMID:25319955

Soler Palacios, Blanca; Estrada-Capetillo, Lizbeth; Izquierdo, Elena; Criado, Gabriel; Nieto, Concha; Municio, Cristina; González-Alvaro, Isidoro; Sánchez-Mateos, Paloma; Pablos, Jose Luis; Corbí, Angel L; Puig-Kröger, Amaya

2015-02-01

354

An immunomodulatory polysaccharide-rich substance from the fruit juice of Morinda citrifolia (noni) with antitumour activity  

Microsoft Academic Search

The fruit juice of Morinda citrifolia (noni) contains a polysaccharide-rich substance (noni-ppt) with anti- tumour activity in the Lewis lung (LLC) peritoneal carcinomatosis model. Therapeutic administration of noni-ppt significantly enhanced the duration of survival of inbred syngeneic LLC tumour bearing mice. It did not exert significant cytotoxic effects in an adapted culture of LLC cells, LLC1, but could activate peritoneal

Anne Hirazumi; Eiichi Furusawa

1999-01-01

355

Immunomodulatory effect of prednisolone (PRD) induced soluble suppressor factor(s) (PRD-SSF) on natural killer (NK) cell activity  

SciTech Connect

The authors have previously reported that peripheral blood lymphocytes precultured for 24 hrs with PRD showed significant suppression of their NK activity. Purified HNK-1/sup +/ lymphocytes were treated either directly with PRD or with supernates from allogeneic lymphocytes precultured with 10/sup -6/ to 10/sup -9/M PRD and examined for any inhibition of NK activity. For the NK assay K562 and U937 cell lines were used as targets in a 4 hr /sup 51/Cr release assay. HNK-1/sup +/ lymphocytes precultured with PRD showed significantly lower level of NK activity. In a single cell assay, both HNK-1/sup +/ and HNK-1/sup -/ subpopulations of PBL precultured with PRD also suppressed the target binding and lytic capacity of allogeneic fresh large granular lymphocytes, suggesting that NK cells/T cells or their precursors can be stimulated by PRD to inhibit NK activity. PBL precultured with increasing concentrations of culture supernates containing PRD-SSF showed a dose dependent inhibitory effect of their NK activity. This data suggest that PRD activated suppressor cells function through the release of soluble mediators. These findings may be of clinical significance to patients receiving corticosteroids for a variety of disorders including malignant, autoimmune and atopic diseases.

Nair, M.P.N.; Cilik, J.M.; Schwartz, S.A.

1986-03-01

356

Effects of Lycium barbarum extract on production and immunomodulatory activity of the extracellular polysaccharopeptides from submerged fermentation culture of Coriolus versicolor  

Microsoft Academic Search

Polysaccharopeptides (PSPs) from Coriolus versicolor have been used as immunomodulatory and anticancer agents. However, most studies have concentrated on the mycelial PSPs and not those in the fermented broth. On the other hand, Lycium barbarum fruit has been used as a traditional Chinese herbal medicine for two millennia. Its extract contains various nutrients, minerals, and also polysaccharide–protein complexes, which are

Fang-Yi Lin; Yiu-Kay Lai; Hao-Chen Yu; Nan-Yin Chen; Chi-Yue Chang; Hui-Chen Lo; Tai-Hao Hsu

2008-01-01

357

Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF1  

Microsoft Academic Search

Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum ?-N-acetylgalactosaminidase (Nagalase) secreted from cancer- ous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be acti-

Nobuto Yamamoto; Hirofumi Suyama; Nobuyuki Yamamoto

2008-01-01

358

Effect of antioxidants and nitric oxide on activity of peritoneal macrophages in albino rats during normal pregnancy.  

