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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.

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

2008-01-01

2

Schisandra polysaccharide evokes immunomodulatory activity through TLR 4-mediated activation of macrophages.  

PubMed

Schisandra chinensis (Turcz.) Baill has been used in traditional Chinese medicine for centuries. Previous studies have shown that Schisandra polysaccharide (SCPP11) has robust antitumor activity in vivo. In this study, the immunomodulatory activity and mechanisms of action of SCPP11 were investigated further to reveal its mechanism of action against tumors. Results showed that SCPP11 increased the thymus and spleen indices, pinocytic activity of peritoneal macrophages, and hemolysin formation in CTX-induced immunosuppressed mice. Moreover, SCPP11 significantly increased immunoglobulin levels, cytokines levels in vivo and induced RAW264.7 cells to secrete cytokines in vitro. RAW264.7 cells pretreated with SCPP11 significantly inhibited the proliferation of HepG-2 cells. In addition, SCPP11 promoted both the expression of iNOS protein and of iNOS and TNF-? mRNA. TLR-4 is a possible receptor for SCPP11-mediated macrophage activation. Therefore, the data suggest that SCPP11 exerted its antitumor activity by improving immune system functions through TLR-4-mediated up-regulation of NO and TNF-?. PMID:24418335

Zhao, Ting; Feng, Yun; Li, Jing; Mao, Riwen; Zou, Ye; Feng, Weiwei; Zheng, Daheng; Wang, Wei; Chen, Yao; Yang, Liuqing; Wu, Xiangyang

2014-04-01

3

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

4

A proteomic insight into the effects of the immunomodulatory hydroxynaphthoquinone lapachol on activated macrophages.  

PubMed

We report the effect of an immunomodulatory and anti-mycobacterial naphthoquinone, lapachol, on the bi-dimensional patterns of protein expression of toll-like receptor 2 (TLR2)-agonised and IFN-?-treated THP-1 macrophages. This non-hypothesis driven proteomic analysis intends to shed light on the cellular functions lapachol may be affecting. Proteins of both cytosol and membrane fractions were analysed. After quantification of the protein spots, the protein levels corresponding to macrophages activated in the absence or presence of lapachol were compared. A number of proteins were identified, the levels of which were appreciably and significantly increased or decreased as a result of the action of lapachol on the activated macrophages: cofilin-1, fascin, plastin-2, glucose-6-P-dehydrogenase, adenylyl cyclase-associated protein 1, pyruvate kinase, sentrin-specific protease 6, cathepsin B, cathepsin D, cytosolic aminopeptidase, proteasome ? type-4 protease, tryptophan-tRNA ligase, DnaJ homolog and protein disulphide isomerase. Altogether, the comparative analysis performed indicates that lapachol could be hypothetically causing an impairment of cell migration and/or phagocytic capacity, an increase in NADPH availability, a decrease in pyruvate concentration, protection from proteosomal protein degradation, a decrease in lysosomal protein degradation, an impairment of cytosolic peptide generation, and an interference with NOS2 activation and grp78 function. The present proteomic results suggest issues that should be experimentally addressed ex- and in-vivo, to establish more accurately the potential of lapachol as an anti-infective drug. This study also constitutes a model for the pre-in-vivo evaluation of drug actions. PMID:22705049

Oliveira, Renato A S; Correia-Oliveira, Janaina; Tang, Li-Jun; Garcia, Rodolfo C

2012-09-01

5

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.

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

2013-01-01

6

Antileishmanial and immunomodulatory activity of Xylopia discreta.  

PubMed

This study aimed at determining the in vitro antileishmanial activity of the essential oil and eight extracts obtained from Xylopia discreta. J774 and U937 macrophages were exposed to the different substances to establish the median lethal concentration (LC(50)). The median effective concentration (EC(50)) was obtained by determining the reduction of Leishmania panamensis-infected cells. A selectivity index (SI) (LC(50)/EC(50)) >or= 20 defined a specific activity for one Xylopia discreta leaf extracts and for the essential oil, being these the two that showed the highest activity (SI = 64.8 and 110, respectively in J774 cells). To assess the substances' immunomodulatory activity, pro- and anti-inflammatory soluble mediators produced after treating infected macrophages were quantified by flow cytometry. The leaf methanol extract and the essential oil induced a differential production of monocyte chemoattractant protein-1, a chemokine associated with a Leishmania-resistant phenotype (Th1). PMID:19751474

López, R; Cuca, L E; Delgado, G

2009-10-01

7

Immunomodulatory Effects of the Tityus serrulatus Venom on Murine Macrophage Functions in Vitro  

PubMed Central

Tityus serrulatus scorpion venom (TSV) consists of a very complex mixture of molecules and demonstrates significant immunomodulatory activities capable of stimulating immune functions in vivo. The purpose of this study was to compare the crude TSV with fractionated toxins extracted from this venom in order to determine which toxin(s) presented immunomodulatory effects on peritoneal macrophages. TSV was fractionated using gel filtration chromatography resulting in 5 heterogeneous fractions. The effects of these different fractions were analysed in vitro using detection by means of cytokines, oxygen intermediate metabolites (H2O2), and nitric oxide (NO) in supernatants of peritoneal macrophages. Several functional bioassays were employed: tumor necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity in L929 cells, and other cytokines were assayed by enzyme-linked immunosorbent assay, whereas NO levels were detected by Griess colorimetric reactions in culture supernatant of macrophages exposed to different fractions. In vitro studies revealed that all fractions studied here presented an increment in H2O2, NO, and cytokines levels. The more pronounced increments were observed in macrophage cultures exposed to fraction FII which demonstrated that (a) the highest levels of IL-1?, IL-?, and TNF were observed after 12 hours and that (b) the maximum levels of IFN-? and NO were observed after 72 hours. Taken together, these data indicate that fractions have a differential immunomodulating effect on macrophage secretion, and that FII is a potent activator of TNF production of macrophages.

Petricevich, Vera L.; Lebrun, Ivo

2005-01-01

8

Assessment of Immunomodulatory Activity of Euphorbia hirta L.  

PubMed Central

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.

Ramesh, K. Vijaya; Padmavathi, K.

2010-01-01

9

Immunomodulatory activity of mesenchymal stem cells.  

PubMed

Mesenchymal stem cells (MSCs) were discovered as a rare population of non-hematopoietic stem cells that reside in the bone marrow and interact closely with hematopoietic stem cells to support their growth and differentiation. MSCs are multipotent cells that have the ability to differentiate into cells of the mesenchymal lineage including adipocytes, osteocytes and chondrocytes and they have been reported to home to areas of tissue injury and participate in tissue repair. More recently, MSCs have also been described to possess anti-inflammatory and immunomodulatory properties that can affect multiple arms of the immune system. MSCs have been shown to inhibit T and B cell proliferation, downregulate the lytic activity of cytotoxic T lymphocytes and NK cells, inhibit the maturation and antigen-presenting function of dendritic cells and modulate macrophage function through both contact-dependent and contact-independent mechanisms. The administration of MSCs in models of autoimmune disease such as collagen-induced arthritis, EAE and autoimmune diabetes has provided additional evidence for an immunoregulatory role of MSCs supporting their use in controlling autoimmunity. The administration of allogeneic MSCs as immunosuppressive agents represents a viable approach as they appear to be largely non-immunogenic and clinical trials with allogeneic MSCs are currently underway in graftversus- host disease, Crohn's disease and type I diabetes indications. The immunomodulatory properties, mechanism of action and potential clinical utility of MSCs are reviewed herein. PMID:21190531

Kaplan, Johanne M; Youd, Michele E; Lodie, Tracey A

2011-12-01

10

Immunomodulatory ?-Glucan from Lentinus edodes Activates Mitogen-activated Protein Kinases and Nuclear Factor-?B in Murine RAW 264.7 Macrophages*  

PubMed Central

Lentinan, a cell wall ?-glucan from the fruiting bodies of Lentinus edodes, is well known to be a biological defense modifier, but the signal transduction pathway(s) induced by Lentinan have not been elucidated. In this study, we extracted Lentinan (LNT-S) by ultrasonication from Lentinus edodes and report that, in murine RAW 264.7 macrophages, LNT-S glucan activated NF-?B p65 and triggered its nuclear translocation as determined by Western blotting. Moreover, LNT-S enhanced NF-?B-luciferase activity in the Dual-Luciferase gene system assay. Its upstream signaling molecules, MAPKs such as ERK1/2 and JNK1/2, were shown to be activated by assessing the level of phosphorylation in a time- and concentration-dependent manner, but its downstream proinflammatory enzyme, inducible NOS, was not observed. The data evaluated using a TNF-? ELISA kit and Griess reagent further demonstrated that no proinflammatory mediators such as TNF-? and NO were produced by LNT-S stimulation in RAW 264.7 cells. In contrast, LPS significantly induced inducible NOS expression and increased NO and TNF-? production, which are associated with activation of the NF-?B p65/p50 heterodimer complex. It is possible that LNT-S did not activate NF-?B p65/p50, and the activation of NF-?B p65 was not sufficient to stimulate cytokine production. These data demonstrate that LNT-S glucan carries out its immunomodulating activity by activating MAPK signaling pathways without secretion of TNF-? and NO.

Xu, Xiaojuan; Pan, Chen; Zhang, Lina; Ashida, Hitoshi

2011-01-01

11

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.

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

2013-01-01

12

Characterization and immunomodulatory activity of polysaccharides derived from Dendrobium tosaense.  

PubMed

Dendrobium tosaense is a medicinal Dendrobium species widely used in traditional medicine. This study demonstrated some structural characterizations and immunomodulatory activity of the water-soluble polysaccharides derived from the stem of D. tosaense (DTP). DTP was fractioned using DEAE-650M anion-exchange gel filtration chromatography, producing one neutral polysaccharide fraction (DTP-N), which was investigated for its structural characteristics, using HPAEC-PAD, HP-SEC, GC-MS, and NMR spectroscopy. DTP and DTP-N consisted of galactose, glucose, and mannose in ratios of 1:9.1:150.7 and 1:12.2:262.5, respectively. DTP-N comprised (1?4)Man as its main backbone, and its average molecular weight was 220kDa. We also investigated the immunomodulatory effects of DTP administered orally to BALB/c mice for 3 weeks. DTP substantially boosted the population of splenic natural killer (NK) cells, NK cytotoxicity, macrophage phagocytosis, and cytokine induction in splenocytes. This is the first study to demonstrate the structural characteristics of an active polysaccharide derived from D. tosaense and its immunopharmacological effects in vivo. PMID:25037425

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

2014-10-13

13

Immunomodulatory Role of Ocimum gratissimum and Ascorbic Acid against Nicotine-Induced Murine Peritoneal Macrophages In Vitro  

PubMed Central

The aim of this present study was to evaluate the immune functions and immune responses in nicotine-induced (10?mM) macrophages and concurrently establish the immunomodulatory role of aqueous extract of Ocimum gratissimum (Ae-Og) and ascorbic acid. In this study, nitrite generations and some phenotype functions by macrophages were studied. Beside that, release of Th1 cytokines (TNF-?, IL-12) and Th2 cytokines (IL-10, TGF-?) was measured by ELISA, and the expression of these cytokines at mRNA level was analyzed by real-time PCR. Ae-Og, at a dose of 10??g/mL, significantly reduced the nicotine-induced NO generation and iNOSII expression. Similar kinds of response were observed with supplementation of ascorbic acid (0.01?mM). The administration of Ae-Og and ascorbic acid increased the decreased adherence, chemotaxis, phagocytosis, and intracellular killing of bacteria in nicotine-treated macrophages. Ae-Og and ascorbic acid were found to protect the murine peritoneal macrophages through downregulation of Th1 cytokines in nicotine-treated macrophages with concurrent activation of Th2 responses. These findings strongly enhanced our understanding of the molecular mechanism leading to nicotine-induced suppression of immune functions and provide additional rationale for application of anti-inflammatory therapeutic approaches by O. gratissimum and ascorbic acid for different inflammatory disease prevention and treatment during nicotine toxicity.

Mahapatra, Santanu Kar; Chakraborty, Subhankari Prasad; Roy, Somenath

2011-01-01

14

Immunomodulatory Activity of Recombinant Ricin Toxin Binding Subunit B (RTB).  

PubMed

Ricin toxin binding subunit B (RTB) is one of the subunits of the ricin protein. RTB has been used as adjuvant, but little is known about its mechanism. In this study, we found that RTB increased not only nitric oxide (NO) release, but also tumor necrosis factor (TNF)-? and interleukin (IL)-6 production in mouse macrophage cell line RAW264.7 cells. They subsequently exhibited enhanced ConA-induced T-cell and LPS-induced B-cell proliferative responses. We also examined the cytokines that were produced from splenocytes following in vitro RTB administration. Increased levels of IL-2, interferon (IFN)-? and TNF-? were observed, while IL-4 and IL-5 were unaffected. These results demonstrate that recombinant RTB can act on the immune system and activate T-cells by introducing a Th1 immune response. Th1 cells might be the primary cellular target affected by RTB. Our results suggest that the recombinant RTB can promote the activation of macrophages and has a beneficial effect on immunomodulatory activity. PMID:23765218

Liu, Wensen; Xu, Na; Yuan, Hongyan; Li, Songyan; Liu, Linna; Pu, Zhaoyang; Wan, Jiayu; Wang, Huiwen; Chang, Yaping; Li, Ruisheng

2013-01-01

15

Immunomodulatory Activity of Recombinant Ricin Toxin Binding Subunit B (RTB)  

PubMed Central

Ricin toxin binding subunit B (RTB) is one of the subunits of the ricin protein. RTB has been used as adjuvant, but little is known about its mechanism. In this study, we found that RTB increased not only nitric oxide (NO) release, but also tumor necrosis factor (TNF)-? and interleukin (IL)-6 production in mouse macrophage cell line RAW264.7 cells. They subsequently exhibited enhanced ConA-induced T-cell and LPS-induced B-cell proliferative responses. We also examined the cytokines that were produced from splenocytes following in vitro RTB administration. Increased levels of IL-2, interferon (IFN)-? and TNF-? were observed, while IL-4 and IL-5 were unaffected. These results demonstrate that recombinant RTB can act on the immune system and activate T-cells by introducing a Th1 immune response. Th1 cells might be the primary cellular target affected by RTB. Our results suggest that the recombinant RTB can promote the activation of macrophages and has a beneficial effect on immunomodulatory activity.

Liu, Wensen; Xu, Na; Yuan, Hongyan; Li, Songyan; Liu, Linna; Pu, Zhaoyang; Wan, Jiayu; Wang, Huiwen; Chang, Yaping; Li, Ruisheng

2013-01-01

16

Alternative activation of macrophages  

Microsoft Academic Search

The classical pathway of interferon-?-dependent activation of macrophages by T helper 1 (TH1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a

Siamon Gordon

2003-01-01

17

In vitro immunomodulatory activity of ruthenium complexes  

Microsoft Academic Search

Objective and Design: We have explored the in vitro immunomodulatory effects of pure ruthenium red and a series of pyridine and imidazole substituted ruthenium complexes (RCs). Material: Human peripheral blood lymphocytes and purified T cells were used in these studies along with various cell lines. Methods: Cells were treated with dilutions of RCs and assessed in various assays of immune

J. R. Newcomb; B. Rivnay; C. M. Bastos; T. D. Ocain; K. Gordon; P. Gregory; S. M. Turci; K. A. Sterne; M. Jesson; J. Krieger; J. C. Jenson; B. Jones

2003-01-01

18

Immunomodulatory activity of an anti-HSV-1 synthetic stigmastane analog.  

PubMed

Many viral infections are associated with the development of immunopathologies and autoimmune diseases, which are of difficult treatment and for which no vaccines are yet available. Obtaining compounds that conjugate both antiviral and immunomodulatory activities in the same molecule would be very useful for the prevention and/or treatment of these immunopathologies. The compound (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) displays anti-Herpes simplex virus type 1 activity in vitro and reduces the incidence of herpetic stromal keratitis (HSK) in mice, a chronic inflammatory syndrome induced by ocular HSV-1 infection. In the present study, compound 1 showed opposite immunomodulatory properties in vitro. It induced the release of pro-inflammatory cytokines in HSV-1-infected epithelial cells of ocular origin, and significantly reduced the production of these cytokines in LPS-activated macrophages. RNA microarrays revealed various overexpressed and repressed genes in compound 1 treated infected epithelial cells and activated macrophages, many of which are associated with innate immune responses and inflammatory processes. These immunomodulatory properties of compound 1, together with its previously reported antiviral activity, make it a potential drug for the treatment of HSK and many other immunopathologies of viral and non-viral origin. PMID:23219855

Michelini, Flavia M; Zorrilla, Pilar; Robello, Carlos; Alché, Laura E

2013-01-15

19

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

20

Picrorhiza scrophulariiflora, from traditional use to immunomodulatory activity  

Microsoft Academic Search

Natural products have been an important resource for the maintenance of life for ages. Evaluation of traditionally used medicines, keeping into account the traditional principles that are applied in drug therapy, may supply leads towards effective\\u000a drug discovery. This thesis deals with the pre-clinical evaluation of the immunomodulatory activity of Picrorhiza\\u000a scrophulariiflora and the activity-guided isolation of active constituents, in

Hobbe Friso Smit

2000-01-01

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.

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

2010-01-01

22

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

PubMed

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

Mariano, Vania Sammartino; Zorzetto-Fernandes, Andre Luiz; da Silva, Thiago Aparecido; Ruas, Luciana Pereira; Nohara, Lilian L; de Almeida, Igor Correia; Roque-Barreira, Maria Cristina

2014-01-01

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.

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

2014-01-01

24

Immunomodulatory effect of prolactin on Atlantic salmon (Salmo salar) macrophage function.  

PubMed

The in vitro and in vivo effect of prolactin (PRL) on kidney macrophages from Atlantic salmon (Salmo salar) was investigated under the assumption that PRL stimulates immune innate response in mammals. Kidney macrophages were treated two ways: first, cultured in RPMI 1640 medium containing 10, 25, 50 and 100 ng/mL of PRL and second, isolated from a fish with a PRL-injected dose of 100 ng/Kg. Reduced nitro blue tetrazolium (formazan) was used to produce intracellular superoxide anion. Phagocytic activity of PRL was determined in treated cells by optical microscopy observation of phagocytized Congo red-stained yeast. Kidney lysozyme activity was measured in PRL-injected fish. In vitro and in vivo macrophages treated with PRL presented an enhanced superoxide anion production, elevated phagocytic index and increased phagocytic activity. Treated fish showed higher levels of lysozyme activity in the head kidney compared to the control. These results indicate that PRL-stimulated innate immune response in Atlantic salmon and future studies will allow us to assess the possibility of using PRL as an immunostimulant in the Chilean salmon industry. PMID:23420569

Paredes, Marco; Gonzalez, Katerina; Figueroa, Jaime; Montiel-Eulefi, Enrique

2013-10-01

25

Macrophage activation: glancing into diversity.  

PubMed

Macrophage activation is a crucial process for innate immunity as well as for tissue and metabolic homeostasis. In this issue of Immunity, Xue et al. (2014) extend our knowledge on macrophage activation and identify unique functional states, thus expanding the M1-M2 paradigm. PMID:24560195

Natoli, Gioacchino; Monticelli, Silvia

2014-02-20

26

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

27

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.

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

2011-01-01

28

Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice.  

PubMed

Interstitial cystitis (IC) is a chronic disorder characterized by bladder discomfort and urinary urgency in the absence of identifiable infection. Despite the expanding use in IC treatment and other chronic conditions, the effects of Elmiron® treatment on immune system remain unknown. Therefore, female B6C3F1/N mice were orally administered Elmiron® daily for 28-days at doses of 63, 125, 250, 500 or 1000mg/kg to evaluate its immunomodulatory effects. Mice treated with Elmiron® had a significant increase in absolute numbers of splenic macrophages (63, 500 and 1000mg/kg) and natural killer (NK) cells (250 and 1000mg/kg). Elmiron® treatment did not affect the humoral immune response or T cell proliferative response. However, innate immune responses such as phagocytosis by liver macrophages (1000mg/kg) and NK cell activity were enhanced (500 and 1000mg/kg). Further analysis using a disease resistance model showed that Elmiron®-treated mice demonstrated significantly increased anti-tumor activity against B16F10 melanoma cells at the 500 and 1000mg/kg doses. Collectively, we conclude that Elmiron® administration stimulates the immune system, increasing numbers of specific cell populations and enhancing macrophage phagocytosis and NK cell activity in female B6C3F1/N mice. This augmentation may have largely contributed to the reduced number of B16F10 melanoma tumors. PMID:24657363

Thakur, Sheetal A; Nyska, Abraham; White, Kimber L; Smith, Matthew J; Auttachoat, Wimolnut; Germolec, Dori R

2014-06-01

29

Immunomodulatory and therapeutic activity of curcumin.  

PubMed

Inflammation is a disease of vigorous uncontrolled activated immune responses. Overwhelming reports have suggested that the modulation of immune responses by curcumin plays a dominant role in the treatment of inflammation and metabolic diseases. Observations from both in-vitro and in-vivo studies have provided strong evidence towards the therapeutic potential of curcumin. These studies have also identified a plethora of biological targets and intricate mechanisms of action that characterize curcumin as a potent 'drug' for numerous ailments. During inflammation the functional influence of lymphocytes and the related cross-talk can be modulated by curcumin to achieve the desired immune status against diseases. This review describes the regulation of immune responses by curcumin and effectiveness of curcumin in treatment of diseases of diverse nature. PMID:20828642

Srivastava, Raghvendra M; Singh, Sarvjeet; Dubey, Shiv K; Misra, Krishna; Khar, Ashok

2011-03-01

30

Extract from Calotropis procera latex activates murine macrophages.  

PubMed

Calotropis procera latex has long been used in traditional medicines. Extracts from C. procera latex have been reported to have various pharmacological actions, including protection from myocardial infarction, hepatoprotective action, antitumor activity, antinociceptive, and pro- and anti-inflammatory actions. To evaluate the immunomodulatory functions of the water-soluble C. procera extract (CPE), we investigated its ability to activate macrophages-effector cells in inflammatory and immune responses. Intraperitoneal injection of CPE in mice (2 mg/mouse) induced migration of macrophages to the intraperitoneal cavity, confirming the proinflammatory effects of water-soluble CPE. The direct effects of CPE on macrophages were then assessed by measuring the production of nitric oxide (NO) as an indicator for macrophage activation. Addition of CPE (1-10 microg/ml) to the culture medium of the murine monocyte/macrophage cell line RAW264.7 caused an increase in NO production in a time- and dose-dependent manner. CPE-elicited NO production was blocked by application of an inhibitor of inducible nitric oxide synthase (iNOS). Expression of iNOS mRNA was induced by treatment of cultured macrophages with CPE. Injection of CPE in mice also resulted in an increase in plasma NO level. The results suggest that CPE activates macrophages and facilitates NO production via up-regulation of iNOS gene expression. PMID:19399577

Seddek, Abdel latif Shaker; Mahmoud, Motamed Elsayed; Shiina, Takahiko; Hirayama, Haruko; Iwami, Momoe; Miyazawa, Seiji; Nikami, Hideki; Takewaki, Tadashi; Shimizu, Yasutake

2009-07-01

31

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

32

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.

2013-01-01

33

Effects of Ferumoxides - Protamine Sulfate Labeling on Immunomodulatory Characteristics of Macrophage-like THP-1 Cells  

PubMed Central

Superparamagnetic Iron Oxide (SPIO) complexed with cationic transfection agent is used to label various mammalian cells. Labeled cells can then be utilized as an in vivo magnetic resonance imaging (MRI) probes. However, certain number of in vivo administered labeled cells may be cleared from tissues by the host's macrophages. For successful translation to routine clinical application of SPIO labeling method it is important that this mode of in vivo clearance of iron does not elicit any diverse immunological effects. The purpose of this study was to demonstrate that SPIO agent ferumoxides-protamine sulfate (FePro) incorporation into macrophages does not alter immunological properties of these cells with regard to differentiation, chemotaxis, and ability to respond to the activation stimuli and to modulate T cell response. We used THP-1 cell line as a model for studying macrophage cell type. THP-1 cells were magnetically labeled with FePro, differentiated with 100 nM of phorbol ester, 12-Myristate-13-acetate (TPA) and stimulated with 100 ng/ml of LPS. The results showed 1) FePro labeling had no effect on the changes in morphology and expression of cell surface proteins associated with TPA induced differentiation; 2) FePro labeled cells responded to LPS with slightly higher levels of NF?B pathway activation, as shown by immunobloting; TNF-? secretion and cell surface expression levels of CD54 and CD83 activation markers, under these conditions, were still comparable to the levels observed in non-labeled cells; 3) FePro labeling exhibited differential, chemokine dependent, effect on THP-1 chemotaxis with a decrease in cell directional migration to MCP-1; 4) FePro labeling did not affect the ability of THP-1 cells to down-regulate T cell expression of CD4 and CD8 and to induce T cell proliferation. Our study demonstrated that intracellular incorporation of FePro complexes does not alter overall immunological properties of THP-1 cells. The described experiments provide the model for studying the effects of in vivo clearance of iron particles via incorporation into the host's macrophages that may follow after in vivo application of any type of magnetically labeled mammalian cells. To better mimic the complex in vivo scenario, this model may be further exploited by introducing additional cellular and biological, immunologically relevant, components.

Janic, Branislava; Iskander, A. S. M.; Rad, Ali M.; Soltanian-Zadeh, Hamid; Arbab, Ali S.

2008-01-01

34

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

35

Induction of secretory and tumoricidal activities in peritoneal macrophages by ginsan  

Microsoft Academic Search

The immunomodulatory effect of ginsan based on the production of cytokines and the activation of macrophage was studied. Murine peritoneal macrophages (PM) on in vitro treatment with ginsan isolated from Panax ginseng induced mRNA of cytokines such as tumor necrosis factor (TNF)-?, interleukin-1 (IL-1)?, interleukin-6 (IL-6) and interleukin-12 (IL-12); TNF-? mRNA induction was maximum within 3 h, IL-6 mRNA was

Jie-Young Song; Seon-Kyu Han; Eun-Hwa Son; Suhk-Neung Pyo; Yeon-Sook Yun; Seh-Yoon Yi

2002-01-01

36

Echinacea-induced macrophage activation.  

PubMed

Public interest in Echinacea is growing rapidly. Unfortunately, there is little scientific evidence to support claims of efficacy of this widely used botanical, and little information about potential mechanism of action. This study examines the ability of Echinacea to upregulate macrophage function and begins to elucidate the mechanism of Echinacea-induced macrophage activation. Murine peritoneal macrophages were cultured with E. purpurea extracts enriched for plant polysaccharide (EP). ELISA was used to measure cytokine production. MAPKs were blocked using specific inhibitors, and Western blotting used to identify phosphorylated proteins involved in signal transduction. To examine in vivo efficacy, EP was administered orally and Listeria monocytogenes given i.v. Mice were sacrificed three days post-infection to determine bacterial load in the spleen. We demonstrate that an endotoxin-free EP extract activates the innate immune response, stimulating production of IL-6, TNF, IL-12, and NO from macrophages in vitro. Along with evidence of enhanced macrophage function, we found that oral EP reduces bacterial burden during infection by Listeria monocytogenes, demonstrating its efficacy in vivo. EP initiates a signaling cascade within macrophages through both TLR4-dependent and -independent mechanisms, involving ERK, p38 and JNK, and ultimately the activation of NF-kappaB. PMID:18618312

Sullivan, Allyn M; Laba, Jennifer G; Moore, Jill A; Lee, Timothy D G

2008-01-01

37

Immunomodulatory activities of Punarnavine, an alkaloid from Boerhaavia diffusa.  