PubMed

We compared activity of peritoneal macrophages in rats during normal pregnancy and under the action of NO-synthase inhibitor L-NAME, of E. coli LPS, SOD, and ?-tocopherol analogue trolox. In non-pregnant rats, E. coli LPS stimulated peritoneal macrophages, while L-NAME produced a dose-dependent effect. During pregnancy, E. coli LPS activated phagocytosis, while antioxidants trolox, SOD, and L-NAME produced an inhibitory effect. PMID:23658872

Ivanova, A S; Popova, I G; Nazarov, S B

2013-03-01

359

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2? and Eicosanoid Production in Monocytes and Macrophages* ?  

PubMed Central

Hyaluronan (HA) is the major glycosaminoglycan in the extracellular matrix. During inflammation, there is an increased breakdown of HA, resulting in the accumulation of low molecular weight (LMW) HA and activation of monocytes and macrophages. Eicosanoids, derived from the cytosolic phospholipase A2 group IVA (cPLA2?) activation, are potent lipid mediators also attributed to acute and chronic inflammation. The aim of this study was to determine the effect of LMW HA on cPLA2? activation, arachidonic acid (AA) release, and subsequent eicosanoid production and to examine the receptors and downstream mechanisms involved in these processes in monocytes and differently polarized macrophages. LMW HA was a potent stimulant of AA release in a time- and dose-dependent manner, induced cPLA2?, ERK1/2, p38, and JNK phosphorylation, as well as activated COX2 expression and prostaglandin (PG) E2 production in primary human monocytes, murine RAW 264.7, and wild-type bone marrow-derived macrophages. Specific cPLA2? inhibitor blocked HA-induced AA release and PGE2 production in all of these cells. Using CD44, TLR4, TLR2, MYD88, RHAMM or STAB2 siRNA-transfected macrophages and monocytes, we found that AA release, cPLA2?, ERK1/2, p38, and JNK phosphorylation, COX2 expression, and PGE2 production were activated by LMW HA through a TLR4/MYD88 pathway. Likewise, PGE2 production and COX2 expression were blocked in Tlr4?/? and Myd88?/? mice, but not in Cd44?/? mice, after LMW HA stimulation. Moreover, we demonstrated that LMW HA activated the M1 macrophage phenotype with the unique cPLA2?/COX2high and COX1/ALOX15/ALOX5/LTA4Hlow gene and PGE2/PGD2/15-HETEhigh and LXA4low eicosanoid profile. These findings reveal a novel link between HA-mediated inflammation and lipid metabolism. PMID:24366870

Sokolowska, Milena; Chen, Li-Yuan; Eberlein, Michael; Martinez-Anton, Asuncion; Liu, Yueqin; Alsaaty, Sara; Qi, Hai-Yan; Logun, Carolea; Horton, Maureen; Shelhamer, James H.

2014-01-01

360

Antimicrobial activity against oral pathogens and immunomodulatory effects and toxicity of geopropolis produced by the stingless bee Melipona fasciculata Smith  

PubMed Central

Background Native bees of the tribe Meliponini produce a distinct kind of propolis called geopropolis. Although many pharmacological activities of propolis have already been demonstrated, little is known about geopropolis, particularly regarding its antimicrobial activity against oral pathogens. The present study aimed at investigating the antimicrobial activity of M. fasciculata geopropolis against oral pathogens, its effects on S. mutans biofilms, and the chemical contents of the extracts. A gel prepared with a geopropolis extract was also analyzed for its activity on S. mutans and its immunotoxicological potential. Methods Antimicrobial activities of three hydroalcoholic extracts (HAEs) of geopropolis, and hexane and chloroform fractions of one extract, were evaluated using the agar diffusion method and the broth dilution technique. Ethanol (70%, v/v) and chlorhexidine (0.12%, w/w) were used as negative and positive controls, respectively. Total phenol and flavonoid concentrations were assayed by spectrophotometry. Immunotoxicity was evaluated in mice by topical application in the oral cavity followed by quantification of biochemical and immunological parameters, and macro-microscopic analysis of animal organs. Results Two extracts, HAE-2 and HAE-3, showed inhibition zones ranging from 9 to 13 mm in diameter for S. mutans and C. albicans, but presented no activity against L. acidophilus. The MBCs for HAE-2 and HAE-3 against S. mutans were 6.25 mg/mL and 12.5 mg/mL, respectively. HAE-2 was fractionated, and its chloroform fraction had an MBC of 14.57 mg/mL. HAE-2 also exhibited bactericidal effects on S. mutans biofilms after 3 h of treatment. Significant differences (p < 0.05) in total phenol and flavonoid concentrations were observed among the samples. Signs toxic effects were not observed after application of the geopropolis-based gel, but an increase in the production of IL-4 and IL-10, anti-inflammatory cytokines, was detected. Conclusions In summary, geopropolis produced by M. fasciculata can exert antimicrobial action against S. mutans and C. albicans, with significant inhibitory activity against S. mutans biofilms. The extract with the highest flavonoid concentration, HAE-2, presented the highest antimicrobial activity. In addition, a geopropolis-based gel is not toxic in an animal model and displays anti-inflammatory effect. PMID:22053900

2011-01-01

361

Role of protein kinase C and intracellular calcium mobilization in the induction of macrophage tumoricidal activity by interferon-gamma.  

PubMed

These studies were designed to test the hypothesis that changes in intracellular Ca2+ levels and activation of the calcium ion- and phospholipid-dependent protein kinase C were required for the induction of macrophage tumoricidal activity by interferon-gamma (IFN-gamma). Phenothiazines and R24571, known antagonists of calcium-binding proteins and therefore nonspecific inhibitors of protein kinase C, blocked in a dose-dependent manner the induction of macrophage cytocidal activity by either natural or recombinant IFN-gamma. Macrophages depleted of intracellular Ca2+ by chelation with Quin 2, were also unresponsive to IFN-gamma. These treatments effected neither the binding of IFN-gamma to its cell surface receptor nor the normal intracellular processing of IFN-gamma. Activators of protein kinase C (such as phorbol esters) and Ca2+ ionophores when added alone did not effect the activation state of the macrophage population. However, macrophages exposed to both drugs in combination were elevated into the primed activation state such that in the presence of a second signal (lipopolysaccharide or heat killed Listeria monocytogenes), the cells were triggered to express full levels of tumoricidal activity. The capacity of phorbol esters to induce cellular activation correlated with their ability to bind and to activate protein kinase C. No synergistic effect was observed between IFN-gamma and protein kinase C activators and/or Ca2+ ionophores, indicating that the drugs could only prime and could not trigger macrophages for tumor cell killing. These results thus support the concept that protein kinase C activation and mobilization of intracellular Ca2+ are essential steps in the pathway of IFN-gamma-dependent induction of non-specific tumoricidal activity in macrophages. PMID:3093574

Celada, A; Schreiber, R D

1986-10-01

362

Genome-Wide Analysis of Antiviral Signature Genes in Porcine Macrophages at Different Activation Statuses  

PubMed Central

Macrophages (M?s) can be polarized to various activation statuses, including classical (M1), alternative (M2), and antiviral states. To study the antiviral activation status of porcine M?s during porcine reproductive and respiratory syndrome virus (PRRSV) infection, we used RNA Sequencing (RNA-Seq) for transcriptomic analysis of differentially expressed genes (DEGs). Sequencing assessment and quality evaluation showed that our RNA-Seq data met the criteria for genome-wide transcriptomic analysis. Comparisons of any two activation statuses revealed more than 20,000 DEGs that were normalized to filter out 153–5,303 significant DEGs [false discovery rate (FDR) ?0.001, fold change ?2] in each comparison. The highest 5,303 significant DEGs were found between lipopolysaccharide- (LPS) and interferon (IFN)?-stimulated M1 cells, whereas only 153 significant DEGs were detected between interleukin (IL)-10-polarized M2 cells and control mock-activated cells. To identify signature genes for antiviral regulation pertaining to each activation status, we identified a set of DEGs that showed significant up-regulation in only one activation state. In addition, pathway analyses defined the top 20–50 significantly regulated pathways at each activation status, and we further analyzed DEGs pertinent to pathways mediated by AMP kinase (AMPK) and epigenetic mechanisms. For the first time in porcine macrophages, our transcriptomic analyses not only compared family-wide differential expression of most known immune genes at different activation statuses, but also revealed transcription evidence of multiple gene families. These findings show that using RNA-Seq transcriptomic analyses in virus-infected and status-synchronized macrophages effectively profiled signature genes and gene response pathways for antiviral regulation, which may provide a framework for optimizing antiviral immunity and immune homeostasis. PMID:24505295