PubMed

The effect of Punarnavine on the immune system was studied using Balb/c mice. Intraperitoneal administration of Punarnavine (40 mg/kg body weight) was found to enhance the total WBC count on 6(th) day. Bone marrow cellularity and number of alpha-esterase positive cells were also increased by the administration of Punarnavine. Treatment of Punarnavine along with the antigen, sheep red blood cells (SRBC), produced an enhancement in the circulating antibody titer and the number of plaque forming cells (PFC) in the spleen. Maximum number of PFC was obtained on the 6(th) day. Punarnavine also showed enhanced proliferation of splenocytes, thymocytes and bone marrow cells both in the presence and absence of specific mitogens in vitro and in vivo. More over administration of Punarnavine significantly reduced the LPS induced elevated levels of proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 in mice. These results indicate the immunomodulatory activity of Punarnavine. PMID:19555203

Manu, Kanjoormana Aryan; Kuttan, Girija

2009-01-01

38

Immunomodulatory impact of leishmania-induced macrophage exosomes: a comparative proteomic and functional analysis.  

PubMed

Released by many eukaryotic cells, the exosomes are 40-100 nm vesicles shown to operate over the complex processes of cell-cell communication. Among the metazoan cell lineages known to generate exosomes is the mononuclear phagocyte lineage, a lineage that parasites such as Leishmania are known to subvert as host cells. We previously reported that mouse macrophage signaling and functions are modified once co-incubated with exoproteome of Leishmania promastigotes. Using mass spectrometry analysis, we were curious to further compare the content of purified exosomes released by the J774 mouse macrophage cell line exposed or not to either LPS or to stationary phase Leishmania mexicana promastigotes. Collectively, our analyses resulted in detection of 248 proteins, ?50-80% of which were shared among the three sources studied. Using exponentially modified protein abundance index (emPAI) and network analyses, we found that the macrophage exosomes display unique signatures with respect to composition and abundance of many functional groups of proteins, such as plasma membrane-associated proteins, chaperones and metabolic enzymes. Moreover, for the first time, L. mexicana surface protease GP63 is shown to be present in exosomes released from J774 macrophages exposed to stationary phase promastigotes. We observed that macrophage exosomes are able to induce signaling molecules and transcription factors in naive macrophages. Finally, using qRT-PCR, we monitored modulation of expression of multiple immune-related genes within macrophages exposed to exosomes. We found all three groups of exosomes to induce expression of immune-related genes, the ones collected from macrophages exposed to L. mexicana sharing properties with exosomes collected from macrophage left unexposed to any agonist. Overall, our results allowed depicting that protein sorting into macrophage-derived exosomes depends upon the cell status and how such distinct protein sorting can in turn impact the functions of naive J774 cells. PMID:23658846

Hassani, Kasra; Olivier, Martin

2013-01-01

39

Immunomodulatory Impact of Leishmania-Induced Macrophage Exosomes: A Comparative Proteomic and Functional Analysis  

PubMed Central

Released by many eukaryotic cells, the exosomes are 40–100 nm vesicles shown to operate over the complex processes of cell-cell communication. Among the metazoan cell lineages known to generate exosomes is the mononuclear phagocyte lineage, a lineage that parasites such as Leishmania are known to subvert as host cells. We previously reported that mouse macrophage signaling and functions are modified once co-incubated with exoproteome of Leishmania promastigotes. Using mass spectrometry analysis, we were curious to further compare the content of purified exosomes released by the J774 mouse macrophage cell line exposed or not to either LPS or to stationary phase Leishmania mexicana promastigotes. Collectively, our analyses resulted in detection of 248 proteins, ?50–80% of which were shared among the three sources studied. Using exponentially modified protein abundance index (emPAI) and network analyses, we found that the macrophage exosomes display unique signatures with respect to composition and abundance of many functional groups of proteins, such as plasma membrane-associated proteins, chaperones and metabolic enzymes. Moreover, for the first time, L. mexicana surface protease GP63 is shown to be present in exosomes released from J774 macrophages exposed to stationary phase promastigotes. We observed that macrophage exosomes are able to induce signaling molecules and transcription factors in naive macrophages. Finally, using qRT-PCR, we monitored modulation of expression of multiple immune-related genes within macrophages exposed to exosomes. We found all three groups of exosomes to induce expression of immune-related genes, the ones collected from macrophages exposed to L. mexicana sharing properties with exosomes collected from macrophage left unexposed to any agonist. Overall, our results allowed depicting that protein sorting into macrophage-derived exosomes depends upon the cell status and how such distinct protein sorting can in turn impact the functions of naive J774 cells.

Hassani, Kasra; Olivier, Martin

2013-01-01

40

Immunomodulatory and antitumor activities of a polysaccharide-peptide complex from a mycelial culture of Tricholoma sp., a local edible mushroom  

Microsoft Academic Search

A polysaccharide-peptide complex (PSPC) with immunomodulatory and antitumor activities was obtained from a submerged mycelial culture of Tricholoma sp., a local edible mushroom. The polysaccharide-peptide complex exhibited a molecular weight of 17 K in gel filtration and a single band after SDS-polyacrylamide gel electrophoresis. It was characterized by non-adsorption on both DEAE-Sepharose CL-6B and CM-cellulose. It could activate the macrophages,

H. X Wang; W. K Liu; T. B Ng; V. E. C Ooi; S. T Chang

1995-01-01

41

Flavonol Glycosides from Euphorbia microsciadia Bioss. with their Immunomodulatory Activities  

PubMed Central

Four known flavonoids: quercetin 3-O-?-D-rutinoside (Q3Rut), myricetin 3-O-?-D-galactopyranoside (M3Gal), quercetin 3-O-?-D-galactopyranoside (Q3Gal) and quercetin 3-O-?-D-glucopyranoside (Q3Glc), for the first time were isolated from aerial parts of Euphorbia microsciadia. The chemical structure of them was elucidated on the basis of 1 and 2 D-NMR spectra and different spectroscopic techniques. The immunomodulatory activities of isolated compounds were compared using standard T-cell proliferation assay. These data showed that lymphocyte suppression activity of flavonoids (1-4) were comparatively lower than prednisolon as a standard drug. Immunosuppressive activity of flavonoids with hydroxyl groups at both 3?-and 4?-positions in their B-ring (Q3Gal) were more than those with 3?-,4?-and 5?-hydroxyl substitution (M3Gal). In these compounds, Q3Gal showed the most inhibitory activity, whereas M3Gal showed the least lymphocyte antiprolifeartive activity.

Ghanadian, Syed Mustafa; Ayatollahi, Abdul Majid; Afsharypour, Suleiman; Hareem, Sumaira; Abdalla, Omer Mohamed; Jules Kezetas Bankeu, Jean

2012-01-01

42

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

43

Schistosoma mansoni Hemozoin Modulates Alternative Activation of Macrophages via Specific Suppression of Retnla Expression and Secretion  

PubMed Central

The trematode Schistosoma mansoni is one of the etiological agents of schistosomiasis, a key neglected tropical disease responsible for an estimated annual loss of 70 million disability-adjusted life years. Hematophagy represents the primary nutrient acquisition pathway of this parasite, but digestion of hemoglobin also liberates toxic heme. Schistosomes detoxify heme via crystallization into hemozoin, which is subsequently regurgitated into the host's circulation. Here we demonstrate that during experimental schistosomiasis, hemozoin accumulating in the mouse liver is taken up by phagocytes at a time coincident with the development of the egg-induced T-helper 2 (Th2) granulomatous immune response. Furthermore, the uptake of hemozoin also coincides with the hepatic expression of markers of alternative macrophage activation. Alternatively activated macrophages are a key effector cell population associated with protection against schistosomiasis, making hemozoin well placed to play an important immunomodulatory role in this disease. To systematically explore this hypothesis, S. mansoni hemozoin was purified and added to in vitro bone marrow-derived macrophage cultures concurrently exposed to cytokines chosen to reflect the shifting state of macrophage activation in vivo. Macrophages undergoing interleukin-4 (IL-4)-induced alternative activation in the presence of hemozoin developed a phenotype specifically lacking in Retnla, a characteristic alternatively activated macrophage product associated with regulation of Th2 inflammatory responses. As such, in addition to its important detoxification role during hematophagy, we propose that schistosome hemozoin also provides a potent immunomodulatory function in the coevolved network of host-parasite relationships during schistosomiasis.

Truscott, Martha; Evans, D. Andrew; Gunn, Matt

2013-01-01

44

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.

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

2009-01-01

45

Immunomodulatory activity of oenothein B isolated from Epilobium angustifolium.  

PubMed

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. In this study, 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 Ca(2+) flux, production of reactive oxygen species, chemotaxis, NF-kappaB activation, and proinflammatory cytokine production. Furthermore, oenothein B was active in vivo, inducing keratinocyte chemoattractant 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

2009-11-15

46

Anti-inflammatory and immunomodulatory activities of rifamycin SV.  

PubMed

There have been several reports showing convincing evidence for non-bactericidal activities of the rifamycin antibiotics. In particular, the parent compound rifamycin SV has been employed in a limited number of cases to treat rheumatoid arthritis. Moreover, rifamycin SV and its derivative rifaximin have been found to be effective in experimental animal models of gut inflammation. The efficacy of rifamycin SV and rifaximin in these settings has been attributed partially to indirect non-bactericidal activities. To better clarify the mechanisms by which these two antibiotics exert their non-bactericidal effects, their activities were compared in in vitro cellular models of immunomodulation and inflammation. Both antibiotics were found to inhibit cytokine and chemokine synthesis from lipopolysaccharide-activated THP-1 monocytes and macrophages. It was also demonstrated, for the first time, that rifamycin SV exerts anti-inflammatory activities in HT-29 colonic epithelial cells. Moreover, rifamycin SV is also very effective in downregulating secretion of inflammatory cytokines from human CD4 T-cells. In general, both antibiotics show similar activities on all four cell types tested. However, rifamycin SV is less cytotoxic than rifaximin when tested in these cells. PMID:23756321

Rosette, Caridad; Buendia-Laysa, Fernando; Patkar, Seema; Moro, Luigi; Celasco, Giuseppe; Bozzella, Roberta; Ajani, Mauro; Gerloni, Mara

2013-08-01

47

ROS sets the stage for macrophage differentiation.  

PubMed

While M1 macrophages are highly pro-inflammatory and microbicidal, M2 macrophages and the related tumor associated macrophages (TAMs) regulate tissue remodeling and angiogenesis and can display immunomodulatory activity. In July issue of Cell Research, Zhang et al. show that ROS production, critical for the activation and functions of M1 macrophages, is necessary for the differentiation of M2 macrophages and TAMs, and that antioxidant therapy blocks TAM differentiation and tumorigenesis in mouse models of cancer. PMID:23835480

Covarrubias, Anthony; Byles, Vanessa; Horng, Tiffany

2013-08-01

48

Immunomodulatory Activity of Red Ginseng against Influenza A Virus Infection  

PubMed Central

Ginseng herbal medicine has been known to have beneficial effects on improving human health. We investigated whether red ginseng extract (RGE) has preventive effects on influenza A virus infection in vivo and in vitro. RGE was found to improve survival of human lung epithelial cells upon influenza virus infection. Also, RGE treatment reduced the expression of pro-inflammatory genes (IL-6, IL-8) probably in part through interference with the formation of reactive oxygen species by influenza A virus infection. Long-term oral administration of mice with RGE showed multiple immunomodulatory effects such as stimulating antiviral cytokine IFN-? production after influenza A virus infection. In addition, RGE administration in mice inhibited the infiltration of inflammatory cells into the bronchial lumens. Therefore, RGE might have the potential beneficial effects on preventing influenza A virus infections via its multiple immunomodulatory functions.

Lee, Jong Seok; Hwang, Hye Suk; Ko, Eun-Ju; Lee, Yu-Na; Kwon, Young-Man; Kim, Min-Chul; Kang, Sang-Moo

2014-01-01

49

In vitro investigation of the potential immunomodulatory and anti-cancer activities of black pepper (Piper nigrum) and cardamom (Elettaria cardamomum).  

PubMed

Although the immunomodulatory effects of many herbs have been extensively studied, research related to possible immunomodulatory effects of various spices is relatively scarce. Here, the potential immunomodulatory effects of black pepper and cardamom are investigated. Our data show that black pepper and cardamom aqueous extracts significantly enhance splenocyte proliferation in a dose-dependent, synergistic fashion. Enzyme-linked immunosorbent assay experiments reveal that black pepper and cardamom significantly enhance and suppress, respectively, T helper (Th)1 cytokine release by splenocytes. Conversely, Th2 cytokine release by splenocytes is significantly suppressed and enhanced by black pepper and cardamom, respectively. Experimental evidence suggests that black pepper and cardamom extracts exert pro-inflammatory and anti-inflammatory roles, respectively. Consistently, nitric oxide production by macrophages is significantly augmented and reduced by black pepper and cardamom, respectively. Remarkably, it is evident that black pepper and cardamom extracts significantly enhance the cytotoxic activity of natural killer cells, indicating their potential anti-cancer effects. Our findings strongly suggest that black pepper and cardamom exert immunomodulatory roles and antitumor activities, and hence they manifest themselves as natural agents that can promote the maintenance of a healthy immune system. We anticipate that black pepper and cardamom constituents can be used as potential therapeutic tools to regulate inflammatory responses and prevent/attenuate carcinogenesis. PMID:20210607

Majdalawieh, Amin F; Carr, Ronald I

2010-04-01

50

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.

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

2014-01-01

51

Macrophage activation syndrome II\\/II  

Microsoft Academic Search

Macrophage activation syndrome (MAS) is a rare systemic disorder which results from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. Primary haemophagocytic lymphohistiocytosis (HLH) is recognized as having a genetic basis, but the secondary haemophagocytic syndrome (HS), also referred to as MAS, occurs in a number of autoimmune disorders including systemic onset juvenile idiopathic arthritis, systemic

K Shanmuganandan; J Kotwal

2009-01-01

52

Lipoteichoic Acid in Streptomyces hygroscopicus: Structural Model and Immunomodulatory Activities  

PubMed Central

Gram positive bacteria produce cell envelope macroamphiphile glycopolymers, i.e. lipoteichoic acids or lipoglycans, whose functions and biosynthesis are not yet fully understood. We report for the first time a detailed structure of lipoteichoic acid isolated from a Streptomyces species, i.e. Streptomyces hygroscopicus subsp. hygroscopicus NRRL 2387T. Chemical, MS and NMR analyses revealed a polyglycerolphosphate backbone substituted with ?-glucosaminyl and ?-N-acetyl-glucosaminyl residues but devoid of any amino-acid substituent. This structure is very close, if not identical, to that of the wall teichoic acid of this organism. These data not only contribute to the growing recognition that lipoteichoic acid is a cell envelope component of Gram positive Actinobacteria but also strongly support the recently proposed hypothesis of an overlap between the pathways of lipoteichoic acid and wall teichoic acid synthesis in these bacteria. S. hygroscopicus lipoteichoic acid induced signalling by human innate immune receptor TLR2, confirming its role as a microbe-associated molecular pattern. Its activity was partially dependant on TLR1, TLR6 and CD14. Moreover, it stimulated TNF-? and IL-6 production by a human macrophage cell line to an extent similar to that of Staphylococcus aureus lipoteichoic acid. These results provide new clues on lipoteichoic acid structure/function relationships, most particularly on the role of the polyglycerolphosphate backbone substituents.

Cot, Marlene; Ray, Aurelie; Gilleron, Martine; Vercellone, Alain; Larrouy-Maumus, Gerald; Armau, Elise; Gauthier, Sophie; Tiraby, Gerard; Puzo, Germain; Nigou, Jerome

2011-01-01

53

Exploring the full spectrum of macrophage activation  

PubMed Central

Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities—host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other ‘shades’ of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

Mosser, David M.; Edwards, Justin P.

2008-01-01

54

Bidirectional immunomodulatory activities of polysaccharides purified from Pleurotus nebrodensis.  

PubMed

A novel Pleurotus nebrodensis polysaccharide (PN50G) was purified, characterized, and cultured with RAW264.7 macrophages to evaluate its bidirectional immunostimulating characteristics. PN50G was purified by using Sepharose 4B gel filtration; the molecular weight of PN50G was distributed at 2,000 kDa. The total protein and carbohydrate constituent ratios in PN50G were 2.6 ± 0.9 % and 92.4 ± 6.1 % (w/w), respectively, which suggests that PN50G may be a major proteo-polysaccharide component. The phagocytosis of macrophages was improved significantly, and remarkable changes were observed in the morphology of PN50G-treated cells. Compared with the control group, the productions of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), interleukin-10 (IL-10), and inducible nitric oxide synthase (iNOS) in the macrophages as well as the messenger RNA expressions were strongly induced by PN50G. Pro-/anti-inflammatory (IL-6/IL-10, TNF-?/IL-10, NO/IL-10) cytokine secretion ratios by lipopolysaccharide-stimulated RAW264.7 macrophages were significantly decreased by PN50G treatments in a dose-dependent manner under an excessive immune experimental model. This study suggests that purified PN50G can improve immunity and suppress immune overactivity in LPS-induced macrophages in a preventive manner to coordinate innate immunity and inflammatory responses. PMID:23963923

Wang, Changlu; Cui, Haiyan; Wang, Yurong; Wang, Zhifang; Li, Zhenjing; Chen, Mianhua; Li, Fengjuan

2014-02-01

55

Different Effects of the Immunomodulatory Drug GMDP Immobilized onto Aminopropyl Modified and Unmodified Mesoporous Silica Nanoparticles upon Peritoneal Macrophages of Women with Endometriosis  

PubMed Central

The aim of the present work was to compare in vitro the possibility of application of unmodified silica nanoparticles (UMNPs) and modified by aminopropyl groups silica nanoparticles (AMNPs) for topical delivery of immunomodulatory drug GMDP to the peritoneal macrophages of women with endometriosis. The absence of cytotoxic effect and high cellular uptake was demonstrated for both types of silica nanoparticles. The immobilization of GMDP on the UMNPs led to the suppression of the stimulatory effect of GMDP on the membrane expression of scavenger receptors SR-AI and SR-B, mRNAs expression of NOD2 and RAGE, and synthesis of proteolytic enzyme MMP-9 and its inhibitor TIMP-1. GMDP, immobilized onto AMNPs, enhanced the initially reduced membrane expression of SRs and increased NOD2, RAGE, and MMP-9 mRNAs expression by macrophages. Simultaneously high level of mRNAs expression of factors, preventing undesirable hyperactivation of peritoneal macrophages (SOCS1 and TIMP-1), was observed in macrophages incubated in the presence of GMDP, immobilized onto AMNPs. The effect of AMNPs immobilized GMDP in some cases exceeded the effect of free GMDP. Thus, among the studied types of silica nanoparticles, AMNPs are the most suitable nanoparticles for topical delivery of GMDP to the peritoneal macrophages.

Antsiferova, Yuliya; Sotnikova, Nataliya

2013-01-01

56

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

57

Immunomodulatory activity of aqueous extract of Achillea wilhelmsii C. Koch in mice  

Microsoft Academic Search

Immunomodulatory activity of aqueous extract of Achillea wilhelmsii (25, 50 and 100 mg\\/kg body weight for 5 days) was evaluated on body weight, relative organ weight, delayed type of hypersensitivity (DTH) response and haemagglutination titre (HT) in female Swiss albino mice. No significant body weight gain differences were recorded in various groups of animals. Significant increase in relative organ weight

Fariba Sharififar; Shirin Pournourmohammadi; Moslem Arabnejad

58

Inhibition of inflammatory mediators by neobavaisoflavone in activated RAW264.7 macrophages.  

PubMed

Flavonoids and coumarins are the major bioactive constituents identified in Psoralea corylifolia. The active fraction isolated from fruits, seeds and roots possesses antibacterial, antioxidative and immunomodulatory properties. Neobavaisoflavone is one of the flavonoids found in Psoralea corylifolia. In the present study we investigated in vitro the anti-inflammatory activity of neobavaisoflavone. Macrophages play an important role in inflammation through the release of inflammatory mediators involved in the immune response. Inappropriate and prolonged macrophage activation is largely responsible for the pathology of acute and chronic inflammatory conditions. Neobavaisoflavone significantly inhibited the production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and cytokines: IL-1?, IL-6, IL-12p40, IL-12p70, TNF-? in LPS+IFN-?- or PMA- stimulated RAW264.7 macrophages. PMID:21540797

Szliszka, Ewelina; Skaba, Dariusz; Czuba, Zenon P; Krol, Wojciech

2011-01-01

59

Antinociceptive, Immunomodulatory and Antipyretic Activity of Nymphayol Isolated from Nymphaea stellata (Willd.) Flowers  

PubMed Central

In the present study, we aimed to analyze the antinociceptive, immunomodulatory and antipyretic activities of nymphayol were investigated in wistar rats and mice. Antinociceptive effect was evaluated by acetic acid induced writhing, formalin induced paw licking and hot-plate tests. Immunomodulatory activity was assessed by neutrophil adhesion test, humoral response to sheep red blood cells, delayed-type hypersensitivity, phagocytic activity and cyclophosphamide induced myelosuppression. Antipyretic activity was evaluated by yeast induced hyperthermia in rats. Nymphayol produced signifi cant (p<0.05) antinociceptive activity in acetic acid induced writhing response and late phase of the formalin induced paw licking response. Pre-treatment with nymphayol (50 mg/kg, oral) evoked a signifi cant increase in neutrophil adhesion to nylon fi bres. The augmentation of humoral immune response to sheep red blood cells by nymphayol (50 mg/kg) was evidenced by increase in antibody titres in rats. Oral administration of nymphayol (50 mg/kg) to rats potentiated the delayed-type hypersensitivity reaction induced by sheep red blood cells. Treatment with nymphayol showed a signifi cant (p<0.05) reduction in pyrexia in rats. The results suggest that nymphayol possesses potent anti-nociceptive, immunomodulatory and antipyretic activities.

Pandurangan, Subash-Babu; Paul, Antony Samy; Savarimuthu, Ignacimuthu; Ali, Alshatwi A

2013-01-01

60

Immunomodulatory Activity of the Water Extract from Medicinal Mushroom Inonotus obliquus.  

PubMed

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

Kim, Yeon-Ran

2005-09-01

61

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.

2005-01-01

62

Tumour cell inhibition of macrophage cytokine activity.  

PubMed

Macrophages elaborate both effector and regulatory immune functions. It was hypothesised that tumours can exert a local alteration of macrophage function. Murine peritoneal macrophage-derived cytokines were assayed in the presence and absence of cells, cytosol fractions or conditioned media (TCCM) from established murine tumour lines. Interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha activities were significantly inhibited by tumour cells or their products, as were the corresponding recombinant human cytokines. Intracellular protein kinase C activation was also measured and was significantly inhibited by murine TCCM, thus suggesting one possible site of inhibitor action. Data analyses indicate that the inhibitory factor(s) is probably not an already well-characterised macrophage inhibitor. PMID:1466902

Hannigan, B M; McNally, O R; Kirrane, O; Eason, S J

1992-12-01

63

Activated Macrophage Survival Is Coordinated by TAK1 Binding Proteins  

PubMed Central

Macrophages play diverse roles in tissue homeostasis and immunity, and canonically activated macrophages are critically associated with acute inflammatory responses. It is known that activated macrophages undergo cell death after transient activation in some settings, and the viability of macrophages impacts on inflammatory status. Here we report that TGF?- activated kinase (TAK1) activators, TAK1-binding protein 1 (TAB1) and TAK1-binding protein 2 (TAB2), are critical molecules in the regulation of activated macrophage survival. While deletion of Tak1 induced cell death in bone marrow derived macrophages even without activation, Tab1 or Tab2 deletion alone did not profoundly affect survival of naïve macrophages. However, in lipopolysaccharide (LPS)-activated macrophages, even single deletion of Tab1 or Tab2 resulted in macrophage death with both necrotic and apoptotic features. We show that TAB1 and TAB2 were redundantly involved in LPS-induced TAK1 activation in macrophages. These results demonstrate that TAK1 activity is the key to activated macrophage survival. Finally, in an in vivo setting, Tab1 deficiency impaired increase of peritoneal macrophages upon LPS challenge, suggesting that TAK1 complex regulation of macrophages may participate in in vivo macrophage homeostasis. Our results demonstrate that TAB1 and TAB2 are required for activated macrophages, making TAB1 and TAB2 effective targets to control inflammation by modulating macrophage survival.

Mihaly, September R.; Morioka, Sho; Ninomiya-Tsuji, Jun; Takaesu, Giichi

2014-01-01

64

Novel chimeric immunomodulatory compounds containing short CpG oligodeoxyribonucleotides have differential activities in human cells  

Microsoft Academic Search

Immunostimulatory DNA sequences (ISS) contain- ing CpG motifs induce interferon-a (IFN-a) and inter- feron-g (IFN-g) from human peripheral blood mononuclear cells and stimulate human B cells to proliferate and produce IL-6. We studied the motif and structural requirements for both types of activ- ity using novel chimeric immunomodulatory com- pounds (CICs), which contain multiple heptameric ISS connected by non-nucleoside spacers

Jason D. Marshall; Edith M. Hessel; Josh Gregorio; Christina Abbate; Priscilla Yee; Mabel Chu; Gary Van Nest; Robert L. Coffman; Karen L. Fearon

2003-01-01

65

TLR4-mediated activation of mouse macrophages by Korean mistletoe lectin-C (KML-C).  

PubMed

Korean mistletoe lectin (KML-C) is an adjuvant that activates systemic and mucosal immune cells to release cytokines including TNF-alpha, which induces immunity against viruses and cancer cells. Although the immunomodulatory activity of KML-C has been well established, the underlying mechanism of action of KML-C has yet to be explored. When mouse peritoneal macrophages were treated with KML-C, both transcription and translation of TLR4 were upregulated. KML-C-induced TLR4 downstream events were similar to those activated by LPS: the upregulation of interleukin-1 receptor-associated kinase-1 (IRAK1); resulting in macrophage activation and TNF-alpha production. When TLR4 was blocked using a TLR4-specific neutralizing antibody, TNF-alpha production from the macrophages was significantly inhibited. Moreover, TLR4-deficient mouse macrophages treated with KML-C also secreted greatly reduced level of TNF-alpha secretion. Finally, TLR4 molecules were co-precipitated with KML-C, to which agarose beads were conjugated, indicating that those molecules are associated. These data indicate that KML-C activates mouse macrophages to secrete TNF-alpha by interacting with the TLR4 molecule and activating its signaling pathways. PMID:20450885

Park, Hong-Jai; Hong, Ju-ho; Kwon, Hyung-Joon; Kim, Youngchan; Lee, Kwan-Hee; Kim, Jong-Bae; Song, Seong K

2010-06-01

66

Immunomodulatory effect of concentrated lime juice extract on activated human mononuclear cells.  

PubMed

In this study, the in vitro immunomodulatory effect of concentrated juice of Citrus aurantifolia cv. swingle (Lime) was investigated. Clarified fresh lime juice was concentrated by freeze-drying. After dialysis against phosphate buffered saline and sterilization by a Millipore filter, it was used for further experiments. Immunogenic property of the CLJ extract was documented by production of specific polyclonal antibodies in rabbits. The immunomodulatory effect of the extract was tested in mitogen activated cultured mononuclear cells. The culture results indicated that proliferation of phytohemagglutinin (PHA) activated mononuclear cells were significantly inhibited by 250 and 500 microg/ml of CLJ extract, whereas only 500 microg/ml of the extract could inhibit proliferation of staphylococcal protein A (SPA) activated mononuclear cells (P<0.05). The abrogation of this inhibitory effect of the CLJ extract was noted by adding anti-CLJ antibody to the lymphocyte culture. Considering these data, it can be concluded that the CLJ extract possesses immunomodulatory principles, which may mainly be due to the protein components of the extract. PMID:11483382

Gharagozloo, M; Ghaderi, A

2001-09-01

67

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.

Ko, Kam Ming; Leung, Hoi Yan

2007-01-01

68

Phagocytic activity of LPS tolerant macrophages.  

PubMed

Endotoxin tolerance is defined as a reduced capacity of the host to respond to LPS activation following a first exposure to this stimulus. It affects all leukocytes and regarding macrophages, most studies focus on the reduced ability of these cells to secrete pro-inflammatory cytokines. Therefore, we evaluated other macrophages functions (fungicidal capacity, reactive oxygen species production and antigen presentation) in cells from tolerant mice. We have performed a tolerance model in our laboratory that does not stimulate directly the place from where the cells will be removed (peritoneal cavity). Mouse received subcutaneous injections of LPS in the scruff for 5 days and we analyze the capacity of peritoneal macrophages to phagocyte using three different receptors: Fc, C3b and mannose receptors. We found a reduction in the phagocytosis of erythrocytes and Candida albicans related to the Fc and mannose receptors. These differences can be due to a macrophage reprogramming, as demonstrated by altered expression of cytokines and chemokines. Despite this reduction in phagocytosis capacity, macrophages from tolerant animals exhibited enhanced hydrogen peroxide production and expression of antigen presentation molecules, suggesting that their ability to combat an infection is improved. In summary, our data indicates that LPS tolerance drives macrophages from a predominant release of proinflammatory mediators that amplify inflammation and host damage toward a better killing and antigen presentation state. PMID:24732064

de Lima, Thais Martins; Sampaio, Sandra Coccuzzo; Petroni, Ricardo; Brigatte, Patrícia; Velasco, Irineu Tadeu; Soriano, Francisco Garcia

2014-07-01

69

The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm  

PubMed Central

Background Patients with cystic fibrosis (CF) experience recurrent infections and develop chronically infected lungs, which initiates an altered immunological alveolar environment. End-stage pulmonary dysfunction is a result of a long sequence of complex events in CF, progressing to alveolar macrophage dysfunction via a T-helper 2 (TH2) dominated alveolar inflammation with CD20 T-cell activation, induced by the chronic infection and showing a poor prognosis. There is great potential for treatment in transforming the TH2 into the more favorable T-helper 1 (TH1) response. Methods Current literature in the PubMed database and other sources was reviewed in order to evaluate aspects of the innate alveolar host defense mechanisms and the potential impact on the immunoinflammatory response of inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with CF. Results It seems that the cellular host defense, (ie, the alveolar macrophage and neutrocyte function) and the inhaled GM-CSF interact in such a way that the so-called tolerant alveolar environment dominated by the TH2 response may be transformed into an active TH1 state with a normal pulmonary host defense. The shift of the TH2 to the TH1 subset dominated by specific and unspecific antibodies may be achieved after the inhalation of GM-CSF. A clinical report has shown promising results with inhalation of GM-CSF in a chronically-infected CF patient treated with several antibacterial and antifungal agents. Inhaled GM-CSF transformed the tolerance toward the Gram-negative infection reflected by the so-called TH2 subset into the more acute TH1 response characterized by recruitment of the T-cells CD8 and CD16, a condition related to better-preserved lung function. This indicated a transformation from a state of passive bacterial tolerance toward the Gram-negative infecting and colonizing bacteria. This GM-CSF effect cannot be achieved by administering the drug via the IV route because the drug is water-soluble and too large to penetrate the alveolocapillary membrane. Conclusions Inhalation of GM-CSF seems to be a novel way to positively modulate the alveolar environment toward an altered immunological state, reflected by a positive change in the pattern of surrogate markers, related to better preservation of pulmonary function and thus improved outcomes in CF patients. It is suggested that future studies examining standard endpoint variables such as number of infections and amount of antibiotics used should be supplemented by surrogate markers, to reveal any positive cellular and cytokine responses reflecting changes in the alveolar compartment after GM-CSF inhalation. The immunological alveolar environment should be monitored by a specific pattern of surrogate markers. Continued research is clearly indicated and the role of inhaled GM-CSF in modulating pulmonary host defense in CF patients should be investigated in a large study.

Heslet, Lars; Bay, Christiane; Nepper-Christensen, Steen

2012-01-01

70

Immunomodulatory activity and chemical characterisation of sangre de drago (dragon's blood) from Croton lechleri.  

PubMed

The immunomodulatory activity of the latex from Croton lechleri (sangre de drago) was determined by in vitro assays. Classical (CP) and alternative (AP) complement pathways activities were determined in human serum. Intracellular generation of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) and monocytes, and phagocytosis of opsonised fluorescent microspheres were measured by flow cytometry. Free radical scavenging activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Activity on proliferation of murine lymphocytes was also investigated. In addition, anti-inflammatory activity was assayed in vivo by carrageenan-induced rat paw oedema test. Some of the activities were compared with those of the isolated alkaloid taspine. Sangre de drago from Croton lechleri showed immunomodulatory activity. It exhibited a potent inhibitory activity on CP and AP of complement system and inhibited the proliferation of activated T-cells. The latex showed free radical scavenging capacity. Depending on the concentration, it showed antioxidant or prooxidant properties, and stimulated or inhibited the phagocytosis. Moreover, the latex has strong anti-inflammatory activity when administered i. p. Taspine cannot be considered the main responsible for these activities, and other constituents, probably proanthocyanidins, should be also involved. PMID:14598201

Risco, Ester; Ghia, Felipe; Vila, Roser; Iglesias, José; Alvarez, Elida; Cañigueral, Salvador

2003-09-01

71

Regulation of Alternative Macrophage Activation by Galectin-31  

Microsoft Academic Search

Alternative macrophage activation is implicated in diverse disease pathologies such as asthma, organ fibrosis, and granulomatous diseases, but the mechanisms underlying macrophage programming are not fully understood. Galectin-3 is a carbohydrate- binding lectin present on macrophages. We show that disruption of the galectin-3 gene in 129sv mice specifically restrains IL-4\\/IL-13-induced alternative macrophage activation in bone marrow-derived macrophages in vitro and

Alison C. MacKinnon; Sarah L. Farnworth; Philip S. Hodkinson; Neil C. Henderson; Kirsten M. Atkinson; Hakon Leffler; Ulf J. Nilsson; Christopher Haslett; Stuart J. Forbes; Tariq Sethi

72

Brazilian propolis antileishmanial and immunomodulatory effects.  

PubMed

The antileishmanial and immunomodulatory effects of propolis collected in Botucatu, São 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 (10(7)/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

73

Brazilian Propolis Antileishmanial and Immunomodulatory Effects  

PubMed Central

The antileishmanial and immunomodulatory effects of propolis collected in Botucatu, São 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.

da Silva, Suelen Santos; Thome, Graciele da Silva; Cataneo, Allan Henrique Depieri; Miranda, Milena Menegazzo; Felipe, Ionice; Andrade, Celia Guadalupe Tardeli de Jesus; Watanabe, Maria Angelica Ehara; Piana, Gilce Maria; Sforcin, Jose Mauricio; Pavanelli, Wander Rogerio; Conchon-Costa, Ivete

2013-01-01

74

Effect of Tityus serrulatus venom on cytokine production and the activity of murine macrophages.  

PubMed Central

THE purpose of this study was to investigate the effects of Tityus serrulatus venom (TSV) on murine peritoneal macrophages evaluated in terms of activation. The effects of crude TSV were analysed by detection of cytokines, oxygen intermediate metabolites (H2O2) and nitric oxide (NO) in supernatants of peritoneal macrophages. Several functional bioassays were employed including an in vitro model for envenomating: cytotoxicity of TSV was assessed using the lyses percentage. Tumor necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity on L-929 cells, and interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) were assayed by enzyme-linked immunosorbent assay, whereas NO levels were detected by Griess colorimetric reactions in culture supernatant of macrophages incubated with TSV and subsequently exposed to either lipopolysaccharide or IFN-gamma. Incubation of macrophages with TSV increased production of IL-6 and IFN-gamma in a dose-dependent manner. TNF production was not detected in supernatants treated with TSV at any concentration. The increase in IL-6 secretion was not associated with concentration-dependent cytoxicity of TSV on these cells. These data suggest that the cytotoxicity does not appear to be the main cause of an increased cytokine production by these cells. Although NO is an important effector molecule in macrophage microbicidal activity, the inducing potential of the test compounds for its release was found to be very moderate, ranging from 125 to 800 mM. Interestingly, NO levels of peritoneal macrophages were increased after IFN-gamma. Moreover, NO production had an apparent effect on macrophage activity. The results obtained here also shown that the TSV induces an important elevation in H2O2 release. These results combined with NO production suggest that TSV possesses significant immunomodulatory activities capable of stimulating immune functions in vitro.

Petricevich, Vera L

2002-01-01

75

Peritoneal macrophage activation indicated by enhanced chemiluminescence.  

PubMed Central

A number of studies have demonstrated the ability of various bacterial preparations, protozoa, and chemicals to activate macrophages and concomitantly to enhance host resistance to both tumors and infections. Recently, viral infections have been shown to have a similar effect upon macrophage function. To better define the metabolic state of activated macrophages, we have evaluated the ability of peritoneal cells (PC) from vaccinia virus- or murine cytomegalovirus-infected or Corynebacterium parvum-treated mice to emit chemiluminescence (CL) during phagocytosis of zymosan particles or yeasts. PC from C. parvum-treated mice (1,400 microgram intraperitoneally) emitted enhanced CL over controls on days 3, 6, 14, and 21 after treatment, thereby establishing the emission of CL as a correlate of metabolic activation. Previous evidence for activation of PC from vaccinia virus-infected mice (10(8) plaque-forming units) was confirmed by demonstration of enhanced levels of CL on days 3, 6, and 13 after murine infection. Likewise, PC from mice infected with murine cytomegalovirus (10(5) plaque-forming units) 3, 6, or 13 days previously demonstrated augmented levels of CL over controls. Opsonized virus particles (vaccinia virus or murine cytomegalovirus) failed to induce the emission of CL with PC from mice infected with the isologous virus. Our data further demonstrate the immunomodulationinduced by virus infections and suggest that the detection of CL is an easily quantitated correlate of macrophage activation which may be helpful in defining metabolic alterations induced during activation.

Schleupner, C J; Glasgow, L A

1978-01-01

76

Immunomodulatory activity of boswellic acids of Boswellia serrata Roxb.  

PubMed

Extract of gum resin of B. serrata containing 60% acetyl 11-keto beta boswellic acid (AKBA) along with other constituents such as 11-keto beta-boswellic acid (KBA), acetyl beta-boswellic acid and beta-boswellic acid has been evaluated for antianaphylactic and mast cell stabilizing activity using passive paw anaphylaxis and compound 48/80 induced degranulation of mast cell methods. The extract inhibited the passive paw anaphylaxis reaction in rats in dose-dependant manner (20, 40 and 80 mg/kg, po). However, the standard dexamethasone (0.27 mg/kg, po) revealed maximum inhibition of edema as compared to the extract. A significant inhibition in the compound 48/80 induced degranulation of mast cells in dose-dependant manner (20, 40 and 80 mg/kg, po) was observed thus showing mast cell stabilizing activity. The standard disodium cromoglycate (50 mg/kg, ip) was found to demonstrate maximum per cent protection against degranulation as compared to the extract containing 60% AKBA. The results suggest promising antianaphylactic and mast cell stabilizing activity of the extract. PMID:15320503

Pungle, Pratibha; Banavalikar, M; Suthar, A; Biyani, M; Mengi, S

2003-12-01

77

Immunomodulatory Drugs Regulate HMGB1 Release from Activated Human Monocytes  

PubMed Central

Several HMGB1-specific antagonists have provided beneficial results in multiple models of inflammatory disease–preclinical trials including arthritis. Since no HMGB1-specific targeted therapy has yet reached the clinic, we have performed in vitro studies to investigate whether any of a selection of well-established antirheumatic drugs inhibit HMGB1 release as part of its mode of action. Freshly purified peripheral blood monocytes from healthy donors were stimulated in cultures with LPS and IFN? to cause HMGB1 and TNF release detected in ELISPOT assays. Effects on the secretion were assessed in cultures supplemented with dexamethasone, cortisone, chloroquine, gold sodium thiomalate, methotrexate, colchicine, etanercept or anakinra. Pharmacologically relevant doses of dexamethasone, gold sodium thiomalate and chloroquine inhibited the extracellular release of HMGB1 in a dose-dependent mode. Immunostaining demonstrated that dexamethasone caused intracellular HMGB1 retention. No effects on HMGB1 secretion were observed in cultures with activated monocytes by any of the other studied agents. TNF production in LPS/IFN?-activated monocytes was readily downregulated by dexamethasone and, to some extent, by chloroquine and etanercept. We conclude that dexamethasone, gold sodium thiomalate and chloroquine share a capacity to inhibit HMGB1 release from activated monocytes.

Schierbeck, Hanna; Wahamaa, Heidi; Andersson, Ulf; Harris, Helena Erlandsson

2010-01-01

78

Crocodylus siamensis serum and macrophage phagocytic activity.  

PubMed

Antimicrobial activity of sera from many crocodilian species has been recognized. This activity was proposed to be mediated, at least in part, by complement. Due to the fact that complement proteins have different functions in the immune system, they may be involved in phagocytic process of phagocytes. In the present study, the effects of Siamese crocodile serum on phagocytic activity of macrophages as well as the possible involvement of complement in this process were examined. The results showed increases in the phagocytosis of both Escherichia coli and to a lesser extent, Staphylococcus aureus upon incubation of murine macrophage cell line with fresh crocodile serum (FS). Similar to FS, other crocodile blood products, including freeze dried serum (DS) and freeze dried whole blood (DWB) exhibited phagocytosis-enhancing property. However the ability of DWB to enhance phagocytosis was less efficient than that of FS and DS, suggesting that serum factors were involved in this process. Treatment of FS with heat at 56 degrees C for 30 min deteriorated the effect of FS on bacterial uptake of macrophages, suggesting that complement proteins play a role in the modulation of the phagocytic process. Collectively, the results of the present study suggested that crocodile serum enhances the macrophage phagocytic activity through complement activity and, therefore, may be taken as an alternative medicine for supporting the human immune responses. PMID:22619919

Aree, Kalaya; Siruntawineti, Jindawan; Chaeychomsri, Win

2011-12-01

79

Three new sesquiterpene glycosides from Dendrobium nobile with immunomodulatory activity.  

PubMed

Dendroside A (1) and dendronobilosides A and B (2 and 3), three new sesquiterpene glycosides, have been isolated from the stems of Dendrobium nobile, a plant used in Chinese traditional medicine. Their structures and stereochemistry were determined as 10beta,12,14-trihydroxyalloaromadendrane 14-O-beta-D-glucopyranoside (1), 10,12-dihydroxypicrotoxane 10,12-di-O-beta-D-glucopyranoside (2), and 6alpha,10,12-trihydroxypicrotoxane 10-O-beta-D-glucopyranoside (3), respectively, on the basis of spectroscopic and chemical methods. Quantum chemistry calculations were used in support of the structural determination of 1. Compounds 1 and 2 were found to stimulate the proliferation of murine T and B lymphocytes in vitro, while compound 3 showed inhibitory activity in this same assay. PMID:11575955

Zhao, W; Ye, Q; Tan, X; Jiang, H; Li, X; Chen, K; Kinghorn, A D

2001-09-01

80

Berberine Chloride Mediates Its Anti-Leishmanial Activity via Differential Regulation of the Mitogen Activated Protein Kinase Pathway in Macrophages  

PubMed Central

Background A complex interplay between Leishmania and macrophages influences parasite survival and necessitates disruption of signaling molecules, eventually resulting in impairment of macrophage function. In this study, we demonstrate the immunomodulatory activity of Berberine chloride in Leishmania infected macrophages. Principal Findings The IC50 of Berberine chloride, a quaternary isoquinoline alkaloid was tested in an amastigote macrophage model and its safety index measured by a cell viability assay. It eliminated intracellular amastigotes, the IC50 being 2.8 fold lower than its IC50 in promastigotes (7.10 µM vs. 2.54 µM) and showed a safety index >16. Levels of intracellular and extracellular nitric oxide (NO) as measured by flow cytometry and Griess assay respectively showed that Berberine chloride in Leishmania infected macrophages increased production of NO. Measurement of the mRNA expression of iNOS, IL-12 and IL-10 by RT-PCR along with levels of IL-12p40 and IL-10 by ELISA showed that in infected macrophages, Berberine chloride enhanced expression of iNOS and IL-12p40, concomitant with a downregulation of IL-10. The phosphorylation status of extracellular signal related kinase (ERK1/2) and p38 mitogen activated protein kinase (p38 MAPK) was studied by western blotting. In infected macrophages, Berberine chloride caused a time dependent activation of p38 MAPK along with deactivation of ERK1/2; addition of a p38 MAPK inhibitor SB203580 inhibited the increased generation of NO and IL-12p40 by Berberine chloride as also prevented its decrease of IL-10. Conclusions Berberine chloride modulated macrophage effector responses via the mitogen activated protein kinase (MAPK) pathway, highlighting the importance of MAPKs as an antiparasite target.

Saha, Piu; Bhattacharjee, Surajit; Sarkar, Avijit; Manna, Alak; Majumder, Subrata; Chatterjee, Mitali

2011-01-01

81

Activation of macrophages by polysaccharide isolated from Paecilomyces cicadae through toll-like receptor 4.  

PubMed

Paecilomyces cicadae have been reported to have immunomodulatory properties. In this study, we investigated the effect of polysaccharide (PCP) isolated from P. cicadae on the macrophages. PCP increased the production of nitric oxide (NO) and the gene expression of IL-1?, IL-6, and TNF-? in RAW 264.7 cells. To investigate the membrane receptor, we examined the effect of PCP on primary macrophages isolated from wild type C3H/HeN and C3H/HeJ mice having mutant-TLR4. PCP induced NO production and cytokine gene expression in macrophages from C3H/HeN, but not from tlr4-mutated C3H/HeJ mice, which suggests that TLR4 is the membrane receptor for PCP. PCP induced the phosphorylation of ERK, JNK, and p38, and the nuclear translocation of NF-?B p50/p65, which are the main signaling molecules downstream from TLR4. Among them, p38 and NF-?B signaling played a crucial role in PCP-induced NO production by macrophages. These results indicate that PCP activates macrophages through the TLR4 signaling pathway. PMID:22687552

Kim, Hyung Sook; Kim, Yeon Jin; Lee, Hong Kyung; Ryu, Hwa Sun; Kim, Ji Sung; Yoon, Mi Jung; Kang, Jong Soon; Hong, Jin Tae; Kim, Youngsoo; Han, Sang-Bae

2012-09-01

82

Legionella pneumophila Replication in Macrophages Inhibited by Selective Immunomodulatory Effects on Cytokine Formation by Epigallocatechin Gallate, a Major Form of Tea Catechins  

Microsoft Academic Search

Epigallocatechin gallate (EGCg) is a major form of tea catechin and has a variety of biological activities, including antitumor as well as antimicrobial activity against some pathogens. Although the biological activities of EGCg have been extensively studied, its immunological effects are not well known. In the present study, the ability of EGCg to modulate macrophage immune functions in an in

KAZUTO MATSUNAGA; THOMAS W. KLEIN; HERMAN FRIEDMAN; YOSHIMASA YAMAMOTO

2001-01-01

83

In-vivo antioxidant and immunomodulatory activity of mesuol isolated from Mesua ferrea L. seed oil.  

PubMed

Mesua ferrea L. (Nagkesar) is traditionally being used for antiseptic, anti-inflammatory, antiasthmatic and antiallergic activities. It is an ingredient of ayurvedic formulations like Brahma Rasayana and Chyavanprash which are being used to improve immunity. The present study was performed to evaluate immunomodulatory activity of mesuol isolated from M. ferrea seed oil in experimental animals. In humoral immune response model, mesuol evoked a significant dose dependent increase in antibody titer values in cyclophosphamide (50 mg/kg, i.p., 9th and 16th day) induced immunosuppression which was sensitized with sheep red blood cells (SRBC) on the 7th and 14th day of experiment. In cellular immune response model, an increase in paw volume was recorded on the 23rd day in cyclophosphamide-induced immunosuppressed rats treated with SRBC (0.03 ml 2% v/v, s.c.) on the 21st day. Mesuol restored the hematological profile in cyclophosphamide induced myelosuppression model. Mesuol potentiated percentage neutrophil adhesion in neutrophil adhesion test in rats and phagocytosis in carbon clearance assay. The study indicated immunomodulatory activity of mesuol. PMID:22634479

Chahar, Manoj Kumar; Sanjaya Kumar, D S; Lokesh, T; Manohara, K P

2012-08-01

84

Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.  

PubMed

Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. PMID:22552008

Lopez-Girona, A; Mendy, D; Ito, T; Miller, K; Gandhi, A K; Kang, J; Karasawa, S; Carmel, G; Jackson, P; Abbasian, M; Mahmoudi, A; Cathers, B; Rychak, E; Gaidarova, S; Chen, R; Schafer, P H; Handa, H; Daniel, T O; Evans, J F; Chopra, R

2012-11-01

85

Brazilian Green Propolis: Anti-Inflammatory Property by an Immunomodulatory Activity  

PubMed Central

The immunomodulatory and anti-inflammatory activities of green propolis extracts from Apis mellifera were investigated using acute and chronic inflammation models. Swiss mice were anesthetized and a cotton pellet granuloma was implanted in subcutaneous tissue. Then the mice were divided into six groups and received apyrogenic water or different propolis extracts by oral route (5?mg/kg). According to the treatment the groups were designated as E1A, E1B, E10, E11, and E12. The control group received apyrogenic water. The treatment was performed by six days when the mice were killed. The blood and the bronchoalveolar lavage (BAL) were collected to measure the leukocyte recruitment. In acute pulmonary inflammation, Balb/c mice received lipopolysaccharide (LPS) of Escherichia coli by intranasal route for three days. Concomitantly the mice received by oral route apyrogenic water (control) or E10 and E11 propolis extracts. BAL was performed to assess the inflammatory infiltrate and cytokine quantification. The results showed that the E11 extract has anti-inflammatory property in both models by the inhibition of proinflammatory cytokines and increase of anti-inflammatory cytokines suggesting an immunomodulatory activity.

Machado, Joleen Lopes; da Silva, Mayara Cristina Pinto; dos Reis, Aramys Silva; Costa, Graciomar Conceicao; Arruda, Diego de Sousa; Rocha, Bruno Alves; Vaz, Mirela Mara de Oliveira Lima Leite; Paes, Antonio Marcus de Andrade; Guerra, Rosane Nassar Meireles; Berretta, Andresa Aparecida; do Nascimento, Flavia Raquel Fernandes

2012-01-01

86

Differential Inhibition of Macrophage Microbicidal Activity by Liposomes.  

National Technical Information Service (NTIS)

In vitro culture of murine resident peritoneal macrophages with lymphokine (LK)-rich leukocyte culture fluids induces enhanced microbicidal activity against amastigotes of the protozoan parasite Leishmania tropica. Macrophages infected with Leishmania and...

M. J. Gilbreath G. M. Swartz C. R. Alving C. A. Nacy D. L. Hoover

1985-01-01

87

Macrophage activation by glycoprotein isolated from Dioscorea batatas  

PubMed Central

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.

Huong, Pham Thi Thu

2011-01-01

88

Cholesteryl ester hydrolase activity is abolished in HSL-/- macrophages but unchanged in macrophages lacking KIAA1363.  

PubMed

Cholesteryl ester (CE) accumulation in macrophages represents a crucial event during foam cell formation, a hallmark of atherogenesis. Here we investigated the role of two previously described CE hydrolases, hormone-sensitive lipase (HSL) and KIAA1363, in macrophage CE hydrolysis. HSL and KIAA1363 exhibited marked differences in their abilities to hydrolyze CE, triacylglycerol (TG), diacylglycerol (DG), and 2-acetyl monoalkylglycerol ether (AcMAGE), a precursor for biosynthesis of platelet-activating factor (PAF). HSL efficiently cleaved all four substrates, whereas KIAA1363 hydrolyzed only AcMAGE. This contradicts previous studies suggesting that KIAA1363 is a neutral CE hydrolase. Macrophages of KIAA1363(-/-) and wild-type mice exhibited identical neutral CE hydrolase activity, which was almost abolished in tissues and macrophages of HSL(-/-) mice. Conversely, AcMAGE hydrolase activity was diminished in macrophages and some tissues of KIAA1363(-/-) but unchanged in HSL(-/-) mice. CE turnover was unaffected in macrophages lacking KIAA1363 and HSL, whereas cAMP-dependent cholesterol efflux was influenced by HSL but not by KIAA1363. Despite decreased CE hydrolase activities, HSL(-/-) macrophages exhibited CE accumulation similar to wild-type (WT) macrophages. We conclude that additional enzymes must exist that cooperate with HSL to regulate CE levels in macrophages. KIAA1363 affects AcMAGE hydrolase activity but is of minor importance as a direct CE hydrolase in macrophages. PMID:20625037

Buchebner, Marlene; Pfeifer, Thomas; Rathke, Nora; Chandak, Prakash G; Lass, Achim; Schreiber, Renate; Kratzer, Adelheid; Zimmermann, Robert; Sattler, Wolfgang; Koefeler, Harald; Fröhlich, Eleonore; Kostner, Gerhard M; Birner-Gruenberger, Ruth; Chiang, Kyle P; Haemmerle, Guenter; Zechner, Rudolf; Levak-Frank, Sanja; Cravatt, Benjamin; Kratky, Dagmar

2010-10-01

89

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

Microsoft Academic Search

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

Kam Ming Ko; Hoi Yan Leung

2007-01-01

90

Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation  

PubMed Central

Expression of the macrophage mannose receptor is inhibited by interferon gamma (IFN-gamma), a T helper type 1 (Th-1)-derived lymphokine. Interleukin 4 (IL-4), a Th-2 lymphocyte product, upregulates major histocompatibility class II antigen expression but inhibits inflammatory cytokine production by macrophages. We have studied the effect of IL-4 on expression of the macrophage mannose receptor (MMR) by elicited peritoneal macrophages. We found that recombinant murine IL-4 enhances MMR surface expression (10-fold) and activity (15-fold), as measured by the respective binding and degradation of 125I-mannose-bovine serum albumin. Polymerase chain reaction analysis of cDNAs from purified primary macrophage populations revealed that MMR, but not lysozyme or tumor necrosis factor alpha, mRNA levels were markedly increased by IL-4. The above effects were associated with morphologic changes. These data establish IL-4 as a potent and selective enhancer of murine MMR activity in vitro. IL-4 induces inflammatory macrophages to adopt an alternative activation phenotype, distinct from that induced by IFN-gamma, characterized by a high capacity for endocytic clearance of mannosylated ligands, enhanced (albeit restricted) MHC class II antigen expression, and reduced proinflammatory cytokine secretion.