Sang, Yongming; Brichalli, Wyatt; Rowland, Raymond R. R.; Blecha, Frank

2014-01-01

363

Shear stress modulates macrophage-induced urokinase plasminogen activator expression in human chondrocytes  

PubMed Central

Introduction Synovial macrophages, which can release proinflammatory factors, are responsible for the upregulation of cartilage-breakdown proteases and play critical roles in cartilage degradation during the progression of osteoarthritis (OA). In addition, shear stress exerts multifunctional effects on chondrocytes by inducing the synthesis of catabolic or anabolic genes. However, the interplay of macrophages, chondrocytes, and shear stress during the regulation of cartilage function remains poorly understood. We investigated the mechanisms underlying the modulation of human chondrocyte urokinase plasminogen activator (uPA) expression by macrophages and shear stress. Methods Human chondrocytes were stimulated by peripheral blood-macrophage- conditioned medium (PB-MCM), or exposure of chondrocytes cultured in PB-MCM to different levels of shear stress (2 to 20 dyn/cm2). Real-time polymerase chain reaction was used to analyze uPA gene expression. Inhibitors and small interfering RNA were used to investigate the mechanism for the effects of PB-MCM and shear stress in chondrocytes. Results Stimulation of human chondrocytes with PB-MCM was found to induce uPA expression. We demonstrated that activation of the JNK and Akt pathways and NF-?B are critical for PB-MCM-induced uPA expression. Blocking assays by using IL-1ra further demonstrated that IL-1? in PB-MCM is the major mediator of uPA expression in chondrocytes. PB-MCM-treated chondrocytes subjected to a lower level of shear stress showed inhibition of MCM-induced JNK and Akt phosphorylation, NF-?B activation, and uPA expression. The PB-MCM-induced uPA expression was suppressed by AMP-activated protein kinase (AMPK) agonist. The inhibitor or siRNA for AMPK abolished the shear-mediated inhibition of uPA expression. Conclusions These data support the hypothesis that uPA upregulation stimulated by macrophages may play an active role in the onset of OA and in the shear-stress protection against this induction. PMID:23597113

2013-01-01

364

Effect of Estragole on Leukocyte Behavior and Phagocytic Activity of Macrophages  

PubMed Central

Estragole, a chemical constituent of the essential oils of many aromatic plants, is used as flavoring in beverage and food industries. In vivo and in vitro experimental assays have shown that EST has sedative, anticonvulsant, antioxidant, antimicrobial, and anesthetic activity. In this work, we evaluate the effect of EST on leukocyte behavior and phagocytic activity of macrophages. In the peritonitis model, EST (500 and 750?mg/kg) decreased the infiltration of peritoneal exudate leukocytes. In vitro chemotaxis assay showed that EST (3, 10, 30, and 60??g/mL) inhibited neutrophil migration toward fMLP. In the in vivo microcirculation assay, EST at doses of 250, 500, and 750?mg/kg significantly reduced the number of rolling and adherent leukocytes and at doses of 250 and 500?mg/kg decreased number of leukocyte migrated to perivascular tissue. The results showed that EST (3, 10, and 30??g/mL) was able to stimulate the macrophages phagocytosis but only at concentration of 10??g/mL promoted an increase in nitric oxide (NO) production. In conclusion, this study showed that EST had potential anti-inflammatory effects, likely by inhibiting leukocyte migration and by stimulating macrophages phagocytosis. PMID:25152763

Wiirzler, Luiz Alexandre Marques; Silva-Filho, Saulo Euclides; Kummer, Raquel; Pedroso, Raissa Bocchi; Spironello, Ricardo Alexandre; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

2014-01-01

365

Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization.  