1992-01-01

91

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

92

An apolipoprotein E mimetic peptide with activities against multidrug-resistant bacteria and immunomodulatory effects.  

PubMed

Apolipoprotein E (apoE) mimetic peptides derived from the low-density lipoprotein receptor-binding region of apoE with both activities against multidrug-resistant bacteria and immunomodulatory effects have not previously been reported. We identified an apoE mimetic peptide analogue of the receptor-binding region of apoE (abbreviated as apoE23) with the sequence of LRKLRKRLVRLASHLRKLRKRLL, which exhibited high antibacterial effects. The minimal inhibitory concentration of apoE23 against multidrug-resistant Acinetobacter baumannii was 6 µg/ml. The antimicrobial activity of apoE23 depended on its amphipathic ?-helical conformation. Moreover, apoE23 downregulated the expression of tumour necrosis factor-?, interleukin-6 and interleukin-10 in lipopolysaccharide-induced THP-1 cells. ApoE23 exhibits potential in future clinical applications. PMID:24243597

Wang, Chuan-qing; Yang, Chang-sheng; Yang, Yi; Pan, Fu; He, Lei-yan; Wang, Ai-min

2013-12-01

93

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

94

In vitro study of the antioxidant and immunomodulatory activity of aqueous infusion of Bidens pilosa.  

PubMed

Bidens pilosa is an annual plant from tropical America with anti-inflammatory properties in hepatitis, laryngitis, headache and digestive disorders, among others. Its wide pharmacological applications can be attributed to its chemical composition, with inhibitory effects on pathogenic microorganisms and flavonoids, which show strong antioxidant capacities. We investigated the antioxidant activity of an aqueous infusion of Bidens pilosa by studying its protective effect on the hemolysis induced by an initiator of radicals such as 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). The immunomodulatory activity of the infusion was tested using whole blood cells. Cytokine production increased in whole blood stimulated or not by lipopolysaccharides (LPSs). The infusion is also characterized by its capacity to protect erythrocytes from the phototoxic effect of chlorpromazine, which allows its use as a potential photoprotector. Finally, it did not show ocular irritation, as demonstrated by the effect on hemoglobin denaturation. This study supports the health benefits of the ingestion of the infusion. PMID:15234771

Abajo, Celia; Boffill, María Angeles; del Campo, Jaime; Alexandra Méndez, María; González, Yisel; Mitjans, Montserrat; Pilar Vinardell, María

2004-08-01

95

Immunomodulatory and neuroprotective effects of inosine  

Microsoft Academic Search

Adenosine has been considered as a potential immunomodulatory and neuroprotective agent for 30 years. Inosine, a major degradation product of adenosine, was thought originally to have no biological effects. However, recent studies demonstrate that inosine has potent immunomodulatory and neuroprotective effects. Inosine enhances mast-cell degranulation, attenuates the production of pro-inflammatory mediators by macrophages, lymphocytes and neutrophils, and is protective in

György Haskó; Michail V. Sitkovsky; Csaba Szabó

2004-01-01

96

Immunomodulatory and Hemagglutinating Activities of Acidic Polysaccharides Isolated from Combretum racemosum  

PubMed Central

Extracts of leaves of different species of the genus Combretum have been used historically to treat a variety of medicinal problems. However, little is known about the active components conferring therapeutic properties to these extracts. In the present studies, we evaluated biochemical properties and immunomodulatory activity of polysaccharides isolated from the leaves of Combretum racemosum. Water-soluble polysaccharides from leaves of C. racemosum were extracted and fractionated by DEAE-cellulose and Diaion HP-20 to obtain a Diaion-bound fraction, designated Combretum polysaccharide-acidic bound or CP-AB, which was eluted with methanol, and an unbound fraction, designated as CP-AU. Molecular weight determination, sugar analysis, and other physical and chemical characterization of the fractions were performed. Fraction CP-AU (mol. weight 5.0 kDa) contained type II arabinogalactan and had potent immunomodulatory activity, inducing the production of interleukin (IL)-1?, -6, -10, and tumor necrosis factor-? (TNF-?) by human peripheral blood mononuclear cells (PBMC) and MonoMac-6 monocytic cells. Likewise, intraperitoneal administration of CP-AU increased in vivo serum levels of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in mice. CP-AU-induced secretion of TNF-? in PBMC was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS. Treatment with CP-AU induced phosphorylation of Akt2, Akt3, GSK-3?, HSP27, mTOR, and all p38 MAPK isoforms (?, ?, ?, and ?), as well as stimulation of AP-1/NF-?B transcriptional activity. In addition, CP-AU effectively agglutinated erythrocytes from several species, including human, mouse, and rabbit. In contrast, fraction CP-AB was inactive in all biological tests, including cytokine production and hemagglutination. These data suggest that at least part of the beneficial therapeutic effects reported for the water extracts of leaves from C. racemosum are due to modulation of leukocyte functions.

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

2013-01-01

97

Direct imaging of macrophage activation during PDT treatment  

NASA Astrophysics Data System (ADS)

Mounting evidence describes a more complex progress of macrophage activation during photodynamic therapy (PDT), which performing distinct immunological functions and different physiologies on surrounding cells and tissues. Macrophage-targeted PDT has been applied in the selective killing of cells involved in inflammation and tumor. We have previously shown that PDT-mediated tumor cells apoptosis can induce a higher level immune response than necrosis, and enhance the macrophage activation. However, the molecular mechanism of macrophage activation during PDT-induced apoptotic cells (AC) still unclear. Here, we use confocal microscopy to image the phagocytosis of tumor cells by macrophages. We also observed that PDT-treated AC can activate Toll-like receptors (TLRs) which are present on macrophages surface. Besides, the increase in nitric oxide (NO) formation in macrophages was detected in real time by a laser scanning microscopy. This study provided more details for understanding the molecular mechanism of the immune response induced by PDT-treated AC.

Song, Sheng; Zhou, Feifan; Chen, Wei R.; Xing, Da

2011-11-01

98

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.

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

99

Genetically engineered immunomodulatory Streptococcus thermophilus strains producing antioxidant enzymes exhibit enhanced anti-inflammatory activities.  

PubMed

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; LeBlanc, Jean Guy

2014-02-01

100

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.

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

2014-01-01

101

The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro  

PubMed Central

Bone marrow-derived mesenchymal stem cells (BM-MSC) are currently being investigated in preclinical and clinical settings because of their self-renewal and multipotent differentiative capacity or their immunosuppressive function. However, BM may be detrimental because of the highly invasive donation procedure and BM-MSC decline with age. Therefore, MSC derived from other sources have been considered as an alternative. However, there is only limited knowledge on their immunomodulatory properties. Human umbilical cord blood (UCB) cells are good substitutes for BM-MSC because of the immaturity of newborn cells. In this study, we successfully isolated MSC from UCB. The morphological phenotypes, cell cycle status, surface markers and differentiation potential of these clonally expanded cells are consistent with BM-MSC. Furthermore, UCB-MSC expanded in vitro retain low immunogenicity and an immunomodulatory effect. Flow cytometry analysis showed that UCB-MSC did not express CD40, CD40 ligand, CD80, CD86 and major histocompatibility complex class II molecules. We have demonstrated that UCB-MSC are incapable of inducing allogeneic peripheral blood mononuclear cell (PBMC) proliferation and have a dose-dependent inhibition of PBMC immune responses in mixed lymphocyte reactions (MLR) and phytohaemagglutinin activation assays, even after interferon-? treatment. Additionally, we have found that UCB-MSC can suppress the function of mature dendritic cells. Using transwell systems, we have demonstrated an inhibition mechanism that depends on both cell contact and soluble factors. Based on the findings we conclude that banked UCB could serve as a potential alternative source of MSC for allogeneic application in the future.

Wang, Meng; Yang, Yuan; Yang, Dongming; Luo, Fei; Liang, Wenjie; Guo, Shuquan; Xu, Jianzhong

2009-01-01

102

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

103

Polarization dictates iron handling by inflammatory and alternatively activated macrophages  

PubMed Central

Background Macrophages play a key role in iron homeostasis. In peripheral tissues, they are known to polarize into classically activated (or M1) macrophages and alternatively activated (or M2) macrophages. Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes. Design and Methods Inflammatory/M1 and alternatively activated/M2 macrophages were propagated in vitro from mouse bone-marrow precursors and polarized in the presence of recombinant interferon-? or interleukin-4. We characterized and compared their ability to handle radioactive iron, the characteristics of the intracellular iron pools and the expression of molecules involved in internalization, storage and export of the metal. Moreover we verified the influence of iron on the relative ability of polarized macrophages to activate antigen-specific T cells. Results M1 macrophages have low iron regulatory protein 1 and 2 binding activity, express high levels of ferritin H, low levels of transferrin receptor 1 and internalize – albeit with low efficiency -iron only when its extracellular concentration is high. In contrast, M2 macrophages have high iron regulatory protein binding activity, express low levels of ferritin H and high levels of transferrin receptor 1. M2 macrophages have a larger intracellular labile iron pool, effectively take up and spontaneously release iron at low concentrations and have limited storage ability. Iron export correlates with the expression of ferroportin, which is higher in M2 macrophages. M1 and M2 cells activate antigen-specific, MHC class II-restricted T cells. In the absence of the metal, only M1 macrophages are effective. Conclusions Cytokines that drive macrophage polarization ultimately control iron handling, leading to the differentiation of macrophages into a subset which has a relatively sealed intracellular iron content (M1) or into a subset endowed with the ability to recycle the metal (M2).

Corna, Gianfranca; Campana, Lara; Pignatti, Emanuele; Castiglioni, Alessandra; Tagliafico, Enrico; Bosurgi, Lidia; Campanella, Alessandro; Brunelli, Silvia; Manfredi, Angelo A.; Apostoli, Pietro; Silvestri, Laura; Camaschella, Clara; Rovere-Querini, Patrizia

2010-01-01

104

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

105

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.

Bafna, Anand; Mishra, Shrihari

2010-01-01

106

Lactobacillus saerimneri and Lactobacillus ruminis: novel human-derived probiotic strains with immunomodulatory activities  

PubMed Central

Human-derived lactobacilli were isolated from fecal samples of healthy volunteers. Forty-six isolates from different volunteers were selected and investigated for their immunomodulatory properties. Conditioned medium from each isolate was assessed for its effect on tumor necrosis factor (TNF) production in lipopolysaccharide (LPS) - activated THP-1 monocytes. Of 46 Lactobacillus isolates, 12 significantly inhibited TNF production in varying magnitude. Lactobacillus strain TH58 displayed the most potent TNF - inhibitory activity (70% inhibition). In contrast, Lactobacillus strain TH14 exhibited immunostimulatory property by activating TNF production in THP-1 monocytes. Lactobacillus TH14 induced NF-?B activation in the absence of LPS stimulation, whereas Lactobacillus TH58 had no effect on NF-?B signaling, irrespective of LPS stimulation. Strain TH58 was identified as Lactobacillus saerimneri and strain TH14 as Lactobacillus ruminis by sequence analysis of the16S rRNA gene. This is the first report of a human isolate of L. saerimneri with TNF inhibitory activity and L. ruminis, an indigenous species to humans, with TNF stimulatory activity. Our data suggest the potential use of these two strains as immunoprobiotic candidates.

Taweechotipatr, Malai; Iyer, Chandra; Spinler, Jennifer K.; Versalovic, James; Tumwasorn, Somying

2014-01-01

107

Functional modifications of macrophage activity after sublethal irradiation. [Toxoplasma gondii  

SciTech Connect

The modifications of macrophage activity following sublethal irradiation, both in vivo and in vitro, were studied using spreading and C3b-receptor-mediated ingestion assays. Nonelicited peritoneal washout cells were examined for changes in activity and selected population characteristics. The cells from irradiated mice were from a resident peritoneal population and not immigrating cells. The macrophage population showed enhanced activity early with a refractory period (24-48) when the macrophages were unresponsive to stimulation by irradiated lymphocytes. The enhanced activity was inversely dose dependent on macrophage. The lymphocytes showed a regulatory function(s) on the time post irradiation at which they were examined. Early lymphocytes exhibited the ability to enhance the activity of normal macrophages while lymphocytes removed 24 hours post irradiation could suppress the activity of already activated macrophages. The effect(s) of the various lymphocyte populations were reproduced with cell-free supernatants which was indicative of the production of lymphokines. Separation on nylon wool columns indicated that the activity resided primarily in the T-cell population of lymphocytes. In vitro irradiation indicated that stimulation of the lymphocytes is macrophage dependent. Additional work indicated that sublethally irradiated macrophages did not inhibit replication of the coccidian protozoon Toxoplasma gondii although they did show increased phagocytosis. Examination of the serum from whole body irradiated mice showed the presence of a postirradiation substance which enhanced the phagocytosis of normal macrophages. It was not present in the serum of normal mice and was not endotoxin.

Swartz, R.P.

1982-01-01

108

Surface interleukin-10 inhibits listericidal activity by primary macrophages.  

PubMed

Interleukin-10 (IL-10) down-regulates multiple functions of monocytes and macrophages, including the ability of macrophages to kill many intracellular microorganisms. The experiments presented here test the hypothesis that IL-10 expressed on the cell surface inhibits the ability of primary mouse macrophages to kill the facultative, intracellular bacterium Listeria monocytogenes. We show that, in contrast to macrophages from normal mice, both bone marrow-derived macrophages (BMDM) and thioglycollate-elicited macrophages obtained from IL-10-/- mice can kill L. monocytogenes. Treatment with anti-IL-10 monoclonal antibody (mAb) enables BMDM from normal mice and thioglycollate-elicited macrophages from RAG-2-/- mice (which lack T or B cell-derived IL-10) to kill L. monocytogenes, and concurrently down-regulates the expression of surface IL-10. Surface IL-10 on paraformaldehyde-fixed cells can inhibit nitric oxide (NO) production by interferon-gamma (IFN-gamma)-stimulated macrophages from IL-10-/- mice, thus directly showing functional activity of surface IL-10. Taken together, these studies indicate that macrophage surface IL-10 is biologically active and down-regulates macrophage bactericidal activity. PMID:10614778

Fleming, S D; Leenen, P J; Freed, J H; Campbell, P A

1999-12-01

109

MiR-125b potentiates macrophage activation1  

PubMed Central

MicroRNA-125b expression is modulated in macrophages in response to stimulatory cues. Here we report a functional role of miR-125b in macrophages. We found that miR-125b is enriched in macrophages compared to lymphoid cells and whole immune tissues. Enforced expression of miR-125b drives macrophages to adapt an activated morphology that is accompanied by increased co-stimulatory factor expression and elevated responsiveness to interferon gamma, while anti-miR-125b treatment decreases CD80 surface expression. To determine whether these alterations in cell signaling, gene expression and morphology have functional consequences, we examined the ability of macrophages with enhanced miR-125b expression to present antigens and found that they better stimulate T cell activation than control macrophages. Further indicating increased function, these macrophages were more effective at killing EL4 tumor cells in vitro and in vivo. Moreover, miR-125b repressed IRF4 and IRF4 knockdown in macrophages mimicked the miR-125b overexpression phenotype. In summary, our evidence suggests that miR-125b is at least partly responsible for generating the activated nature of macrophages, at least partially by reducing IRF4 levels, and potentiates the functional role of macrophages in inducing immune responses.

Chaudhuri, Aadel A.; So, Alex Yick-Lun; Sinha, Nikita; Gibson, William S.J.; Taganov, Konstantin D.; O'Connell, Ryan M.; Baltimore, David

2011-01-01

110

A Subset of Human Uterine Endometrial Macrophages is Alternatively Activated  

PubMed Central

Problem Human uterine macrophages must maintain an environment hospitable to implantation and pregnancy and simultaneously provide protection against pathogens. Although macrophages comprise a significant portion of leukocytes within the uterine endometrium, the activation profile and functional response of these cells to endotoxin is unknown. Method of Study Flow cytometric analysis of surface receptors and intracellular markers expressed by macrophages isolated from human endometria was performed. Uterine macrophages were stimulated with LPS. Cytokines, chemokines, and growth factors expressed by these cells were analyzed using Bio-Plex analysis. Results CD163high human endometrial macrophages constitutively secrete both pro- and anti-inflammatory cytokines as well as pro-angiogenic factors and secretion of these factors is LPS-inducible. Conclusions A major population of human uterine macrophages is alternatively activated. These cells secrete factors in response to LPS that are involved in the activation of immune responses and tissue homeostasis.

Jensen, Amy L.; Collins, Jane; Shipman, Emilie P.; Wira, Charles R.; Guyre, Paul M.; Pioli, Patricia A.

2012-01-01

111

Macrophage Activation by a Series of Unique Polnanionic Polymers  

Microsoft Academic Search

Polyanionic polymers with differing molecular weight, lipophilicity, and charge density were synthesized and their ability to nonspecifically “activatemacrophages was avaluated. The level of activation of test polymer-elicited macrophages was monitored by their nonspecific tumoricidal capacity and ectoenzyme profiles. In addition, the ability of test polymers to inhibit growth of Lewis lung in vivo was evaluated. We have determined that

Raphael M. Ottenbrite; Kristine Kuus; Alan M. Kaplan

1988-01-01

112

Characterization of two homogalacturonan pectins with immunomodulatory activity from green tea.  

PubMed

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

113

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.

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

114

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.

Espinoza-Jimenez, Arlett; Peon, Alberto N.; Terrazas, Luis I.

2012-01-01

115

Immunomodulatory function of ?-carrageenan oligosaccharides acting on LPS-activated microglial cells.  

PubMed

The major neurodegenerative diseases are characterized by increasing of activated-microglial cells and inflammatory cytokines in the central nervous system. Carrageenan extracted from red algae is a kind of polysaccharide with sulfate groups. The oligosaccharides were obtained from carrageenan by enzymatic degradation. To detect the immunomodulatory activity of ?-carrageenan oligosaccharides (KOS) on microglial cells and the relationship to the sulfate group content, the desulfated derivatives of KOS (DSK) were obtained by dimethyl sulfoxide-methanol-pyridine method. KOS was labeled with fluorescein isothiocyanate. The effect of KOS and DSK on lipopolysaccharide (LPS)-activated microglial cells was detected. Hematoxylin-eosin staining and flow cytometric were used to detect the cell viability. The "scratch" migration assay, ornithine analysis and RT-PCR were used to determine the cell migration, arginase and TNF-? released by microglial cells, respectively. The effect of LPS and KOS on microglial cells was determined by flow cytometry and laser scanning confocal microscopy. The results showed that KOS and DSK could inhibit the cell viability, arginase and TNF-? released by LPS-activated microglia cell with concentration dependent manner. But the effect of DSK was weaker than that of KOS. KOS aggregated on the cell surface firstly, and then they enter into the cell to the nucleus, spread over the entire cell finally. But the exist of LPS could prevent the entrance of KOS. It could be concluded that KOS could protect microglial cells from being activated by LPS, and its inhibition function had relationship to the sulfate group content of KOS, while there were competition between LPS and KOS. PMID:24357352

Yao, Zi-Ang; Xu, Ling; Wu, Hai-Ge

2014-02-01

116

Cytotoxic effect of asbestos on macrophages in different activation states.  

PubMed Central

The in vitro effects due to phagocytosis of asbestos by mouse peritoneal macrophages in various stages of activation have been compared. The amphiboles proved relatively inert; chrysotile, however, expressed a greater degree of cytotoxicity toward those populations of macrophages induced in vivo with asbestos, than toward any of the other populations of cells. These results are compared with data concerning the enzyme release from the different populations of macrophages following phagocytosis of asbestos. The results indicate that those macrophages that have been exposed to a prior stimulation of either amphibole or serpentine asbestos in vivo are particularly sensitive to exposure to a second dose of a toxic fiber.

Wright, A; Donaldson, K; Davis, J M

1983-01-01

117

Control of tumor-associated macrophage alternative activation by MIF  

PubMed Central

Tumor stromal alternatively activated macrophages are important determinants of anti-tumor T lymphocyte responses, intratumoral neovascularization and metastatic dissemination. Our recent efforts to investigate the mechanism of macrophage migration inhibitory factor (MIF) in antagonizing anti-melanoma immune responses reveal that macrophage-derived MIF participates in macrophage alternative activation in melanoma-bearing mice. Both peripheral and tumor-associated macrophages (TAMs) isolated from melanoma bearing MIF-deficient mice display elevated pro-inflammatory cytokine expression and reduced anti-inflammatory, immunosuppressive and pro-angiogenic gene products compared to macrophages from tumor bearing MIF wildtype mice. Moreover, TAMs and myeloid-derived suppressor cells (MDSCs) from MIF-deficient mice exhibit reduced T lymphocyte immunosuppressive activities than do those from their wildtype littermates. Corresponding with reduced tumor immunosuppression and neoangiogenic potential by TAMs, MIF-deficiency confers protection against transplantable subcutaneous melanoma outgrowth and melanoma lung metastatic colonization. Finally, we report for the first time that our previously discovered MIF small molecule antagonist, 4-iodo-6-phenylpyrimidine (4-IPP), recapitulates MIF-deficiency in vitro and in vivo and attenuates tumor polarized macrophage alternative activation, immunosuppression, neoangiogenesis and melanoma tumor outgrowth. These studies describe an important functional contribution by MIF to tumor-associated macrophage alternative activation and provide justification for immunotherapeutic targeting of MIF in melanoma patients.

Yaddanapudi, Kavitha; Putty, Kalyani; Rendon, Beatriz E.; Lamont, Gwyneth J.; Faughn, Jonathan D.; Satoskar, Abhay; Lasnik, Amanda; Eaton, John W.; Mitchell, Robert A.

2013-01-01

118

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

119

Human macrophage polarization in vitro: Maturation and activation methods compared.  

PubMed

Macrophages form a heterogeneous cell population displaying multiple functions, and can be polarized into pro- (M1) or anti-inflammatory (M2) macrophages, by environmental factors. Their activation status reflects a beneficial or detrimental role in various diseases. Currently several in vitro maturation and activation protocols are used to induce an M1 or M2 phenotype. Here, the impact of different maturation factors (NHS, M-CSF, or GM-CSF) and activation methods (IFN-?/LPS, IL-4, dexamethason, IL-10) on the macrophage phenotype was determined. Regarding macrophage morphology, pro-inflammatory (M1) activation stimulated cell elongation, and anti-inflammatory (M2) activation induced a circular appearance. Activation with pro-inflammatory mediators led to increased CD40 and CD64 expression, whereas activation with anti-inflammatory factors resulted in increased levels of MR and CD163. Production of pro-inflammatory cytokines was induced by activation with IFN-?/LPS, and TGF-? production was enhanced by the maturation factors M-CSF and GM-CSF. Our data demonstrate that macrophage marker expression and cytokine production in vitro is highly dependent on both maturation and activation methods. In vivo macrophage activation is far more complex, since a plethora of stimuli are present. Hence, defining the macrophage activation status ex vivo on a limited number of markers could be indecisive. From this study we conclude that maturation with M-CSF or GM-CSF induces a moderate anti- or pro-inflammatory state respectively, compared to maturation with NHS. CD40 and CD64 are the most distinctive makers for human M1 and CD163 and MR for M2 macrophage activation and therefore can be helpful in determining the activation status of human macrophages ex vivo. PMID:24916404

Vogel, Daphne Y S; Glim, Judith E; Stavenuiter, Andrea W D; Breur, Marjolein; Heijnen, Priscilla; Amor, Sandra; Dijkstra, Christine D; Beelen, Robert H J

2014-09-01

120

Evaluation of Agaricus blazei in vivo for antigenotoxic, anticarcinogenic, phagocytic and immunomodulatory activities.  

PubMed

The development of various types of cancer results from the interaction among endogenous, environmental and hormonal factors, where the most notable of these factors is diet. The aim of the present study was to determine the antigenotoxic, anticarcinogenic, phagocytic and immunomodulatory activities of Agaricus blazei. The test antigenotoxicity (Comet Assay) and anticarcinogenic (Test of Aberrant Crypt Foci) assess changes in DNA and/or intestinal mucosa that correlate to cancer development. Tests of phagocytosis in the spleen and differential count in blood cells allow the inference of modulation of the immune system as well as to propose a way of eliminating cells with DNA damage. Supplementation with the mushroom was carried out under pre-treatment, simultaneous treatment, post-treatment and pre-treatment+continuous conditions. Statistical analysis demonstrated that the mushroom did not have genotoxic activity but showed antigenotoxic activity. Supplementation caused an increase in the number of monocytes and in phagocytic activity, suggesting that supplementation increases a proliferation of monocytes, consequently increasing phagocytic capacity especially in the groups pre-treatment, simultaneous and pre-treatment+continuous. The data suggest that A. blazei could act as a functional food capable of promoting immunomodulation which can account for the destruction of cells with DNA alterations that correlate with the development of cancer, since this mushroom was demonstrated to have a preventive effect against pre-neoplastic colorectal lesions evaluated by the aberrant crypt foci assay. According to these results and the literature, it is believed that supplementation with A. blazei can be an efficient method for the prevention of cancer as well as possibly being an important coadjuvant treatment in chemotherapy. PMID:21295629

Ishii, Priscila Lumi; Prado, Carolina Kato; Mauro, Mariana de Oliveira; Carreira, Clísia Mara; Mantovani, Mário Sérgio; Ribeiro, Lúcia Regina; Dichi, Jane Bandeira; Oliveira, Rodrigo Juliano

2011-04-01

121

Nitric oxide production does not directly increase macrophage candidacidal activity.  

PubMed Central

Some activated murine macrophages produced nitrite but were unable to kill Candida albicans. Furthermore, a nitric oxide (NO) generator inhibited C. albicans growth but was not candidacidal. Our results suggest that NO is candidastatic and that No is not directly involved but is associated with or induces other macrophage candidacidal mechanisms.

Vazquez-Torres, A; Jones-Carson, J; Balish, E

1995-01-01

122

Ginger extract inhibits LPS induced macrophage activation and function  

Microsoft Academic Search

BACKGROUND: Macrophages play a dual role in host defence. They act as the first line of defence by mounting an inflammatory response to antigen exposure and also act as antigen presenting cells and initiate the adaptive immune response. They are also the primary infiltrating cells at the site of inflammation. Inhibition of macrophage activation is one of the possible approaches

Sudipta Tripathi; David Bruch; Dilip S Kittur

2008-01-01

123

Immunomodulatory mechanisms of lactobacilli  

PubMed Central

Abstract Over the past decade it has become clear that lactobacilli and other probiotic and commensal organisms can interact with mucosal immune cells or epithelial cells lining the mucosa to modulate specific functions of the mucosal immune system. The most well understood signalling mechanisms involve the innate pattern recognition receptors such as Toll-like receptors, nucleotide oligomerization domain-like receptors and C-type lectin receptors. Binding of microbe-associated molecular patterns with these receptors can activate antigen presenting cells and modulate their function through the expression of surface receptors, secreted cytokines and chemokines. In vitro the cytokine response of human peripheral blood mononuclear cells and dendritic cells to lactobacilli can be strikingly different depending on both the bacterial species and the strain. Several factors have been identified in lactobacilli that influence the immune response in vitro and in vivo including cell surface carbohydrates, enzymes modifying the structure of lipoteichoic acids and metabolites. In mice mechanistic studies point to a role for the homeostatic control of inducible T regulatory cells in the mucosal tissues as one possible immunomodulatory mechanism. Increasing evidence also suggests that induction of epithelial signalling by intestinal lactobacilli can modulate barrier functions, defensin production and regulate inflammatory signalling. Other probiotic mechanisms include modulation of the T cell effector subsets, enhancement of humoral immunity and interactions with the epithelial-associated dendritic cells and macrophages. A major challenge for the future will be to gain more knowledge about the interactions occurring between lactobacilli and the host in vivo and to understand the molecular basis of innate signalling in response to whole bacteria which trigger multiple signalling pathways.

2011-01-01

124

Toll-like receptor 4-mediated ROS signaling pathway involved in Ganoderma atrum polysaccharide-induced tumor necrosis factor-? secretion during macrophage activation.  

PubMed

Ganoderma atrum has been used as Chinese traditional medicine and healthful mushroom for thousands of years. The polysaccharide is regarded as the major bioactive substances in G. atrum. To delineate the underlying mechanism and signaling cascade involved in the immunomodulatory property of G. atrum polysaccharide (PSG-1). Specifically, this study is designed to examine the possibility of TLR4 as a candidate receptor interacted with G. atrum polysaccharide (PSG-1) and elucidate the role of reactive oxygen species (ROS) in PSG-1-induced tumor necrosis factor-? (TNF-?) production during macrophage activation. Flow cytometric and confocal laser-scanning microscopy analysis showed that fluorescence-labeled PSG-1 bind specifically to the macrophages. Moreover, PSG-1 stimulated TNF-? secretion of peritoneal macrophages from C3H/HeN mice, but not from C3H/HeJ mice. PSG-1-indcued TNF-? production was suppressed by anti-TLR4 mAb. Furthermore, ROS production was mediated by TLR4, and NADPH oxidase-derived ROS act as upstream of phosphoinositide 3-kinase(PI3K)/Akt/mitogen-activated protein kinases(MAPKs)/nuclear factor(NF)-?B signaling pathway in the regulation of PSG-1 stimulated TNF-? production. Taken together, we conclude that PSG-1 induces TNF-? secretion through TLR4/ROS/PI3K/Akt/MAPKs/NF-?B pathways during macrophage activation. Our findings provide a molecular basis for the potential of PSG-1 as a novel immunomodulatory agent. PMID:24447977

Yu, Qiang; Nie, Shao-Ping; Wang, Jun-Qiao; Yin, Peng-Fei; Huang, Dan-Fei; Li, Wen-Juan; Xie, Ming-Yong

2014-04-01

125

Microarray analysis of activated mixed glial (microglia) and monocyte-derived macrophage gene expression  

Microsoft Academic Search

Since macrophage activation can now be studied at a global level using modern microarray and proteomic analyses, discovery of novel macrophage activation genes is inevitable and important for understanding HIV-associated dementia (HAD). We isolated two different types of primary human macrophages: microglia and monocyte-derived macrophages (MDM) from brain tissue and whole blood, respectively. The microarray analysis of differentially regulated macrophage

Andrew V. Albright; Francisco González-Scarano

2004-01-01

126

Maternal immune activation leads to activated inflammatory macrophages in offspring.  

PubMed

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 20mg/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 10weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24h 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; Berman, Robert F; Ashwood, Paul

2014-05-01

127

Analyzing classical and alternative macrophage activation in macrophage/neutrophil-specific IL-4 receptor-alpha-deficient mice.  

PubMed

Macrophage activation can be divided into a classical and an alternative pathway. Interferon-gamma-induced, classically activated macrophages are indispensable for protective effector responses against intracellular pathogens. However, excessive inflammatory immune responses mediated by classical macrophage activation can also be detrimental to the host. In contrast, the IL-4 receptor-alpha-mediated alternative pathway of macrophage activation has been proposed as a mechanism to attenuate excessive inflammation. Indeed, the generation of macrophage/neutrophil-specific IL-4 receptor-alpha-deficient mice (LysMcreIL-4Ralphaalpha-/lox) enables us now to evaluate the importance of this type of macrophage activation in vivo. Thus, the analysis of LysMcreIL-4Ralpha-/lox mice and the phenotypic characterization of macrophage activation during inflammatory immune responses become of major importance for inflammation research, and useful markers have been identified that allow classically and alternatively activated macrophages to be distinguished. Inducible nitric oxide synthase and arginase-1 are not only prototypical markers of classical and alternative macrophage activation, but both enzymes are also strongly involved in regulating macrophage effector mechanisms and inflammatory immune responses. In this chapter, we describe the use of LysMcreIL-4Ralpha-/lox mice and present experimental procedures to determine classical versus alternative macrophage activation by analyzing nitric oxide synthase and arginase-1 in vitro and in vivo in this murine model. PMID:19347321

Brombacher, Frank; Arendse, Berenice; Peterson, Reagon; Hölscher, Alexandra; Hölscher, Christoph

2009-01-01

128

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

129

Relationships Between Oxidative Metabolism, Macrophage Activation, and Antilisterial Activity  

Microsoft Academic Search

Previous reports from this laboratory have revealed that macrophages ob- tamed from 7-day Listeria-immune mice elicited 15 h before harvest with heat- killed homologous microorganisms were able to kill Listeria monocytogenes while resident or elicited cells were not (14,16). In the present study, experi- ments were conducted to determine if phagocytosis-associated oxidative met- abolic activity participates in the enhanced destruction

R. W. Godfrey

130

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

131

Differential inhibition of macrophage microbicidal activity by liposomes.  

PubMed

In vitro culture of murine resident peritoneal macrophages with lymphokine (LK)-rich leukocyte culture fluids induces enhanced microbicidal activity against amastigotes of the protozoan parasite Leishmania tropica. Macrophages infected with Leishmania and treated with LKs after infection acquire the capacity to kill the intracellular parasite within 72 h. When compared with control macrophage cultures treated with medium lacking LKs, 80 to 90% fewer macrophages treated with LKs contained amastigotes. In experiments designed to test liposome delivery of LKs to infected macrophages, addition of multilamellar liposomes composed of phosphatidylcholine and phosphatidylserine (molar ratio, 7:3) completely abrogated LK-induced microbicidal activity. Liposomes containing only phosphatidylcholine were not inhibitory. Inhibition of LK activity by the liposomes occurred regardless of whether the liposomes contained LKs. Liposomal inhibition of activated macrophage effector activity was limited to intracellular killing; LK-induced macrophage extracellular cytolysis (i.e., tumor cytotoxicity) was not affected by liposome treatment. These data indicate that elucidation of the effects of liposome composition on acquired host defense mechanisms may be useful for the design of drug delivery systems that allow expression or augmentation of immunologically induced mechanisms for the intracellular destruction of infectious agents. PMID:3967927

Gilbreath, M J; Swartz, G M; Alving, C R; Nacy, C A; Hoover, D L; Meltzer, M S

1985-02-01

132

Pulmonary macrophages are attracted to inhaled particles through complement activation.  

PubMed

Pulmonary macrophages play a central role in clearing inhaled particles from the lung. Previously, we showed that inhaled asbestos fibers activate complement-dependent chemotactic factors on alveolar surfaces to facilitate macrophage recruitment to sites of fiber deposition. In the studies presented here, we have tested a variety of inorganic particles for complement activation in vitro and correlated these data with results on particle-induced macrophage accumulation in vivo. We found that significant chemotactic activity was activated in rat serum and concentrated lavaged proteins by chrysotile and crocidolite asbestos, iron-coated chrysotile asbestos, fiberglass, and wollastonite fibers, as well as by carbonyl iron and zymosan particles. Ash from the Mt. St. Helens volcano did not induce chemotactic activity in either the serum or lavaged proteins. Rats were exposed to brief aerosols of each of the particles listed above (except zymosan). All the particle types studied were deposited primarily at first alveolar duct bifurcations. In addition, all of the particles, except Mt. St. Helens ash, induced at 48 h postexposure significant accumulations of macrophages at these sites. Time-course studies of carbonyl iron particle exposure demonstrated that iron induced a rapid macrophage response, but both particles and phagocytic macrophages were cleared from alveolar surfaces within 8 days after exposure. The Mt. St. Helens ash induced no macrophage accumulation at any time postexposure. We conclude that particles with a wide variety of physical characteristics are capable of activating complement and consequently attracting macrophages, both in vitro and in vivo. We suggest that complement activation is a mechanism through which pulmonary macrophages can detect inhaled particles on alveolar surfaces. PMID:2830106

Warheit, D B; Overby, L H; George, G; Brody, A R

1988-01-01

133

Generation and characterization of murine alternatively activated macrophages.  

PubMed

Macrophages play a key role in the innate immune response and help to direct the acquired immune response. Early in the innate immune response, they produce reactive oxygen species and pro-inflammatory cytokines and chemokines to drive inflammation and are referred to as "classically activated" or "killer" macrophages (M1). During the resolution phase of inflammation, they switch to what is known as an "alternatively activated" phenotype or "healer" macrophage (M2) and contribute to debris scavenging, angiogenesis, and wound healing. M1 macrophages are activated by treatment with IFN? or LPS and M2 macrophages are activated by treatment with Th2 cytokines IL-4 or IL-13 and the M2 phenotype switch can be enhanced by IL-10. Macrophages can also be skewed during differentiation in vitro, and the resultant phenotype depends upon the cytokine provided to support their differentiation. In murine macrophages, MCSF promotes differentiation to an M1 phenotype, GM-CSF promotes differentiation to an M2 phenotype and IL-3 promotes differentiation into a profoundly M2 skewed phenotype. A defining feature of the phenotype of murine M1 versus M2 macrophages is how they metabolize L-arginine. In response to an inflammatory stimulus like LPS, M1 macrophages produce inducible nitric oxide synthase (iNOS) which uses L-arginine as a substrate to produce nitric oxide (NO). M2 macrophages constitutively produce the enzyme arginase I (argI), which sequesters L-arginine from iNOS and results in the production of ornithine and downstream polyamines and L-proline. M1 macrophages also produce relatively higher levels of pro-inflammatory IL-12 and lower levels of anti-inflammatory IL-10 relative to M2 macrophages. In this chapter, we describe in vitro derivation of polarized bone marrow macrophages and methods to analyze the resulting phenotype including Q-PCR, Western blotting, and enzyme assays to determine argI and iNOS expression and activity, as well as production of IL-12p40 and IL-10 and determination of IL-12/IL-10 ratios. Production of iNOS, NO, IL-12p40, and IL-10 are measured after treatment with LPS. PMID:23179835

Weisser, Shelley B; McLarren, Keith W; Kuroda, Etsushi; Sly, Laura M

2013-01-01

134

Ginger extract inhibits LPS induced macrophage activation and function  

PubMed Central

Background Macrophages play a dual role in host defence. They act as the first line of defence by mounting an inflammatory response to antigen exposure and also act as antigen presenting cells and initiate the adaptive immune response. They are also the primary infiltrating cells at the site of inflammation. Inhibition of macrophage activation is one of the possible approaches towards modulating inflammation. Both conventional and alternative approaches are being studied in this regard. Ginger, an herbal product with broad anti inflammatory actions, is used as an alternative medicine in a number of inflammatory conditions like rheumatic disorders. In the present study we examined the effect of ginger extract on macrophage activation in the presence of LPS stimulation. Methods Murine peritoneal macrophages were stimulated by LPS in presence or absence of ginger extract and production of proinflammatory cytokines and chemokines were observed. We also studied the effect of ginger extract on the LPS induced expression of MHC II, B7.1, B7.2 and CD40 molecules. We also studied the antigen presenting function of ginger extract treated macrophages by primary mixed lymphocyte reaction. Results We observed that ginger extract inhibited IL-12, TNF-?, IL-1? (pro inflammatory cytokines) and RANTES, MCP-1 (pro inflammatory chemokines) production in LPS stimulated macrophages. Ginger extract also down regulated the expression of B7.1, B7.2 and MHC class II molecules. In addition ginger extract negatively affected the antigen presenting function of macrophages and we observed a significant reduction in T cell proliferation in response to allostimulation, when ginger extract treated macrophages were used as APCs. A significant decrease in IFN-? and IL-2 production by T cells in response to allostimulation was also observed. Conclusion In conclusion ginger extract inhibits macrophage activation and APC function and indirectly inhibits T cell activation.

2008-01-01

135

Study on immunostimulating activity of macrophage treated with purified polysaccharides from liquid culture and fruiting body of Lentinus edodes.  

PubMed

Lentinus edodes is a well-known edible and medicinal mushroom used in Oriental cultures. Recently, L. edodes has attracted a lot of attention owing to its antifungal activity, antibacterial activity, antiviral activity, hepatoprotective effect, antitumor activities, and immunomodulatory and cytotoxic effects. In this study, the water-soluble crude polysaccharides, CPF and CPB, which were obtained from the fruiting body and culture cell-free broth of L. edodes by hot-water extraction and ethanol precipitation, were fractionated by DEAE cellulose and Sepharose CL-6B column chromatography, resulting in six polysaccharide fractions, CPFN-G-I, CPFN-G-II, CPFN-G-III, CPFA-G, CPBN-G, and CPBA-G. Among these fractions, CPFN-GI, CPBN-G, and CPBA-G were shown to stimulate the functional activation of macrophages including NO production cytokine expression and phagocytosis. PMID:19597314

Lee, Hee Hwan; Lee, Jong Seok; Cho, Jae Youl; Kim, Young Eon; Hong, Eock Kee

2009-06-01

136

Thymic Stromal Lymphopoietin Amplifies the Differentiation of Alternatively Activated Macrophages  

PubMed Central

The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) has been associated with the promotion of type 2 inflammation and the induction of allergic disease. In humans TSLP is elevated in the lungs of asthma patients and in the lesional skin of individuals with atopic dermatitis, whereas mice lacking TSLP responses are refractory to models of Th2-driven allergic disease. Although several cell types, including dendritic cells, basophils, and CD4 T cells, have been shown to respond to TSLP, its role in macrophage differentiation has not been studied. Type 2 cytokines (i.e., IL-4 and IL-13) can drive the differentiation of macrophages into alternatively activated macrophages (aaM?s, also referred to as M2 macrophages). This population of macrophages is associated with allergic inflammation. We therefore reasoned that TSLP/TSLPR signaling may be involved in the differentiation and activation of aaM?s during allergic airway inflammation. In this study, we report that TSLP changes the quiescent phenotype of pulmonary macrophages toward an aaM? phenotype during TSLP-induced airway inflammation. This differentiation of airway macrophages was IL-13–, but not IL-4–, dependent. Taken together, we demonstrate in this study that TSLP/TSLPR plays a significant role in the amplification of aaM? polarization and chemokine production, thereby contributing to allergic inflammation.

Han, Hongwei; Headley, Mark B.; Xu, Whitney; Comeau, Michael R.; Zhou, Baohua

2013-01-01

137

Macrophages  

PubMed Central

Females are more susceptible to development of asthma than are males. In a mouse model of ovalbumin-induced airway inflammation, with aggravated disease in females compared with males, we studied interactions between immune and resident lung cells during asthma development to elucidate which processes are affected by sex. We studied numbers of regulatory T cells (Tregs), effector T cells, myeloid dendritic cells (mDCs), and alternatively activated macrophages (AAM?), and their functional capabilities. Male and female mice had comparable Treg numbers in lung tissue and comparable Treg function, but effector T cells had expanded to a greater extent in lungs of females after ovalbumin exposure. This difference in T cell expansion was therefore not the result of lack of Treg control, but appeared to be driven by a greater number of inflammatory mDCs migrating from the lungs to lymph nodes in females. Resident lung cells can influence mDC migration, and AAM? in lung tissue were found to be involved. Artificially elevating the number of AAM? in lung tissue increased the migration of mDCs and airway inflammation. We found greater numbers of AAM? in female lungs than in males; we therefore postulate that AAM? are involved in increased airway inflammation found in female mice.

Melgert, Barbro N.; Oriss, Timothy B.; Qi, Zengbiao; Dixon-McCarthy, Barbara; Geerlings, Marie; Hylkema, Machteld N.; Ray, Anuradha

2010-01-01

138

Polypotency of the immunomodulatory effect of pectins.  

PubMed

Pectins are the major component of plant cell walls, and they display diverse biological activities including immunomodulation. The pectin macromolecule contains fragments of linear and branched regions of polysaccharides such as homogalacturonan, rhamnogalacturonan-I, xylogalacturonan, and apiogalacturonan. These structural features determine the effect of pectins on the immune system. The backbones of pectic macromolecules have immunosuppressive activity. Pectins containing greater than 80% galacturonic acid residues were found to decrease macrophage activity and inhibit the delayed-type hypersensitivity reaction. Branched galacturonan fragments result in a biphasic immunomodulatory action. The branched region of pectins mediates both increased phagocytosis and antibody production. The fine structure of the galactan, arabinan, and apiogalacturonan side chains determines the stimulating interaction between pectin and immune cells. This review summarizes data regarding the relationship between the structure and immunomodulatory activity of pectins isolated from the plants of the European north of Russia and elucidates the concept of polypotency of pectins in native plant cell walls to both stimulate and suppress the immune response. The possible mechanisms of the immunostimulatory and anti-inflammatory effects of pectins are also discussed. PMID:24010844

Popov, S V; Ovodov, Yu S

2013-07-01

139

Itaconic acid is a mammalian metabolite induced during macrophage activation.  

PubMed

Itaconic acid (ITA), or methylenesuccinic acid, is not generally classified as a mammalian metabolite. Using NMR-based metabolomics and (13)C-labeling, we have detected ITA in both macrophage-like VM-M3 and RAW 264.7 tumor cell lines as well as stimulated and unstimulated primary murine macrophages. Macrophage activation by addition of lipopolysaccharide and IFN-? markedly increased ITA production and secretion. Crude cell extracts synthesize ITA via decarboxylation of cis-aconitate, indicative of a novel mammalian cis-aconitic decarboxylase activity. Our results highlight a previously unidentified biosynthetic pathway related to TCA cycle metabolism in mammalian cells and a novel metabolite that likely plays a role in macrophage-based immune response. PMID:21919507

Strelko, Cheryl L; Lu, Wenyun; Dufort, Fay J; Seyfried, Thomas N; Chiles, Thomas C; Rabinowitz, Joshua D; Roberts, Mary F

2011-10-19

140

Transcriptional network dynamics in macrophage activation  

Microsoft Academic Search

Transcriptional regulatory networks govern cell differentiation and the cellular response to external stimuli. However, mammalian model systems have not yet been accessible for network analysis. Here, we present a genome-wide network analysis of the transcriptional regulation underlying the mouse macrophage response to bacterial lipopolysaccharide (LPS). Key to uncovering the network structure is our combination of time-series cap analysis of gene

Roland Nilsson; Vladimir B. Bajic; Harukazu Suzuki; Diego di Bernardo; Johan Björkegren; Shintaro Katayama; James F. Reid; Matthew J. Sweet; Manuela Gariboldi; Piero Carninci; Yosihide Hayashizaki; David A. Hume; Jesper Tegner; Timothy Ravasi

2006-01-01

141

Enhancement of anti-tumor activity of gamma-irradiated silk fibroin via immunomodulatory effects.  

PubMed

Silk fibers have proven to be effective in many clinical applications as well as for clothing. In addition to the substantial effect of silk fibers, the present study was conducted to explore its importance in a new dimension to reinforce the effects of its physiological function regarding anti-tumor activity and immune response with gamma-irradiated silk fibroin (GISF). The cytotoxicity results showed that pre-treatment of GISF in the mouse peritoneal macrophages (MPM) indicated a higher proliferative effect than that of non-irradiated silk fibroin (NISF) in a concentration-dependent manner. Based on the cytotoxicity result of MPM, GISF (50 and 150 kGy) was selected for an ex vivo study in an animal (C57BL6) system and evaluated about whether the non-specific immune response was also related to GISF. GISF (50 and 150 kGy) augmented immune responsiveness via activation of NK cells, T lymphocytes proliferation, NO production, and cytokine level, such as IL-6, IL-2, IL-12, IFN-gamma, TNF-alpha, as compared with NISF, which strongly suggested that GISF significantly augmented an important element of all aspects of the innate and adaptive immune system. Therefore, from these results, it seems likely that the GISF will play a potent role in eliciting the effect of the non-specific immune response and anti-tumor activity as a value-added product in the medical industry. PMID:20338156

Byun, Eui-Baek; Sung, Nak-Yun; Kim, Jae-Hun; Choi, Jong-il; Matsui, Toshiro; Byun, Myung-Woo; Lee, Ju-Woon

2010-06-01

142

C/EBP? regulates macrophage activation and systemic metabolism.  

PubMed

Macrophage infiltration plays an important role in obesity-induced insulin resistance. CCAAT enhancer-binding protein-? (C/EBP?) is a transcription factor that is highly expressed in macrophages. To examine the roles of C/EBP? in regulating macrophage functions and energy homeostasis, macrophage-specific C/EBP? knockout (M?KO) mice were created. Chow-fed M?KO mice exhibited higher body fat mass and decreased energy expenditure despite no change in food intake. However, the obese phenotype disappeared after high-fat (HF) diet feeding. Although there was a transient decrease in insulin sensitivity of chow-fed young M?KO mice, systemic insulin sensitivity was protected during HF-feeding due to preserved insulin sensitivity in skeletal muscle. We also found that C/EBP?-deficient macrophages exhibited a blunted response of cytokine-induced expression of M1 and M2 macrophage markers, suggesting that C/EBP? controls both M1 and M2 polarization. Consistent with decreased exercise capacity, mitochondrial respiration rates and signal pathways for fatty acid oxidation were remarkably reduced in the skeletal muscle of chow-fed M?KO mice. Furthermore, expression levels of inflammatory cytokines were reduced in skeletal muscle of HF-fed M?KO mice. Together, these results imply that C/EBP? is required for macrophage activation, which plays an important role in maintaining skeletal muscle energy metabolism. PMID:24691027

Lee, Bonggi; Qiao, Liping; Lu, Min; Yoo, Hyung Sun; Cheung, Wai; Mak, Robert; Schaack, Jerome; Feng, Gen-Sheng; Chi, Nai-Wen; Olefsky, Jerrold M; Shao, Jianhua

2014-05-15

143

Elevation of rainbow trout Oncorhynchus mykiss macrophage respiratory burst activity with macrophage-derived supernatants  

Microsoft Academic Search

A variety of supernatants were prepared by stimulating rainbow trout Oncorhynchus mykiss head kid- ney macrophages with lipopolysaccharide (LPS), tumor necrosis factor a (TNF-ct), or a leucocyte-derived macro- phage-activating factor (1-MAF), individually and in com- bination. If generated using a 12-h stimulation period,

Seon I. Jang; Laura J. Hardie; Christopher J. Secombes

144

Cholesteryl ester hydrolase activity is abolished in HSL macrophages but unchanged in macrophages lacking KIAA1363[S  

PubMed Central

Cholesteryl ester (CE) accumulation in macrophages represents a crucial event during foam cell formation, a hallmark of atherogenesis. Here we investigated the role of two previously described CE hydrolases, hormone-sensitive lipase (HSL) and KIAA1363, in macrophage CE hydrolysis. HSL and KIAA1363 exhibited marked differences in their abilities to hydrolyze CE, triacylglycerol (TG), diacylglycerol (DG), and 2-acetyl monoalkylglycerol ether (AcMAGE), a precursor for biosynthesis of platelet-activating factor (PAF). HSL efficiently cleaved all four substrates, whereas KIAA1363 hydrolyzed only AcMAGE. This contradicts previous studies suggesting that KIAA1363 is a neutral CE hydrolase. Macrophages of KIAA1363?/? and wild-type mice exhibited identical neutral CE hydrolase activity, which was almost abolished in tissues and macrophages of HSL?/? mice. Conversely, AcMAGE hydrolase activity was diminished in macrophages and some tissues of KIAA1363?/? but unchanged in HSL?/? mice. CE turnover was unaffected in macrophages lacking KIAA1363 and HSL, whereas cAMP-dependent cholesterol efflux was influenced by HSL but not by KIAA1363. Despite decreased CE hydrolase activities, HSL?/? macrophages exhibited CE accumulation similar to wild-type (WT) macrophages. We conclude that additional enzymes must exist that cooperate with HSL to regulate CE levels in macrophages. KIAA1363 affects AcMAGE hydrolase activity but is of minor importance as a direct CE hydrolase in macrophages.

Buchebner, Marlene; Pfeifer, Thomas; Rathke, Nora; Chandak, Prakash G.; Lass, Achim; Schreiber, Renate; Kratzer, Adelheid; Zimmermann, Robert; Sattler, Wolfgang; Koefeler, Harald; Frohlich, Eleonore; Kostner, Gerhard M.; Birner-Gruenberger, Ruth; Chiang, Kyle P.; Haemmerle, Guenter; Zechner, Rudolf; Levak-Frank, Sanja; Cravatt, Benjamin; Kratky, Dagmar

2010-01-01

145

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

146

Thymosin ?1 activates complement receptor-mediated phagocytosis in human monocyte-derived macrophages.  