PubMed

Mitochondrial complex I (CI) deficiency is associated with multiple neurological and metabolic disorders. However, its effect on innate immunity and bone remodeling is unclear. Using deletion of the essential CI subunit Ndufs4 as a model for mitochondrial dysfunction, we report that mitochondria suppress macrophage activation and inflammation while promoting osteoclast differentiation and bone resorption via both cell-autonomous and systemic regulation. Global Ndufs4 deletion causes systemic inflammation and osteopetrosis. Hematopoietic Ndufs4 deletion causes an intrinsic lineage shift from osteoclast to macrophage. Liver Ndufs4 deletion causes a metabolic shift from fatty acid oxidation to glycolysis, accumulating fatty acids and lactate (FA/LAC) in the circulation. FA/LAC further activates Ndufs4(-/-) macrophages via reactive oxygen species induction and diminishes osteoclast lineage commitment in Ndufs4(-/-) progenitors; both inflammation and osteopetrosis in Ndufs4(-/-) mice are attenuated by TLR4/2 deletion. Together, these findings reveal mitochondrial CI as a critical rheostat of innate immunity and skeletal homeostasis. PMID:25130399

Jin, Zixue; Wei, Wei; Yang, Marie; Du, Yang; Wan, Yihong

2014-09-01

366

Epigenome-Guided Analysis of the Transcriptome of Plaque Macrophages during Atherosclerosis Regression Reveals Activation of the Wnt Signaling Pathway  

PubMed Central

We report the first systems biology investigation of regulators controlling arterial plaque macrophage transcriptional changes in response to lipid lowering in vivo in two distinct mouse models of atherosclerosis regression. Transcriptome measurements from plaque macrophages from the Reversa mouse were integrated with measurements from an aortic transplant-based mouse model of plaque regression. Functional relevance of the genes detected as differentially expressed in plaque macrophages in response to lipid lowering in vivo was assessed through analysis of gene functional annotations, overlap with in vitro foam cell studies, and overlap of associated eQTLs with human atherosclerosis/CAD risk SNPs. To identify transcription factors that control plaque macrophage responses to lipid lowering in vivo, we used an integrative strategy – leveraging macrophage epigenomic measurements – to detect enrichment of transcription factor binding sites upstream of genes that are differentially expressed in plaque macrophages during regression. The integrated analysis uncovered eight transcription factor binding site elements that were statistically overrepresented within the 5? regulatory regions of genes that were upregulated in plaque macrophages in the Reversa model under maximal regression conditions and within the 5? regulatory regions of genes that were upregulated in the aortic transplant model during regression. Of these, the TCF/LEF binding site was present in promoters of upregulated genes related to cell motility, suggesting that the canonical Wnt signaling pathway may be activated in plaque macrophages during regression. We validated this network-based prediction by demonstrating that ?-catenin expression is higher in regressing (vs. control group) plaques in both regression models, and we further demonstrated that stimulation of canonical Wnt signaling increases macrophage migration in vitro. These results suggest involvement of canonical Wnt signaling in macrophage emigration from the plaque during lipid lowering-induced regression, and they illustrate the discovery potential of an epigenome-guided, systems approach to understanding atherosclerosis regression. PMID:25474352

Menon, Prashanthi; Podolsky, Irina; Feig, Jonathan E.; Aderem, Alan; Fisher, Edward A.; Gold, Elizabeth S.

2014-01-01

367