PubMed

Thymosin ?1 (T?1) is a naturally occurring thymic peptide used worldwide in clinical trials for the treatment of infectious diseases and cancer. The immunomodulatory activity of T?1 on innate immunity effector cells has been extensively described, but its mechanism of action is not completely understood. We report that T?1-exposed human monocyte-derived macrophages (MDMs) assume the typical activated morphology also exhibited by lipopolysaccharide-activated MDMs, but show a comparatively higher ability of internalizing fluorescent beads and zymosan particles. T?1 exposure also promptly and dramatically stimulates MDM phagocytosis and killing of Aspergillus niger conidia starting as soon as 30 min after challenge. The effect is dose dependent and early coupled to low transcription of the proinflammatory cytokines tumor necrosis factor ? and interleukin-6 and unmodified Toll-like receptor expression. The T?1-stimulated phagocytosis is strictly dependent on the integrity of the microtubule network and protein kinase C activity and occurs by a variation in the classic zipper model, with recruitment of vinculin and actin at the phagosome exhibiting a punctate distribution. These findings indicate that, in human mature MDMs, T?1 implements pathogen internalization and killing via the stimulation of the complement receptor-mediated phagocytosis. Our observations document that T?1 is an early and potent activator of innate immunity and reinforce the concept of its pleiotropy. PMID:23797159

Serafino, Annalucia; Pica, Francesca; Andreola, Federica; Gaziano, Roberta; Moroni, Noemi; Moroni, Gabriella; Zonfrillo, Manuela; Pierimarchi, Pasquale; Sinibaldi-Vallebona, Paola; Garaci, Enrico

2014-01-01

147

Activity of the Novel Immunomodulatory Compound Tucaresol against Experimental Visceral Leishmaniasis  

Microsoft Academic Search

Tucaresol, a novel immunomodulator, was inactive against Leishmania donovani amastigotes in both peri- toneal and bone marrow macrophages in vitro at concentrations between 100 and 1 mM, with toxicity to macrophages and parasites at 300 mM. However, against L. donovani in BALB\\/c mice at doses between 80 and 1.25 mg\\/kg of body weight administered once daily by the oral route

ADEN C. SMITH; VANESSA YARDLEY; JOHN RHODES; SIMON L. CROFT

2000-01-01

148

Biotechnological Approach to Evaluate the Immunomodulatory Activity of Ethanolic Extract of Tinospora cordifolia Stem (Mango Plant Climber)  

PubMed Central

The present study was designed to investigate the immunomodulatory activity of the ethanolic extract of Tinospora cordifolia (Family: Menispermaceae) stem (climbing shrub, mango plant) at cellular level. For antioxidant study, the liver mitochondria were separated and the concentration of enzymes like lipid peroxidation (LPO), reduced glutathione (GSH), catalase (CAT) and superoxide Dismutase (SOD) were estimated; melatonin secretion characterization was carried out through SDS-PAGE. The spleen lymphocyte proliferation assay was performed through measuring its optical density at 570 nm using Elisa Reader. The cytokines viz. IL-2, IL-10 and TNF-? expression in spleen cells were determined through Real Time PCR. Tinospora cordifolia (Tc) ethanolic extract (100 mg/Kg/p.o.) increased the level of liver mitochondrial enzymes like GSH, CAT and SOD but decreased the level of LPO in liver as compared to the vehicle, SRBC and cyclophosphamide-treated groups. The secretion of melatonin via pineal gland was enhanced with Tc treatment. The extract also increased the spleen lymphocyte proliferation. In RT-PCR analysis, the expression of cytokines viz. IL-2, IL-10 and TNF-? was more in Tc-treated animals than vehicle and cyclophosphamide treatment. Hence, the study confirms the immunomodulatory activity of Tc stem through altering the concentration of antioxidant enzymes, increasing T and B cells and antibody which play an important role in immunity, enhancing the concentration of melatonin in pineal gland and increasing the level of cytokines like IL-2, IL-10 and TNF-? which plays an important role in immunity.

Aher, Vaibhav; Kumar Wahi, Arun

2012-01-01

149

Biotechnological Approach to Evaluate the Immunomodulatory Activity of Ethanolic Extract of Tinospora cordifolia Stem (Mango Plant Climber).  

PubMed

The present study was designed to investigate the immunomodulatory activity of the ethanolic extract of Tinospora cordifolia (Family: Menispermaceae) stem (climbing shrub, mango plant) at cellular level. For antioxidant study, the liver mitochondria were separated and the concentration of enzymes like lipid peroxidation (LPO), reduced glutathione (GSH), catalase (CAT) and superoxide Dismutase (SOD) were estimated; melatonin secretion characterization was carried out through SDS-PAGE. The spleen lymphocyte proliferation assay was performed through measuring its optical density at 570 nm using Elisa Reader. The cytokines viz. IL-2, IL-10 and TNF-? expression in spleen cells were determined through Real Time PCR. Tinospora cordifolia (Tc) ethanolic extract (100 mg/Kg/p.o.) increased the level of liver mitochondrial enzymes like GSH, CAT and SOD but decreased the level of LPO in liver as compared to the vehicle, SRBC and cyclophosphamide-treated groups. The secretion of melatonin via pineal gland was enhanced with Tc treatment. The extract also increased the spleen lymphocyte proliferation. In RT-PCR analysis, the expression of cytokines viz. IL-2, IL-10 and TNF-? was more in Tc-treated animals than vehicle and cyclophosphamide treatment. Hence, the study confirms the immunomodulatory activity of Tc stem through altering the concentration of antioxidant enzymes, increasing T and B cells and antibody which play an important role in immunity, enhancing the concentration of melatonin in pineal gland and increasing the level of cytokines like IL-2, IL-10 and TNF-? which plays an important role in immunity. PMID:24250513

Aher, Vaibhav; Kumar Wahi, Arun

2012-01-01

150

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

151

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

Microsoft Academic Search

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

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

152

The immunomodulatory and anticancer properties of propolis.  

PubMed

Propolis, a waxy substance produced by the honeybee, has been adopted as a form of folk medicine since ancient times. It has a wide spectrum of alleged applications including potential anti-infection and anticancer effects. Many of the therapeutic effects can be attributed to its immunomodulatory functions. The composition of propolis can vary according to the geographic locations from where the bees obtained the ingredients. Two main immunopotent chemicals have been identified as caffeic acid phenethyl ester (CAPE) and artepillin C. Propolis, CAPE, and artepillin C have been shown to exert summative immunosuppressive function on T lymphocyte subsets but paradoxically activate macrophage function. On the other hand, they also have potential antitumor properties by different postulated mechanisms such as suppressing cancer cells proliferation via its anti-inflammatory effects; decreasing the cancer stem cell populations; blocking specific oncogene signaling pathways; exerting antiangiogenic effects; and modulating the tumor microenvironment. The good bioavailability by the oral route and good historical safety profile makes propolis an ideal adjuvant agent for future immunomodulatory or anticancer regimens. However, standardized quality controls and good design clinical trials are essential before either propolis or its active ingredients can be adopted routinely in our future therapeutic armamentarium. PMID:22707327

Chan, Godfrey Chi-Fung; Cheung, Ka-Wai; Sze, Daniel Man-Yuen

2013-06-01

153

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.

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

2013-01-01

154

Periodontitis-activated monocytes/macrophages cause aortic inflammation.  

PubMed

A relationship between periodontal disease and atherosclerosis has been suggested by epidemiological studies. Ligature-induced experimental periodontitis is an adequate model for clinical periodontitis, which starts from plaque accumulation, followed by inflammation in the periodontal tissue. Here we have demonstrated using a ligature-induced periodontitis model that periodontitis activates monocytes/macrophages, which subsequently circulate in the blood and adhere to vascular endothelial cells without altering the serum TNF-? concentration. Adherent monocytes/macrophages induced NF-?B activation and VCAM-1 expression in the endothelium and increased the expression of the TNF-? signaling cascade in the aorta. Peripheral blood-derived mononuclear cells from rats with experimental periodontitis showed enhanced adhesion and increased NF-?B/VCAM-1 in cultured vascular endothelial cells. Our results suggest that periodontitis triggers the initial pathogenesis of atherosclerosis, inflammation of the vasculature, through activating monocytes/macrophages. PMID:24893991

Miyajima, Shin-Ichi; Naruse, Keiko; Kobayashi, Yasuko; Nakamura, Nobuhisa; Nishikawa, Toru; Adachi, Kei; Suzuki, Yuki; Kikuchi, Takeshi; Mitani, Akio; Mizutani, Makoto; Ohno, Norikazu; Noguchi, Toshihide; Matsubara, Tatsuaki

2014-01-01

155

Periodontitis-activated monocytes/macrophages cause aortic inflammation  

PubMed Central

A relationship between periodontal disease and atherosclerosis has been suggested by epidemiological studies. Ligature-induced experimental periodontitis is an adequate model for clinical periodontitis, which starts from plaque accumulation, followed by inflammation in the periodontal tissue. Here we have demonstrated using a ligature-induced periodontitis model that periodontitis activates monocytes/macrophages, which subsequently circulate in the blood and adhere to vascular endothelial cells without altering the serum TNF-? concentration. Adherent monocytes/macrophages induced NF-?B activation and VCAM-1 expression in the endothelium and increased the expression of the TNF-? signaling cascade in the aorta. Peripheral blood-derived mononuclear cells from rats with experimental periodontitis showed enhanced adhesion and increased NF-?B/VCAM-1 in cultured vascular endothelial cells. Our results suggest that periodontitis triggers the initial pathogenesis of atherosclerosis, inflammation of the vasculature, through activating monocytes/macrophages.

Miyajima, Shin-ichi; Naruse, Keiko; Kobayashi, Yasuko; Nakamura, Nobuhisa; Nishikawa, Toru; Adachi, Kei; Suzuki, Yuki; Kikuchi, Takeshi; Mitani, Akio; Mizutani, Makoto; Ohno, Norikazu; Noguchi, Toshihide; Matsubara, Tatsuaki

2014-01-01

156

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

157

Peroxisome proliferator-activated receptor-? in macrophage lipid homeostasis  

Microsoft Academic Search

Peroxisome proliferator-activated receptor-? (PPAR?), a fatty acid receptor, has received particular attention as the molecular target of insulin-sensitizing drugs, and as a regulator of lipid accumulation by the coronary artery macrophages known as foam cells. Controversial results have been reported regarding the consequences of PPAR? activation in the inflammatory response, the progression or improvement of the atherosclerotic lesion, and the

Chih-Hao Lee; Ronald M Evans

2002-01-01

158

Cathepsin B and D activity in stimulated peritoneal macrophages  

Microsoft Academic Search

Highly sensitive and specific synthetic substrates were used to quantitate cathepsin B and D activity in peritoneal macrophages in response to stimulation in vivo with mineral oil and thioglycollate. After intraperitoneal instillation of mineral oil the activity of cathepsin B increased significantly (to 15 300 units\\/mg protein versus 7 340 in saline controls), reaching values approaching those found in alveolar

Marvin Lesser; Jui C. Change; Marian Orlowski

1985-01-01

159

Transcriptome-based network analysis reveals a spectrum model of human macrophage activation.  

PubMed

Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease. PMID:24530056

Xue, Jia; Schmidt, Susanne V; Sander, Jil; Draffehn, Astrid; Krebs, Wolfgang; Quester, Inga; De Nardo, Dominic; Gohel, Trupti D; Emde, Martina; Schmidleithner, Lisa; Ganesan, Hariharasudan; Nino-Castro, Andrea; Mallmann, Michael R; Labzin, Larisa; Theis, Heidi; Kraut, Michael; Beyer, Marc; Latz, Eicke; Freeman, Tom C; Ulas, Thomas; Schultze, Joachim L

2014-02-20

160

Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation  

PubMed Central

Summary Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.

Xue, Jia; Schmidt, Susanne V.; Sander, Jil; Draffehn, Astrid; Krebs, Wolfgang; Quester, Inga; De Nardo, Dominic; Gohel, Trupti D.; Emde, Martina; Schmidleithner, Lisa; Ganesan, Hariharasudan; Nino-Castro, Andrea; Mallmann, Michael R.; Labzin, Larisa; Theis, Heidi; Kraut, Michael; Beyer, Marc; Latz, Eicke; Freeman, Tom C.; Ulas, Thomas; Schultze, Joachim L.

2014-01-01

161

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

162

Dysregulation of macrophage activation profiles by engineered nanoparticles.  

PubMed

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 pretreatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pretreatment 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 pretreatment 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 an 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

2013-08-27

163

Innate immunity and monocyte-macrophage activation in atherosclerosis  

PubMed Central

Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.

2011-01-01

164

Immunomodulatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) at the clinically available doses  

Microsoft Academic Search

Non-steroidal anti-inflammatory drugs (NSAIDs) with cyclooxygenase (COX) inhibitory activity are commonly used in various\\u000a inflammatory diseases. In this study, to examine the immunomodulatory effects of well known NSAIDs at clinically available\\u000a doses, macrophage- and T cell-mediated immune responses such as tumor necrosis factor (TNF)-a release and nitric oxide (NO)\\u000a production, cell-cell adhesion, phagocytic uptake and lymphocyte proliferation were investigated. NSAIDs

Jae Youl Cho

2007-01-01

165

Immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation.  

PubMed

Revlimid (Lenalidomide, CC-5013) and CC-4047 are IMiDs immunomodulatory drugs that have been described as having immunomodulatory properties and anti-tumor activity. Here we report proapoptotic effects of CC-5013 and CC-4047 on tumor cells in a co-culture model of PBMC and tumor cells. CC-5013 and CC-4047 enhanced PBMC activity leading to tumor cell apoptosis in K562/PBMC co-culture model. We also demonstrate that the natural killer (NK) cell population of PBMC was essential in inducing K562 apoptosis. Increases of NK and natural killer T (NKT) cell populations by CC-5013 and CC-4047 was observed along with modulation of NK cell CD56 adhesion marker. In addition, our data indicate that NK activation by CC-4047 was dependent on other cell types of PBMC. We expanded the application of K562/PBMC co-culture model to other hematological and solid tumors. In Raji/PBMC co-culture model, CC-5013 and CC-4047 dose-dependently augmented tumor cell apoptosis. Pre-treatment of Raji cells with Rituximab further enhanced apoptosis induced by CC-5013 or CC-4047-treated PBMC. Moreover, CC-5013 and CC-4047 significantly increased PC-3 prostate cancer cell apoptosis in PC-3/PBMC co-culture, either as single agent or in combination with Docetaxel. Together, the results reveal that co-culture models are suitable cellular systems to assess anti-tumor activities of these compounds. Our findings support clinical evaluation of CC-5013 and CC-4047 in relapsed NHL with Rituximab and in prostate cancer with Docetaxel. PMID:18392823

Zhu, Dan; Corral, Laura G; Fleming, Yuedi W; Stein, Bernd

2008-12-01

166

Effect of perorally administered lactobacilli on macrophage activation in mice.  

PubMed Central

The effect of perorally (p.o) administered Lactobacillus casei and L. bulgaricus on macrophage activation in mice was studied. L. casei and L. bulgaricus were administered p.o. to mice for 8 days. The macrophage activation was measured on days 2, 3, 5, and 8 of lactobacillus administration by using biochemical and functional criteria. We measured the release of lysosomal hydrolases, the level of a nonlysosomal enzyme, and in vitro phagocytic activity of mouse peritoneal macrophages. All the assays were performed comparatively with mice inoculated with L. casei and L. bulgaricus (viable and nonviable cells) intraperitoneally (i.p.) at the same dose as for p.o. administration. The phagocytic activity was significantly higher in mice treated i.p. than in control mice. For p.o. administration, there was an increase only when L. casei was used. L. bulgaricus had little effect. No differences were found between viable and nonviable cells. The phagocytic function of the reticuloendothelial system was tested by the carbon clearance test, which showed that L. casei and L. bulgaricus accelerate the phagocytic function in mice treated p.o and i.p., from day 2 onward. These observations show that L. casei and L. bulgaricus given by p.o. administration are able to activate macrophages in mice and suggest that these bacteria, when passing through the intestinal tract, may be responsible for the enhanced host immune response. This fact is very significant because the diet includes fermented and manufactured products containing lactobacilli.

Perdigon, G; de Macias, M E; Alvarez, S; Oliver, G; de Ruiz Holgado, A A

1986-01-01

167

Formation of distinct chromatin conformation signatures epigenetically regulate macrophage activation.  

PubMed

Microbial-lipopolysacharide (LPS), interleukin 4 (IL-4) and interferon gamma (IFN-?) polarise macrophages into "innate", "alternative" and "classical", activation states by selective gene regulation. Expression of MARCO, CD200, CD200R1 (innate), MRC1 (alternative) and H2-Eb1 (classical) selectively marks these distinct activation states. Epigenetic events drive such activation upon stimuli and here we study one such mechanism, chromatin conformation signatures implicated in long-range chromatin interactions that regulate transcriptional switch and gene expression. The EpiSwitch™ technology was used to identify and analyse potential markers bordering such conformational signatures for these genes and juxtaposition of markers was compared between resting and activated macrophages. LPS, IL-4 and IFN-? selectively altered chromatin conformations of their responsive genes in wild type, but not in MyD88(-/-), IL-4R(-/-) and IFN-?R(-/-) macrophages. In addition, two distinct conformations were observed in CD200R1 after LPS and IFN-? stimulation. In summary, signal-specific alterations in chromatin conformation provide biomarkers that identify and determine distinct gene expression programmes during macrophage activation. PMID:24211766

Mukhopadhyay, Subhankar; Ramadass, Aroul Selvam; Akoulitchev, Alexandre; Gordon, Siamon

2014-01-01

168

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

169

Macrophage activation syndrome and other systemic inflammatory conditions after BMT  

Microsoft Academic Search

Autologous hematopoietic cell transplantation (HCT) is being used to treat autoimmune diseases refractory to conventional therapy, including rheumatoid arthritis. Macrophage activation syndrome (MAS) is a descriptive term for a systemic inflammatory disorder that has been described in patients with juvenile rheumatoid arthritis (JRA). This case report describes a young adult with systemic JRA (sJRA) who developed MAS on day #

A Sreedharan; S Bowyer; C A Wallace; M J Robertson; K Schmidt; A E Woolfrey; R P Nelson

2006-01-01

170

Chapter 3 Nitroalkenes: Synthesis, Characterization, and Effects on Macrophage Activation  

Microsoft Academic Search

Nitroalkenes derivatives of free as well as esterified unsaturated fatty acids are present in human plasma and tissue, representing novel pluripotent cell signaling mediators. Lipid nitration occurs in response to pro?inflammatory stimuli as an adaptative mechanism to downregulate inflammatory responses. This chapter first discusses the generation of nitroalkenes during macrophage activation following chemical and biological characterization. In particular, it describes

Ana María Ferreira; Andrés Trostchansky; Mariana Ferrari; José M. Souza; Homero Rubbo

2008-01-01

171

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

172

Dynamics of lung macrophage activation in response to helminth infection  

Microsoft Academic Search

Most of our understanding of the devel- opment and phenotype of alternatively activated macrophages (AAMs) has been obtained from stud- ies investigating the response of bone marrow- and peritoneal-derived cells to IL-4 or IL-13 stimula- tion. Comparatively little is known about the devel- opment of AAMs in the lungs, and how the complex signals associated with pulmonary inflammation in- fluence

Mark C. Siracusa; Joshua J. Reece; Joseph F. Urban Jr.; Alan L. Scott

2008-01-01

173

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

174

Effects of Pfaffia paniculata (Brazilian ginseng) extract on macrophage activity.  

PubMed

The roots of Pfaffia paniculata (Brazilian ginseng) have been indicated for the treatment of several diseases and as an analgesic and antiinflamatory drug. Treatment of mice with 200 mg/kg of the powdered root of P. paniculata reduced the Ehrlich ascitic volume [Matsuzaki, P., Akisue, G., Salgado Oloris, S.C., Gorniak, S.L., Zaidan Dagli, M.L., 2003. Effect of Pffafia paniculata (Brazilian ginseng) on the Ehrlich tumor on its ascitic form. Life Sciences, Dec 19; 74 (5), 573-579.]. One of the putative means to control the Ehrlich tumor growth is by increasing macrophage activity [Kleeb, S.R., Xavier, J.G., Frussa-Filho, R., Dagli, M.L.Z., 1997. Effect of haloperidol on the development of the solid Ehrlich tumor in mice. Life Sciences, 60 (4/5), 69-742.]. The aim of this study was to investigate experimentally the effects of the methanolic extract of P. paniculata roots on macrophage activity. Male mice received, by gavage, once a day, different doses (100, 250, or 500 mg/kg) of the methanolic extract of P. paniculata or filtered water, as control, for 10 days. Macrophage activity was evaluated through the phagocytosis index (PI), spreading index (SI), production of peroxide oxigen and nitric oxide. The peritoneal cells were activated with ip inoculation of Ehrlich ascitic cells, 24 h before the macrophage harvesting. The methanolic extract raised significantly the SI of mice from group of 500 mg/kg in comparison with the control group and group of 100 mg/kg. This raise of SI possibly induced the higher phagocytic activity observed in the experimental situation. Increased macrophage activity may be one of the effects contributing to inhibition of the Ehrlich ascitic tumor growth in mice. PMID:16214177

Pinello, Kátia Cristina; Fonseca, Evelise de S M; Akisue, Gokithi; Silva, Ana Paula; Salgado Oloris, Silvia Catarina; Sakai, Mônica; Matsuzaki, Patrícia; Nagamine, Márcia Kazumi; Palermo Neto, João; Dagli, Maria Lúcia Zaidan

2006-02-16

175

Attenuated Activation of Macrophage TLR9 by DNA from Virulent Mycobacteria  

Microsoft Academic Search

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 vitrodifferentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were

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

2009-01-01

176

Immunomodulatory activity of geranial, geranial acetate, gingerol, and eugenol essential oils: evidence for humoral and cell-mediated responses  

PubMed Central

Objective: The immunomodulatory effect of geranial, geranial acetate, gingerol, and eugenol essential oils were evaluated by studying humoral and cell-mediated immune responses. Materials and Method: The essential oils were evaluated for immunomodulatory activity in in vivo studies, using rats as the animal model. The essential oils were tested for hypersensitivity and hemagglutination reactions, using sheep red blood cells (SRBC) as the antigen while sodium carboxy methyl cellulose (SCMC) served as the control in all the tests. Result: Orally administrated essential oils showed a significant increase of test parameters, viz., haemagglutinating antibody titre (HAT) and delayed type hypersensitivity (DTH) response. In rats immunized with sheep RBC, essential oils enhanced the humoral antibody response to the antigen and significantly potentiated the cellular immunity by facilitating the foot pad thickness response to sheep RBC in sensitized rats with doses of 50-800 mg/ml. Haemagglutination titre of geraniol showed the highest increase of 139.3±6.38 and with 5.9±0.7 DTH, respectively. For geranial acetate, the haemagglutination titre showed a moderate increase of 87.5±5.9 and highest increase in DTH with 5.9±0.8, respectively. Using gingerol, the haemagglutination titre showed a moderate increase with 88.2±6.306 and DTH 3.5±0.5, respectively and for eugenol, the haemaggulation titre showed a moderate increase with 112.06±6.169 and DTH 4.4±0.6, respectively. These differences were statistically significant. Conclusion: The essential oils were found to have a significant immunostimulant activity on both the specific and non-specific immune mechanisms.

Farhath, Seema; Vijaya, PP; Vimal, Manivannan

2013-01-01

177

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

178

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.

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

1995-01-01

179

RIG-I activation inhibits HIV replication in macrophages.  

PubMed

The RIG-I signaling pathway is critical in the activation of the type I IFN-dependent antiviral innate-immune response. We thus examined whether RIG-I activation can inhibit HIV replication in macrophages. We showed that the stimulation of monocyte-derived macrophages with 5'ppp-dsRNA, a synthetic ligand for RIG-I, induced the expression of RIG-I, IFN-?/?, and several IRFs, key regulators of the IFN signaling pathway. In addition, RIG-I activation induced the expression of multiple intracellular HIV-restriction factors, including ISGs, several members of the APOBEC3 family, tetherin and CC chemokines, the ligands for HIV entry coreceptor (CCR5). The inductions of these factors were associated with the inhibition of HIV replication in macrophages stimulated by 5'ppp-dsRNA. These observations highlight the importance of RIG-I signaling in macrophage innate immunity against HIV, which can be beneficial for the treatment of HIV disease, where intracellular immune defense is compromised by the virus. PMID:23744645

Wang, Yizhong; Wang, Xu; Li, Jieliang; Zhou, Yu; Ho, Wenzhe

2013-08-01

180

Antimycobacterial Effect of Lysates Prepared from Immunologically Activated Macrophages  

PubMed Central

Lysates or heptane extracts of peritoneal (P) and alveolar (A) normal macrophages (N-M), immune macrophages (I-M), and immune-activated macrophages (IA-M) were examined for antimycobacterial activity by the agar-plate diffusion test. This test has been found suitable to reveal the antibacterial activity in 3-day incubated, but not in freshly prepared, lysates. Results showed that materials of IA-AM or I-AM and of IA-PM exerted antimycobacterial effects, whereas materials of N-PM, I-PM, and of N-AM were usually inactive. Antimycobacterial activity of lysates of AM was stronger than that of PM. The formation of antibacterial factors during an incubation of M lysates, the solubility of the factors in heptane, and various other characteristics suggested that the antimycobacterial effect was caused by the formation of toxic levels of non-esterified fatty acids. M lysates exerted equal activities against BCG, H37Ra, and H37Rv strains of tubercle bacilli. The presence of antimycobacterial activity in lysates prepared from IA-M of either BCG- or BCG-sensitized animals indicated that the potential to generate antimycobacterial activity is associated with the state of delayed hypersensitivity and the state of activation of M. Images

Kochan, Ivan; Golden, Carole A.

1973-01-01

181

Monocyte to macrophage differentiation-associated (MMD) positively regulates ERK and Akt activation and TNF-? and NO production in macrophages.  

PubMed

Macrophage activation is modulated by both environmental cues and endogenous programs. In the present study, we investigated the role of a PAQR family protein, monocyte to macrophage differentiation-associated (MMD), in macrophage activation and unveiled its underlying molecular mechanism. Our results showed that while MMD expression could be detected in all tissues examined, its expression level is significantly up-regulated upon monocyte differentiation. Within cells, EGFP-MMD fusion protein could be co-localized to endoplasmic reticulum, mitochondria, Golgi apparatus, but not lysosomes and cytoplasm. MMD expression is up-regulated in macrophages after LPS stimulation, and this might be modulated by RBP-J, the critical transcription factor of Notch signaling. Overexpression of MMD in macrophages increased the production of TNF-? and NO upon LPS stimulation. We found that MMD overexpression enhanced ERK1/2 and Akt phosphorylation in macrophages after LPS stimulation. Blocking Erk or Akt by pharmacological agent reduced TNF-? or NO production in MMD-overexpressing macrophages, respectively. These results suggested that MMD modulates TNF-? and NO production in macrophages, and this process might involves Erk or Akt. PMID:22203480

Liu, Qiang; Zheng, Jin; Yin, Dan-Dan; Xiang, Jie; He, Fei; Wang, Yao-Chun; Liang, Liang; Qin, Hong-Yan; Liu, Li; Liang, Ying-Min; Han, Hua

2012-05-01

182

Macrophages make me sick: how macrophage activation states influence sickness behavior  

PubMed Central

Summary The macrophage (M?) is an essential cellular first responder in the innate immune system, sensing, alerting, removing and destroying intrinsic and extrinsic pathogens. While congenital aplasia of granulocytes, T or B lymphocytes leads to serious disease, lack of M?s is incompatible with life. The M?, however, is not a monomorphic entity. These constructers, repairers and defenders of the body are diverse in form and function. What controls M? phenotype is beginning to be understood and involves a complex interplay of origination, location and microenvironment. Common to all M? developmental pathways are pro-inflammatory and anti-inflammatory cytokines. M?s respond to these bioactives in distinct ways developing recently recognized activation phenotypes that canonically support bacterial clearance (classical activation), parasite defense/tissue repair (alternative activation) and anti-inflammation (deactivation). Critically, the same cytokines which orchestrate immune defense and homeostasis dramatically impact sense of well being and cognition by eliciting sickness symptoms. Such behaviors are the manifestation of pro/anti-inflammatory cytokine action in the brain and are a direct consequence of M? function. This review describes the “new” archetypal M? activation states, delineates microglia phenotypic plasticity and explores the importance of these macrophage activation states to sickness behavior.

Moon, Morgan L.; McNeil, Leslie K.; Freund, Gregory G.

2011-01-01

183

Macrophage activation for microbicidal activity against Leishmania major: inhibition of lymphokine activation by phosphatidylcholine-phosphatidylserine liposomes.  

PubMed

Resident peritoneal macrophages from untreated mice develop microbicidal activity against amastigotes of the protozoan parasite Leishmania tropica (current nomenclature = Leishmania major) after in vitro exposure to LK from antigen-stimulated leukocyte culture fluids. This LK-induced macrophage microbicidal activity was completely abrogated by addition of 7:3 phosphatidylcholine: phosphatidylserine liposomes. Liposome inhibition was not due to direct toxic effects against the parasite or macrophage effector cell; factors in LK that induce macrophage microbicidal activity were not adsorbed or destroyed by liposome treatment. Other phagocytic particles, such as latex beads, had no effect on microbicidal activity. Moreover, liposome inhibition of activated macrophage effector function was relatively selective: LK-induced macrophage tumoricidal activity was not affected by liposome treatment. Liposome inhibition was dependent upon liposome dose (5 nmoles/culture) and time of addition of leishmania-infected, LK-treated macrophage cultures. Addition of liposomes through the initial 8 hr of culture completely inhibited LK-induced macrophage microbicidal activity; liposomes added after 16 hr had no effect. Similarly, microbicidal activity by macrophages activated in vivo by BCG or Corynebacterium parvum was not affected by liposome treatment. Liposome treatment also did not affect the increased resistance to infection induced in macrophages by LK. These data suggest that liposomes interfere with one or more early events in the induction of activated macrophages (macrophage-LK interaction) and not with the cytotoxic mechanism itself (parasite-macrophage interaction). These studies add to the growing body of data that implicate cell lipid in regulatory events controlling macrophage effector function. PMID:3980997

Gilbreath, M J; Nacy, C A; Hoover, D L; Alving, C R; Swartz, G M; Meltzer, M S

1985-05-01

184

Immunomodulatory/anti-inflammatory effects of Baccharis dracunculifolia leaves.  

PubMed

A possible immunomodulatory/anti-inflammatory effect of Baccharis dracunculifolia (Bd) and its major compound--caffeic acid (Ca)--on cytokines production (IL-1?, IL-6 and IL-10) by murine macrophages was investigated. Cells were incubated with Bd and Ca, and the inhibitory concentrations were tested before or after macrophages challenge with LPS. Bd and Ca stimulated IL-1? and inhibited IL-6 and IL-10 production. In LPS-challenge protocols, Bd prevented LPS action either before or after LPS challenge, whereas Ca prevented LPS effects only after LPS addition. Bd modulatory action on cytokines production may be at least in part mediated by Ca, since it has been shown to inhibit the transcription factor NF-?B. Further studies are still needed to evaluate Bd efficacy in inflammatory diseases, in order to explore its antiinflammatory activity in vivo. PMID:23163304

Bachiega, T F; de Sousa, J P B; Bastos, J K; Sforcin, J M

2013-01-01

185

Immunomodulatory activity of thunberginol A and related compounds isolated from Hydrangeae Dulcis Folium on splenocyte proliferation activated by mitogens.  

PubMed

We investigated the immunomodulatory effects of antiallergic constituents from Hydrangeae Dulcis Folium, the processed leaves of Hydrangea macrophylla SERINGE var. thunbergii MAKINO, on splenocyte proliferation in mice. Thunberginol A and hydrangenol significantly suppressed T lymphocyte proliferation induced by concanavalin A. Thunberginol A also suppressed B lymphocyte proliferation induced by lipopolysaccharide, but other constituents induced significant increases. These inhibitory effects of thunberginol A on splenocyte proliferation seemed to contribute to the suppressive effect on type IV allergy. PMID:9871657

Matsuda, H; Shimoda, H; Yamahara, J; Yoshikawa, M

1998-02-01

186

[Study of antituberculous activity of moxifloxacin conjugate with macrophage scavenger-receptor ligand].  

PubMed

Mycobacterium tuberculosis is an intracellular pathogen that persists in macrophages of the human host. An approach to improving the treatment of tuberculosis is target delivery of antibiotics to macrophages using ligands to macrophage receptors. The antituberculous activity of the conjugate of the antituberculous antibiotic moxifloxacin with carboxymethylglucan was studied in vitro using the J774 macrophage cell line and peritoneal macrophages. The antituberculous activity of the conjugate was higher than of the free moxifloxacin. The target antibiotic delivery to macrophage cells in tuberculosis infection was shown perspective. PMID:18318141

Azaev, M Sh; Agafonov, A P; Bodnev, S A; Blinov, V M

2006-01-01

187

Multimodality PET/MRI agents targeted to activated macrophages.  

PubMed

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 have become a popular platform for the fabrication of PET/MRI probes owing to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this article, we report the synthesis of dextran-coated iron oxide nanoparticles (DIO) labeled with the positron emitter (64)Cu to generate a PET/MRI probe, and modified with maleic anhydride to increase the negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-(64)Cu-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-(64)Cu-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 r 2 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 nonmodified analog, the accumulation of MDIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-(64)Cu-DOTA for identification of vulnerable atherosclerotic plaques via the targeting of macrophages. PMID:24166283

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

2014-02-01

188

Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct.  

PubMed

Macrophages adopt an alternatively activated phenotype (AAMs) when activated by the interleukin-4receptor(R)?. AAMs can be derived either from proliferation of tissue resident macrophages or recruited inflammatory monocytes, but it is not known whether these different sources generate AAMs that are phenotypically and functionally distinct. By transcriptional profiling analysis, we show here that, although both monocyte and tissue-derived AAMs expressed high levels of Arg1, Chi3l3, and Retnla, only monocyte-derived AAMs up-regulated Raldh2 and PD-L2. Monocyte-derived AAMs were also CX3CR1-green fluorescent protein (GFP)(high) and expressed CD206, whereas tissue-derived AAMs were CX3CR1-GFP and CD206 negative. Monocyte-derived AAMs had high levels of aldehyde dehydrogenase activity and promoted the differentiation of FoxP3(+) cells from naïve CD4(+) cells via production of retinoic acid. In contrast, tissue-derived AAMs expressed high levels of uncoupling protein 1. Hence monocyte-derived AAM have properties associated with immune regulation, and the different physiological properties associated with AAM function may depend on the distinct lineage of these cells. PMID:24695852

Gundra, Uma Mahesh; Girgis, Natasha M; Ruckerl, Dominik; Jenkins, Stephen; Ward, Lauren N; Kurtz, Zachary D; Wiens, Kirsten E; Tang, Mei San; Basu-Roy, Upal; Mansukhani, Alka; Allen, Judith E; Loke, P'ng

2014-05-15

189

Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct  

PubMed Central

Macrophages adopt an alternatively activated phenotype (AAMs) when activated by the interleukin-4receptor(R)?. AAMs can be derived either from proliferation of tissue resident macrophages or recruited inflammatory monocytes, but it is not known whether these different sources generate AAMs that are phenotypically and functionally distinct. By transcriptional profiling analysis, we show here that, although both monocyte and tissue-derived AAMs expressed high levels of Arg1, Chi3l3, and Retnla, only monocyte-derived AAMs up-regulated Raldh2 and PD-L2. Monocyte-derived AAMs were also CX3CR1-green fluorescent protein (GFP)high and expressed CD206, whereas tissue-derived AAMs were CX3CR1-GFP and CD206 negative. Monocyte-derived AAMs had high levels of aldehyde dehydrogenase activity and promoted the differentiation of FoxP3+ cells from naïve CD4+ cells via production of retinoic acid. In contrast, tissue-derived AAMs expressed high levels of uncoupling protein 1. Hence monocyte-derived AAM have properties associated with immune regulation, and the different physiological properties associated with AAM function may depend on the distinct lineage of these cells.

Gundra, Uma Mahesh; Girgis, Natasha M.; Ruckerl, Dominik; Jenkins, Stephen; Ward, Lauren N.; Kurtz, Zachary D.; Wiens, Kirsten E.; Tang, Mei San; Basu-Roy, Upal; Mansukhani, Alka; Allen, Judith E.

2014-01-01

190

Immunomodulatory effects of a traditional Chinese medicine with potential antiviral activity: a self-control study.  

PubMed

Traditional Chinese medicine (TCM) has been used for prevention and treatment of severe acute respiratory syndrome (SARS) in Hong Kong during the outbreak in spring 2003. We investigated the immunomodulating effects of an innovative TCM regimen derived from two herbal formulas (Sang Ju Yin and Yu Ping Feng San) for treating febrile diseases. Thirty-seven healthy volunteers were given the oral TCM regimen daily for 14 days. Peripheral venous blood samples were taken on days 0, 15 and 29 for hematology, biochemistry and immunology tests, including the measurement of blood lymphocyte subsets and plasma T-helper lymphocyte types 1 and 2 cytokines and receptor. After 3 months, 23 of the volunteers participated in a control study without TCM treatment for the same time course of blood tests. Two volunteers withdrew on day 2, due to headache and dizziness. All others remained well without any side effects. No participants showed significant changes in their blood test results, except that the T-lymphocyte CD4/CD8 ratio increased significantly from 1.31 +/- 0.50 (mean +/- SD) on day 0 to 1.41 +/- 0.63 on day 15 (p < 0.02), and reduced to 1.32 +/- 0.47 on day 29 (p < 0.05). In the control study, there were no changes in the CD4/CD8 ratio. The transient increase in CD4/CD8 ratio was likely due to the TCM intake. We postulate that the administration of the innovative TCM may have beneficial immunomodulatory effects for preventing viral infections including SARS. PMID:16437735

Poon, P M K; Wong, C K; Fung, K P; Fong, C Y S; Wong, E L Y; Lau, J T F; Leung, P C; Tsui, S K W; Wan, D C C; Waye, M M Y; Au, S W N; Lau, C B S; Lam, C W K

2006-01-01

191

An immunomodulatory polysaccharide-rich substance from the fruit juice of Morinda citrifolia (noni) with antitumour activity.  

PubMed

The fruit juice of Morinda citrifolia (noni) contains a polysaccharide-rich substance (noni-ppt) with antitumour 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 exudate cells (PEC) to impart profound toxicity when co-cultured with the tumour cells. This suggested the possibility that noni-ppt may suppress tumour growth through activation of the host immune system. Concomitant treatment with the immunosuppressive agent, 2-chloroadenosine (C1-Ade) or cyclosporin (cys-A) diminished its activity, thereby substantiating an immunomodulatory mechanism. Noni-ppt was also capable of stimulating the release of several mediators from murine effector cells, including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-10, IL-12 p70, interferon-gamma (IFN-gamma) and nitric oxide (NO), but had no effect on IL-2 and suppressed IL-4 release. Improved survival time and curative effects occurred when noni-ppt was combined with sub-optimal doses of the standard chemotherapeutic agents, adriamycin (Adria), cisplatin (CDDP), 5-fluorouracil (5-FU), and vincristine (VCR), suggesting important clinical applications of noni-ppt as a supplemental agent in cancer treatment. PMID:10441776

Hirazumi, A; Furusawa, E

1999-08-01

192

Immunomodulatory effects of curcumin: in-vivo.  

PubMed

Curcumin specifically exhibits cytostatic and cytotoxic effects against tumors of multiple origin. Previously we have demonstrated apoptotic activity of curcumin against tumor cells with no effect on normal cells in-vitro. Many anti-cancer drugs exhibit deleterious effects on immune cells, which restrict their wide use in-vivo. In the present study, we have evaluated the effect of curcumin on the major functions of T cells, natural killer cells, macrophages and on total splenocytes in-vivo, which insight the role of curcumin on their broad effector functions. This study demonstrates that prolonged curcumin-injections (i.p.) do not impair the cytotoxic function of natural killer cells, the generation of reactive oxygen species and nitric oxide from macrophages and the levels of Th1 regulatory cytokines remained unaltered. Interestingly, curcumin-injections enhanced the mitogen and antigen induced proliferation potential of T cells. We have also evaluated immunomodulatory effects of curcumin in ascites-bearing animals. This study strengthens our belief that curcumin is a safe and useful immunomodulator for the immune system. PMID:18387511

Varalakshmi, Ch; Ali, A Mubarak; Pardhasaradhi, B V V; Srivastava, Raghvendra M; Singh, Sarvjeet; Khar, Ashok

2008-05-01

193

Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status  

PubMed Central

Background Macrophages play a dual role in multiple sclerosis (MS) pathology. They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators. The effector function of macrophages is determined by the way they are activated. Stimulation of monocyte-derived macrophages in vitro with interferon-? and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages. Methods For this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry. This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively. Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples. Results Our data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions. M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages. Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status. Conclusions Our findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status.

2013-01-01

194

Myelin-Derived Lipids Modulate Macrophage Activity by Liver X Receptor Activation  

PubMed Central

Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor ?. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.

Huynh-Thu, Van Anh; Irrthum, Alexandre; Smeets, Hubert J. M.; Gustafsson, Jan-Ake; Steffensen, Knut R.; Mulder, Monique; Stinissen, Piet; Hellings, Niels; Hendriks, Jerome J. A.

2012-01-01

195

Activation of Macrophages From Aging Mice by Detoxified Lipid A  

Microsoft Academic Search

A detoxified derivative of endotoxic llpopolysaccharides (LPS), monophosphoryl lipid A (MPL), which is capable of inducing nonspecific resistance against several infectious organisms, was tested for its capacity to activate peritoneal macrophages (M4) from youngandimmunodeficient agingBALB\\/candC3H\\/HeNmice.Superoxidegenerationand hydrogen peroxide release by M4 from aging mice were elevated following intraperitoneal injection with 25 p.gof LPS or MPL, although they did not reach the

Yifang Chen; Laura Solem; Arthur G. Johnson

196

Antitumor and immunomodulatory activity of a water-soluble low molecular weight polysaccharide from Schisandra chinensis (Turcz.) Baill.  

PubMed

A water-soluble low molecular weight polysaccharide (SCPP11) was extracted and purified using DEAE-cellulose and Sephadex G-100 column from Schisandra chinensis (Turcz.) Baill. Its in vivo and in vitro antitumor and immunomodulatory activity were investigated. The results showed that SCPP11 with a molecular weight of 3.4×10(3)Da exhibited indirect cyctotoxic activity against tumor cells in vitro, but could significantly inhibit the growth of Heps cells in vivo at dose of 50mg/kg, and its inhibition rate is higher than that in the positive group. Moreover, SCPP11 could ameliorate the hematological and biochemical parameters to almost normal and no significant changes in organ weight, and could increase the body weight. In addition, SCPP11 (at 50mg/kg) could also increased in thymus indexes as well as IL-2 and TNF-? levels in serum in vivo and significantly enhance the phagocytosis activity and the productions of NO of RAW264.7 in vitro. The results indicated that antitumor properties of SCPP11 might be achieved by improving immune response. It could be explored as a potential adjuvant against cancer used in the health food and pharmaceutical therapy. PMID:23416131

Zhao, Ting; Mao, Guanghua; Mao, Riwen; Zou, Ye; Zheng, Daheng; Feng, Weiwei; Ren, Yuena; Wang, Wei; Zheng, Wei; Song, Jia; Chen, Yuanqing; Yang, Liuqing; Wu, Xiangyang

2013-05-01

197

Subcellular organelle lipidomics in TLR-4-activated macrophages1[S  

PubMed Central

Lipids orchestrate biological processes by acting remotely as signaling molecules or locally as membrane components that modulate protein function. Detailed insight into lipid function requires knowledge of the subcellular localization of individual lipids. We report an analysis of the subcellular lipidome of the mammalian macrophage, a cell type that plays key roles in inflammation, immune responses, and phagocytosis. Nuclei, mitochondria, endoplasmic reticulum (ER), plasmalemma, and cytoplasm were isolated from RAW 264.7 macrophages in basal and activated states. Subsequent lipidomic analyses of major membrane lipid categories identified 229 individual/isobaric species, including 163 glycerophospholipids, 48 sphingolipids, 13 sterols, and 5 prenols. Major subcellular compartments exhibited substantially divergent glycerophospholipid profiles. Activation of macrophages by the Toll-like receptor 4-specific lipopolysaccharide Kdo2-lipid A caused significant remodeling of the subcellular lipidome. Some changes in lipid composition occurred in all compartments (e.g., increases in the levels of ceramides and the cholesterol precursors desmosterol and lanosterol). Other changes were manifest in specific organelles. For example, oxidized sterols increased and unsaturated cardiolipins decreased in mitochondria, whereas unsaturated ether-linked phosphatidylethanolamines decreased in the ER. We speculate that these changes may reflect mitochondrial oxidative stress and the release of arachidonic acid from the ER in response to cell activation.

Andreyev, Alexander Y.; Fahy, Eoin; Guan, Ziqiang; Kelly, Samuel; Li, Xiang; McDonald, Jeffrey G.; Milne, Stephen; Myers, David; Park, Hyejung; Ryan, Andrea; Thompson, Bonne M.; Wang, Elaine; Zhao, Yihua; Brown, H. Alex; Merrill, Alfred H.; Raetz, Christian R. H.; Russell, David W.; Subramaniam, Shankar; Dennis, Edward A.

2010-01-01

198

Prostaglandin E2 does not inhibit tumoricidal activity of mouse macrophages against adherent tumor cells.  

PubMed

We determined whether endogenously produced PGE2 can down-regulate the tumoricidal properties of macrophages by a negative feedback mechanism. Peritoneal exudate macrophages or resident peritoneal macrophages of mice were incubated in medium (control) or in medium containing IFN-gamma and LPS. Activated macrophages were highly tumoricidal against syngeneic melanoma cells and secreted high levels of PGE2. Treatment with indomethacin or diclofenac sodium (voltaren) completely inhibited the production and secretion of PGE2 but not the tumoricidal activity of activated macrophages measured either immediately after activation or 1 to 3 days thereafter. Finally, the addition of exogenous PGE2 did not alter the ability of peritoneal exudate macrophages to respond to IFN-gamma or of LPS to produce high levels of tumor cell lysis. Collectively, these results show that PGE2 produced by activated macrophages is not a down-regulator of their tumoricidal activity against adherent tumor cells. PMID:2005391

Utsugi, T; Fidler, I J

1991-03-15

199

In vitro immunoregulatory effects of Korean mistletoe lectin on functional activation of monocytic and macrophage-like cells.  

PubMed

Korean mistletoe lectin (KML) is one of the major active components in Viscum album var. (coloratum), displaying various biological effects such as anti-tumor and anti-metastatic activities. Even though it has been shown to boost host immune defense mechanisms, the immunomodulatory effects of KML on specific immune responses mediated by macrophages have not been fully elucidated. Therefore, in this study, we aimed to demonstrate KML's regulatory roles on macrophage-mediated immune responses. KML clearly blocked lipopolysaccharide (LPS)-induced events [expression of interleukin (IL)-10, nitric oxide (NO) production and phagocytic uptake], and suppressed the normal expression levels of IL-10 (at 2 ng/ml) and tumor necrosis factor (TNF)-alpha (at 10 ng/ml). In contrast, (1) the expression of cytokine (TNF-alpha) and (2) the generation of reactive oxygen species (ROS) induced by LPS were significantly up-regulated with KML co-treatment. In addition, KML itself increased the mRNA levels of IL-3 and IL-23; phagocytic uptake; the surface levels of co-stimulatory molecules (CD80 and CD86), pattern recognition receptors (PRRs) [such as dectin-1 and toll like receptor (TLR)-2] and adhesion molecules [beta1-integrins (CD29) and CD43]; and CD29-mediated cell adhesion events. Finally, according to co-treatment of D-galactose with KML under LPS-induced NO production conditions, KML inhibition seems to be mediated by binding to proteins with D-galactose. Therefore, these data suggest that KML may participate in regulating various macrophage-mediated innate and adaptive responses via binding to surface protein with D-galactose and that some of these may deserve in KML's therapeutic activities such as anti-tumor and anti-microbial effects. PMID:17978473

Lee, Ji Yeon; Kim, Joo Young; Lee, Yong Gyu; Byeon, Se Eun; Kim, Byung Hun; Rhee, Man Hee; Lee, Albert; Kwon, Moosik; Hong, Sungyoul; Cho, Jae Youl

2007-11-01

200

Induction of macrophage antitumor activity by gamma radiation  

SciTech Connect

The authors have developed a model system for examination of macrophage-mediated tumor cells lysis, using the murine macrophage tumor cell line RAW 264.7. These cells, like normal macrophages, exhibit a strict requirement for interaction with both interferon-..gamma.. (IFN-..gamma.., the priming signal) and bacterial lipopolysaccharide (LPS, the triggering signal) in the development of tumor cytolytic activity. In this system, the priming effects of IFN-..gamma.. decay rapidly following withdrawal of this mediator and the cells become unresponsive to LPS. They have recently observed that gamma radiation of the RAW 264.7 cells results in development of a primed state which is stable and responsive to LPS triggering for a least 48 hours. Irradiation-induced development of the primed phenotype is not solely the result of cytostatic effects as LPS treatment alone results in marked decreases in /sup 3/H-TdR incorporation in the absence of cytolytic potential. In addition to delivering the priming signal for tumor cytotoxicity, irradiation of this cell line results in changes in cell morphology that are typical of activation. Finally, treatment with irradiation results in increased cell surface expression of MHC-encoded Class I antigens; however, Class II antigen expression is not induced. Thus, the effects of gamma radiation on this cell line are strikingly similar to those resulting from incubation with IFN-..gamma...

Lambert, L.; Paulnock, D.M.

1986-03-05

201

Zein-based oral drug delivery system targeting activated macrophages.  

PubMed

Reactive oxygen species (ROS) play an important role in the pathogenesis of rheumatoid arthritis (RA). ROS such as hydrogen peroxide and superoxide are overproduced by activated macrophages in RA. As scavengers of ROS, enzymatic proteins such as catalase and superoxide dismutase (SOD) have a great therapeutic potential; however, in vivo application is limited especially when they are orally administered. Although, the oral route is the most convenient for drug administration, therapeutic proteins are easily degraded in vivo by the harsh conditions of gastrointestinal (GI) tract. Here, we introduce a novel drug delivery system composed of zein, a plant storage protein derived from maize. We demonstrate that zein nanoparticles can protect therapeutic proteins, catalase and SOD, from the harsh conditions of GI tract. Folate-conjugated catalase or SOD in zein nanoparticles can target the activated macrophages and scavenge the ROS generated by macrophages in vitro. This novel drug delivery system will be applicable to other orally administered treatments based on the protective property in the harsh conditions of GI tract. PMID:23876501

Lee, Sungmun; Alwahab, Noaf Salah Ali; Moazzam, Zainab Muhammad

2013-09-15

202

Induction of antitumor activity in macrophages by mycoplasmas in concert with interferon  

Microsoft Academic Search

Summary The in vitro growth of tumor cells infected with mycoplasmas was suppressed by macrophages pretreated with interferon (IFN), but the growth of mycoplasma-free tumor cells was not suppressed. Pretreatment of macrophages with IFN plus mycoplasmas or their soluble factors either simultaneously or sequentially, IFN first and mycoplasmas second, but not in the reverse order, was effective in activating macrophages

Kazuko Uno; Morio Takema; Shigetaka Hidaka; Reishi Tanaka; Takao Konishi; Takuma Kato; Shinji Nakamura; Shigeru Muramatsu

1990-01-01

203

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

204

PSP activates monocytes in resting human peripheral blood mononuclear cells: immunomodulatory implications for cancer treatment.  

PubMed

Polysaccharopeptide (PSP), from Coriolus versicolor, has been used as an adjuvant to chemotherapy, and has demonstrated anti-tumor and immunomodulating effects. However its mechanism remains unknown. To elucidate how PSP affects immune populations, we compared PSP treatments both with and without prior incubation in phytohaemagglutinin (PHA) - a process commonly used in immune population experimentation. We first standardised a capillary electrophoresis fingerprinting technique for PSP identification and characterisation. We then established the proliferative capability of PSP on various immune populations in peripheral blood mononuclear cells, using flow cytometry, without prior PHA treatment. It was found that PSP significantly increased the number of monocytes (CD14(+)/CD16(-)) compared to controls without PHA. This increase in monocytes was confirmed using another antibody panel of CD14 and MHCII. In contrast, proliferations of T-cells, NK, and B-cells were not significantly changed by PSP. Thus, stimulating monocyte/macrophage function with PSP could be an effective therapeutic intervention in targeting tumors. PMID:23497877

Sekhon, Bhagwant Kaur; Sze, Daniel Man-Yuen; Chan, Wing Keung; Fan, Kei; Li, George Qian; Moore, Douglas Edwin; Roubin, Rebecca Heidi

2013-06-15

205

Chain conformation and immunomodulatory activity of a hyperbranched polysaccharide from Cordyceps sinensis.  

PubMed

A polysaccharide, named as cordysinan, extracted from natural Cordyceps sinensis, was identified as a hyperbranched heteropolysaccharide from the results of FT-IR, GC-MS, and carbohydrate analysis by carbohydrate gel electrophoresis analysis, as well as the degree of branching of cordysinan was 43.3%. The solution properties of cordysinan were investigated by using size exclusion chromatography coupled with multi-angle laser light scattering and triple detector array, respectively. The molecular weights, the radius of gyration and the intrinsic viscosity of cordysinan were determined as 22.45±0.26kDa and 22.37kDa, 15.4±2.4nm and 1.41mL/g, respectively. By applying the polymer solution theory, the exponent (? and ?) values of [Formula: see text] and [?]=kMw(?) were calculated as 0.28 and 0.42, respectively, which firstly revealed that cordysinan existed as a globular shape in 0.9% NaCl aqueous solution. Moreover, the results showed that cordysinan could obviously stimulate macrophages functions. PMID:24906773

Wu, Ding-Tao; Meng, Lan-Zhen; Wang, Lan-Ying; Lv, Guang-Ping; Cheong, Kit-Leong; Hu, De-Jun; Guan, Jia; Zhao, Jing; Li, Shao-Ping

2014-09-22

206

Spherical Lactic Acid Bacteria Activate Plasmacytoid Dendritic Cells Immunomodulatory Function via TLR9-Dependent Crosstalk with Myeloid Dendritic Cells  

PubMed Central

Plasmacytoid dendritic cells (pDC) are a specialized sensor of viral and bacterial nucleic acids and a major producer of IFN-? that promotes host defense by priming both innate and acquired immune responses. Although synthetic Toll-like receptor (TLR) ligands, pathogenic bacteria and viruses activate pDC, there is limited investigation of non-pathogenic microbiota that are in wide industrial dietary use, such as lactic acid bacteria (LAB). In this study, we screened for LAB strains, which induce pDC activation and IFN-? production using murine bone marrow (BM)-derived Flt-3L induced dendritic cell culture. Microbial strains with such activity on pDC were absent in a diversity of bacillary strains, but were observed in certain spherical species (Lactococcus, Leuconostoc, Streptococcus and Pediococcus), which was correlated with their capacity for uptake by pDC. Detailed study of Lactococcus lactis subsp. lactis JCM5805 and JCM20101 revealed that the major type I and type III interferons were induced (IFN-?, -?, and ?). IFN-? induction was TLR9 and MyD88-dependent; a slight impairment was also observed in TLR4-/- cells. While these responses occurred with purified pDC, IFN-? production was synergistic upon co-culture with myeloid dendritic cells (mDC), an interaction that required direct mDC-pDC contact. L. lactis strains also stimulated expression of immunoregulatory receptors on pDC (ICOS-L and PD-L1), and accordingly augmented pDC induction of CD4+CD25+FoxP3+ Treg compared to the Lactobacillus strain. Oral administration of L. lactis JCM5805 induced significant activation of pDC resident in the intestinal draining mesenteric lymph nodes, but not in a remote lymphoid site (spleen). Taken together, certain non-pathogenic spherical LAB in wide dietary use has potent and diverse immunomodulatory effects on pDC potentially relevant to anti-viral immunity and chronic inflammatory disease.

Jounai, Kenta; Ikado, Kumiko; Sugimura, Tetsu; Ano, Yasuhisa; Braun, Jonathan; Fujiwara, Daisuke

2012-01-01

207

Targeting macrophage activation for the prevention and treatment of S. aureus biofilm infections†  

PubMed Central

Biofilm infections often lead to significant morbidity due to their chronicity and recalcitrance to antibiotics. We have demonstrated that methicillin-resistant Staphylococcus aureus (MRSA) biofilms can evade macrophage antibacterial effector mechanisms by skewing macrophages towards an alternatively activated M2 phenotype. To overcome this immune evasion, we have utilized two complementary approaches. In the first, a proinflammatory milieu was elicited by local administration of classically-activated M1 macrophages and second, by treatment with the C5a receptor (CD88) agonist EP67, which invokes macrophage proinflammatory activity. Early administration of M1-activated macrophages or EP67 significantly attenuated biofilm formation in a mouse model of MRSA catheter-associated infection. Several proinflammatory mediators were significantly elevated in biofilm infected tissues from macrophage- and EP67-treated animals, revealing effective reprogramming of the biofilm environment to a proinflammatory milieu. A requirement for macrophage proinflammatory activity was demonstrated by the fact that transfer of MyD88-deficient macrophages had minimal impact on biofilm growth. Likewise, neutrophil administration had no effect on biofilm formation. Treatment of established biofilm infections with M1-activated macrophages also significantly reduced catheter-associated biofilm burdens compared to antibiotic treatment. Collectively, these results demonstrate that targeting macrophage proinflammatory activity can overcome the local immune inhibitory environment created during biofilm infections and represents a novel therapeutic strategy.

Hanke, Mark L.; Heim, Cortney E.; Angle, Amanda; Sanderson, Sam D.; Kielian, Tammy

2013-01-01

208

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

209

Immunomodulatory drugs in multiple myeloma.  

PubMed

The introduction of new agents immunomodulatory drugs (IMiDs) and proteasome inhibitors has brought a major shift in therapeutic paradigm in the treatment of newly diagnosed and refractory multiple myeloma (MM). Thalidomide was the first immunomodulatory agent approved for use in myeloma. Although highly active, it is associated with considerable toxicity, particularly in older patients. Lenalidomide, an analog of thalidomide, was developed because of its more potent anti-MM activity and better toxicity profile than the parent compound. Since its introduction in 2004, lenalidomide has established a role in all phases of treatment in MM. The pleiotropic antitumor effects of lenalidomide have translated into clinical efficacy in diseases other than MM. Pomalidomide is a highly potent third-generation IMiD that shares similar pharmacologic properties as thalidomide, with very promising activity in MM and myelofibrosis. This review summarizes the mechanisms of action and clinical activity of IMiDs in MM. PMID:23373782

Andhavarapu, Swati; Roy, Vivek

2013-02-01

210

Macrophages inhibit migration, metabolic activity and osteogenic differentiation of human mesenchymal stem cells in vitro.  

PubMed

To better elucidate the role of macrophages in bone morphogenetic protein (BMP)-induced bone repair, this study evaluated the effects of macrophages on the migration, metabolic activity and BMP-2-induced osteogenic differentiation of human mesenchymal stem cells (hMSCs). Human monocytes were induced into a macrophage phenotype, and the conditioned media (CM) from undifferentiated monocytes and differentiated macrophages were collected for treatment of hMSCs. Expression levels of osteoblastic marker genes, alkaline phosphatase (ALP) activity and mineral deposition were assessed. The migration of hMSCs was significantly decreased after treatment with the macrophage CM (but not monocyte CM), in a dose-dependent manner. Significant inhibition of hMSC metabolism was observed on days 3 and 7 after treatment with the macrophage CM. The osteoblastic marker genes analyzed (ALP, bone sialoprotein, osteocalcin and runt-related transcription factor-2) after exposure of hMSCs to BMP-2 were all significantly downregulated in cells treated with the macrophage CM. The hMSCs treated with macrophage CM showed significantly decreased enzymatic activity of ALP and calcium content compared with those treated with monocyte CM or basal medium. High levels of interleukin-1? and tumor necrosis factor-? found in macrophage CM may mediate these observed effects on hMSCs. We conclude that macrophage CM suppressed the BMP-2-induced osteogenic differentiation of hMSCs, suggesting that macrophages might contribute to decreased osteogenic effects of BMPs in a clinical setting. PMID:22156615

Chen, Chao; Uluda?, Hasan; Wang, Zhixiang; Rezansoff, Alex; Jiang, Hongxing

2012-01-01

211

A subpopulation of CD163-positive macrophages is classically activated in psoriasis.  

PubMed

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 with normal skin and were identified by CD163, RFD7, CD68, lysosomal-associated membrane protein 2 (LAMP2), stabilin-1, and macrophage receptor with collagenous structure (MARCO). CD163(+) macrophages expressed C-lectins CD206/macrophage mannose receptor and CD209/DC-SIGN, as well as costimulatory molecules CD86 and CD40. They did not express mature dendritic cell (DC) markers CD208/DC-lysosomal-associated membrane glycoprotein, 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 tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS). These data show that CD163 is a superior marker of macrophages, and identifies a subpopulation of "classically activated" macrophages in psoriasis. We conclude that macrophages are likely to contribute to the pathogenic inflammation in psoriasis, a prototypical T helper 1 (Th1) and Th17 disease, by releasing key inflammatory products. PMID:20555352

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

2010-10-01

212

[Action of Corynebacterium parvum on the activity of glycosidases and proteases of peritoneal macrophages in the mice].  

PubMed

Glycosidase and peptidase of non-treated Mouse peritoneal macrophages were characterized. The enzymatic activities of Corynebacterium parvum stimulated Mouse macrophages were compared to those of macrophages obtained from non-treated animals. All the enzymatic activities, but beta-C-galactosidase, were higher in stimulated Mouse macrophages. PMID:102445

Scharfman, A; Houdret, N; Roussel, P; Biserte, G

1978-09-11

213

Future directions in immunomodulatory therapy  

Microsoft Academic Search

The role of immunomodulatory-based therapy with thalidomide or lenalidomide is clearly established in the management of patients\\u000a with myeloma in all phases of their disease. Recent preclinical and clinical works have demonstrated that in addition to combination\\u000a therapy with dexamethasone, there is significant activity when combined with the proteasome inhibitor bortezomib. More recent\\u000a clinical studies have also demonstrated significant activity

Sagar Lonial

2010-01-01

214

Immunomodulatory Activity of Lactococcus lactis A17 from Taiwan Fermented Cabbage in OVA-Sensitized BALB/c Mice  

PubMed Central

From fermented Taiwan foods, we have isolated numerous lactic acid bacteria (LAB) of plant origin and investigated their biological activities. This study aimed to investigate the immunomodulatory effect and mechanism of Lactococcus lactis A17 (A17), isolated from Taiwan fermented cabbage, on ovalbumin (OVA)-sensitized mice. Human peripheral blood mononuclear cells were used to verify immune responses of A17 by IFN-? production. Live (A17-A) and heat-killed A17 (A17-H) were orally administered to OVA-sensitized BALB/c mice to investigate their effects on immunoglobulin (Ig) and cytokine production. The mRNA expression of Toll-like receptors (TLR) and nucleotide binding oligomerization domain (NOD)-like protein receptors in spleen cells was analyzed by real-time RT-PCR. Both live and heat-killed A17 modulate OVA-induced allergic effects. B-cell response was modulated by diminishing IgE production and raising OVA-specific IgG2a production, while T-cell response was modulated by increasing IFN-? production and decreasing IL-4 production. The mRNA expression of NOD-1, NOD-2, and TLR-4 was down-regulated by A17 as well. This is the first report to describe a naïve Lactococcus lactis A17 strain as a promising candidate for prophylactic and therapeutic treatments of allergic diseases via oral administration. Our results suggest the ameliorative effects of A17 may be caused by modulating NOD-1 NOD-2, and TLR-4 expression.

Mei, Hui-Ching; Liu, Yen-Wenn; Chiang, Yi-Chin; Chao, Shiou-Huei; Mei, Nai-Wen; Liu, Yu-Wen; Tsai, Ying-Chieh

2013-01-01

215

Characterization of the Conditioned Medium from Amniotic Membrane Cells: Prostaglandins as Key Effectors of Its Immunomodulatory Activity  

PubMed Central

We previously demonstrated that cells isolated from the mesenchymal region of the human amniotic membrane (human amniotic mesenchymal tissue cells, hAMTC) possess immunoregulatory roles, such as inhibition of lymphocyte proliferation and cytokine production, and suppression of generation and maturation of monocyte-derived dendritic cells, as reported for MSC from other sources. The precise factors and mechanisms responsible for the immunoregulatory roles of hAMTC remain unknown. In this study, we aimed to identify the soluble factors released by hAMTC and responsible for the anti-proliferative effect on lymphocytes, and the mechanisms underlying their actions, in vitro. Conditioned medium (CM) was prepared under routine culture conditions from hAMTC (CM-hAMTC) and also from fragments of the whole human amniotic membrane (CM-hAM). We analyzed the thermostability, chemical nature, and the molecular weight of the factors likely responsible for the anti-proliferative effects. We also evaluated the participation of cytokines known to be involved in the immunomodulatory actions of MSC from other sources, and attempted to block different synthetic pathways. We demonstrate that the inhibitory factors are temperature-stable, have a small molecular weight, and are likely of a non-proteinaceous nature. Only inhibition of cyclooxygenase pathway partially reverted the anti-proliferative effect, suggesting prostaglandins as key effector molecules. Factors previously documented to take part in the inhibitory effects of MSCs from other sources (HGF, TGF-?, NO and IDO) were not involved. Furthermore, we prove for the first time that the anti-proliferative effect is intrinsic to the amniotic membrane and cells derived thereof, since it is manifested in the absence of stimulating culture conditions, as opposed to MSC derived from the bone marrow, which possess an anti-proliferative ability only when cultured in the presence of activating stimuli. Finally, we show that the amniotic membrane could be an interesting source of soluble factors, without referring to extensive cell preparation.

Rossi, Daniele; Pianta, Stefano; Magatti, Marta; Sedlmayr, Peter; Parolini, Ornella

2012-01-01

216

Resident macrophages influence stem cell activity in the mammary gland  

Microsoft Academic Search

INTRODUCTION: Macrophages in the mammary gland are essential for morphogenesis of the ductal epithelial tree and have been implicated in promoting breast tumor metastasis. Although it is well established that macrophages influence normal mammopoiesis, the mammary cell types that these accessory cells influence have not been determined. Here we have explored a role for macrophages in regulating mammary stem cell

David E Gyorki; Marie-Liesse Asselin-Labat; Nico van Rooijen; Geoffrey J Lindeman; Jane E Visvader

2009-01-01

217

A defect in the inflammation-primed macrophage-activation cascade in osteopetrotic rats.  

PubMed

Macrophages were activated by administration of lysophosphatidylcholine (lyso-Pc) or dodecylglycerol (DDG) to wild-type rats but not in osteopetrotic (op) mutant rats. In vitro treatment of wild-type rat peritoneal cells with lyso-Pc or DDG efficiently activated macrophages whereas treatment of op mutant rat peritoneal cells with lyso-Pc or DDG did not activate macrophages. The inflammation-primed macrophage activation cascade in rats requires participation of B lymphocytes and vitamin D binding protein (DBP). Lyso-Pc-inducible beta-galactosidase of wild-type rat B lymphocytes can convert DBP to the macrophage-activating factor (MAF), whereas B lymphocytes of the op mutant rats were shown to be deficient in lyso-Pc-inducible beta-galactosidase. DBP is conserved among mammalian species. Treatment of human DBP (Gc1 protein) with commercial glycosidases yields an extremely high titrated MAF as assayed on mouse and rat macrophages. Because the enzymatically generated MAF (GcMAF) bypasses the role of lymphocytes in macrophage activation, the op mutant rat macrophages were efficiently activated by administration of a small quantity (100 pg/rat) of GcMAF. Likewise, in vitro treatment of op rat peritoneal cells with as little as 40 pg GcMAF/ml activated macrophages. PMID:8176226

Yamamoto, N; Lindsay, D D; Naraparaju, V R; Ireland, R A; Popoff, S N

1994-05-15

218

Activation of macrophages by lymphokines: enhancement of phagosome-lysosome fusion and killing of Coccidioides immitis.  

PubMed Central

Previously, it was shown that arthroconidia of Coccidioides immitis appear to inhibit phagosome-lysosome fusion and survive within normal mouse peritoneal macrophages. However, when these macrophages are exposed to antigen-stimulated T lymphocytes from immune mice, activation occurs, leading to enhanced phagosome-lysosome fusion and killing of C. immitis. Results indicate that the activation of macrophages can be effected after incubation with soluble lymphocyte product(s) (lymphokines). The activation of macrophages results if the macrophages are exposed to the lymphokine before, but not after, infection. The results indicate that the lymphocyte population responsible for the elaboration of the lymphokine is phenotypically Lyt1+2- and that activation of macrophages by the lymphokine can occur across H-2 histocompatibility barriers.

Beaman, L; Benjamini, E; Pappagianis, D

1983-01-01

219

Anti-leishmanial and immunomodulatory activities of extracts from Portulaca hirsutissima and Portulaca werdermannii.  

PubMed

Ethyl acetate and chloroform extracts from aerial parts of Portulaca werdermannii and P. hirsutissima were tested in lymphoproliferation assays and axenic cultures of Leishmania amazonensis and Trypanosoma cruzi. Both extracts of P. werdermannii and P. hirsutissima had a potent inhibitory activity on lymphocyte proliferation. On the contrary, only the chloroformic extract of both plants inhibited L. amazonensis growth, without effect on T. cruzi cultures. These results indicate these Portulaca species as potential sources of new active molecules for the treatment of leishmaniasis and immune-mediated pathologies. PMID:17651913

Costa, José Fernando Oliveira; Kiperstok, Alice Costa; David, Juceni Pereira de Lima; David, Jorge Maurício; Giulietti, Ana Maria; de Queiroz, Luciano Paganucci; dos Santos, Ricardo Ribeiro; Soares, Milena Botelho Pereira

2007-12-01

220

Activation of peritoneal macrophages to cytoxicity against B16 melanoma cells by Serratia marcescens polyribosome fractions  

SciTech Connect

Serratia marcescens polyribosomes (SMPR) have been shown to elicit an anti-tumor response in vivo. The in-vitro effects of SMPR on macrophages as the nonspecific mediators of the anti-tumor response have not previously been examined. The first objective of this research project is to corroborate and analyze the in-vivo results by the development and application of an in-vitro cytotoxicity assay. The second objective is to examine the effect of SMPR upon previously unstimulated peritoneal macrophages as representing the mechanism of cytotoxicity. The third objective is to identify the minimal effective component of SMPR responsible for an effect on macrophages. Results revealed that SMPR preparations exert a number of effects upon macrophages. Morphologic changes included increased spreading and increased perinuclear vacuolization. Macrophages were shown to be metabolically activate by two lines of evidence. SMPR-treated macrophages exhibited increased cellular metabolism by the increased uptake of /sup 3/H-thymidine and by the increased levels of secreted leucine aminopeptidase as compared to control macrophages. Results also showed that SMPR activates macrophages to cytotoxicity against syngeneic tumor target cells. Buoyant-density fractions were isolated and assayed for macrophage activating ability. Results showed 50S ribosomal subunits to be the smallest fraction effective for macrophage activation. Both the RNA and protein were necessary for complete effectiveness.

Hoover, S.K.

1985-01-01

221

In vitro study of the antioxidant and immunomodulatory activity of aqueous infusion of Bidens pilosa  

Microsoft Academic Search

Bidens pilosa is an annual plant from tropical America with anti-inflammatory properties in hepatitis, laryngitis, headache and digestive disorders, among others. Its wide pharmacological applications can be attributed to its chemical composition, with inhibitory effects on pathogenic microorganisms and flavonoids, which show strong antioxidant capacities. We investigated the antioxidant activity of an aqueous infusion of Bidens pilosa by studying its

Celia Abajo; Mar??a Ángeles Boffill; Jaime del Campo; Mar??a Alexandra Méndez; Yisel González; Montserrat Mitjans; Mar??a Pilar Vinardell

2004-01-01

222

Immunomodulatory effect of albizzia lebbeck.  

PubMed

The immunomodulatory effect of the bark of Albizzia lebbeck (Sirisha) was evaluated by studying humoral and cell mediated immune responses. The hot aqueous extract and its butanolic fraction were administered once daily for one week in mice, immunised previously with sheep red blood cells (SRBC). At the dose levels tested (6.25, 12.5 and 25 mg/kg, p.o.), A. lebbeck treated mice developed higher serum antibody titres compared to the vehicle treated group and the effect was comparable to the standard drug muramyl dipeptide (MDP). Delayed type hypersensitivity response was suppressed in SRBC immunised mice treated with A. lebbeck extract. The macrophage migration index remained unaltered in both mice and rats. These results are discussed in the light of possible immunopotentiating effects of A. lebbeck. PMID:21214455

Barua, C C; Gupta, P P; Patnaik, G K; Misra-Bhattacharya, S; Goel, R K; Kulshrestha, D K; Dubey, M P; Dhawan, B N

2000-01-01

223

In vivo and in vitro activation of macrophages with a cyanine photosensitizing dye, platonin  

Microsoft Academic Search

A cyanine photosensitizing dye, platonin, is a potent macrophage-activating agent. Four days after the administration to mice of small amounts of platonin (20–40 ng\\/mouse), peritoneal macrophages exhibited greatly enhanced Fc-receptor-mediated phagocytic and superoxide-generating capacities. Much higher doses (more than 3000 ng\\/mouse) did not have this effect. Photodynamic experiments for macrophage activation were performed by exposing mouse peritoneal cells (mixture of

Yoshinori Nakagawa; Sadamu Homma; Itaru Yamamoto; Masaru Banno; Hiroaki Nakazato; Hajime Imanaga; Nobuto Yamamoto

1993-01-01

224

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; Faragò, 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

225

Iron modulates the replication of virulent Mycobacterium bovis in resting and activated bovine and possum macrophages.  

PubMed

Bovine and possum macrophages were infected in vitro with a virulent strain of Mycobacterium bovis, and mycobacterial replication was measured in the infected macrophages cultured under a variety of conditions. Virulent M. bovis replicated substantially in alveolar possum macrophages as well as in bovine blood monocyte-derived macrophages. Addition of recombinant bovine interferon-gamma (IFN-gamma) with low concentrations of lipopolysaccharide (LPS) rendered bovine macrophages significantly more resistant to M. bovis replication. Disruption of iron levels in infected macrophages by addition of apotransferrin or bovine lactoferrin blocked replication of M. bovis in both bovine and possum macrophages. On the other hand, addition of exogenous iron, either in the form of iron citrate or iron-saturated transferrin, rendered macrophages of both species much more permissive for the replication of M. bovis. The impact of iron deprivation/loading on the mycobacteriostatic activity of cells was independent of nitric-oxide release, as well as independent of the generation of oxygen radical species in both possum and bovine macrophages. Exogenous iron was shown to reverse the ability of IFN-gamma/LPS pulsed bovine macrophages to restrict M. bovis replication. When autologous possum lymphocytes from animals vaccinated with M. bovis strain BCG were added to infected macrophages, they rendered the macrophages less permissive for virulent M. bovis replication. Loading the cells with iron prior to this macrophage-lymphocyte interaction, reversed this immune effect induced by sensitized cells. We conclude that, in two important animal species, intracellular iron level plays an important role in M. bovis replication in macrophages, irrespective of their activation status. PMID:15993492

Denis, Michel; Buddle, Bryce M

2005-09-15

226

[Immunomodulatory drugs (IMiDs)].  

PubMed

Immunomodulatory drugs (IMiDs) are a new class of anti-inflammatory and antineoplastic agents that have structural and functional similarities with their prototype compound, thalidomide. Although thalidomide and its derivatives, lenalidomide and pomalidomide, are widely used as an essential component in the treatment of selected hematologic neoplasms including multiple myeloma, the precise mechanisms by which these agents exert anti-tumor effects have yet to be clarified. Recently, a component of E3 ubiquitin ligase complex, cereblon (CRBN), has been identified as a direct molecular target for anti-neoplastic activities of IMiDs. CRBN has also been shown to be involved in IMiDs-mediated T-cell co-stimulation and cytokine production. Further studies are necessary to elucidate the CRBN-related molecular pathways that are essential for antitumor and immunomodulatory activities of IMiDs. PMID:25016816

Oshima, Kumi; Ichinohe, Tatsuo

2014-06-01

227

Immunomodulatory activity of alcoholic extract of Mangifera indica L. in mice.  

PubMed

Mangifera indica Linn, a plant widely used in the traditional medicinal systems of India, has been reported to possess antiviral, antibacterial and anti-inflammatory activities. In the present study, the alcoholic extract of stem bark of Mangifera indica Linn (Extract I containing mangiferin 2.6%), has been investigated for its effect on cell mediated and humoral components of the immune system in mice. Administration of test extract I produced increase in humoral antibody (HA) titre and delayed type hypersensitivity (DTH) in mice. It is concluded that test extract I is a promising drug with immunostimulant properties. PMID:11694357

Makare, N; Bodhankar, S; Rangari, V

2001-12-01

228

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

PubMed Central

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.

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

229

miR-125a-5p regulates differential activation of macrophages and inflammation.  

PubMed

Macrophage activation is a central event in immune responses. Macrophages undergoing classical activation (M1 macrophages) are proinflammatory, whereas alternatively activated macrophages (M2 macrophages) are generally anti-inflammatory. miRNAs play important regulatory roles in inflammatory response. However, the manner in which miRNAs regulate macrophage activation in response to different environmental cues has not been well defined. In this study, we found that M-BMM macrophages (M2) express greater levels of miR-125a-5p than do GM-BMM macrophages (M1). Stimulation of macrophages through TLR2 and TLR4 but not through TLR3 enhanced miR-125a-5p expression. Up-regulation of miR-125a-5p after TLR2/4 activation requires the adaptor MYD88 but not TRIF. Overexpression of miR-125a-5p diminished M1 phenotype expression induced by LPS but promoted M2 marker expression induced by IL-4. In contrast, knockdown of miR-125a-5p promoted M1 polarization and diminished IL-4-induced M2 marker expression. We found that miR-125a-5p targets KLF13, a transcriptional factor that has an important role in T lymphocyte activation and inflammation. KLF13 knockdown had similar effects on M1 activation as did miR-125a-5p overexpression. In addition, miR-125a-5p regulates phagocytic and bactericidal activities of macrophages. Our data suggest that miR-125a-5p has an important role in suppressing classical activation of macrophages while promoting alternative activation. PMID:24151079

Banerjee, Sami; Cui, Huachun; Xie, Na; Tan, Zheng; Yang, Shanzhong; Icyuz, Mert; Thannickal, Victor John; Abraham, Edward; Liu, Gang

2013-12-01

230

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

231

Thrombospondin 1 activates the macrophage Toll-like receptor 4 pathway.  

PubMed

Previously, we demonstrated that macrophages from thrombospondin 1 (TSP1)-deficient mice have a reduced inflammatory phenotype, suggesting that TSP1 plays a role in macrophage activation. In this study, we determined how TSP1 regulates macrophage function. We found that recombinant or purified platelet human TSP1 treatment stimulated tumor-necrosis factor (TNF)-? expression in bone marrow-derived macrophages in a time- and dose-dependent manner. Toll-like receptor 4 (TLR4) expression (at the mRNA and protein levels) and nuclear factor-kappaB (NF-?B) activity were also stimulated by TSP1 treatment. The TSP1-mediated increase in TNF-? production was abolished in TLR4-deficient macrophages, suggesting that TSP1 activates macrophages through a TLR4-dependent pathway. TSP1 also stimulated TLR4 activation in macrophages in vivo. Furthermore, TSP1-mediated macrophage activation was attenuated by using a peptide or an antibody to block the association between TSP1 and CD36. Taken together, these data suggest that the stimulation of the macrophage TLR4 pathway by TSP1 is partially mediated by the interaction of TSP1 with its receptor, CD36. PMID:23954950

Li, Yanzhang; Qi, Xinyu; Tong, Xiaopeng; Wang, Shuxia

2013-11-01

232

Immunomodulatory activity of Lactobacillus rhamnosus strains isolated from goat milk: impact on intestinal and respiratory infections.  

PubMed

The immune stimulation induced by Lactobacillus rhamnosus CRL1505 (Lr05) and L. rhamnosus CRL1506 (Lr06) on the resistance to infection with an intestinal pathogen (Salmonella typhimurium) and a respiratory pathogen (Streptococcus pneumoniae) was studied in swiss-albine mice experimental models. The cytokine profiles that induced the innate and specific immune response in both infectious processes were investigated. Both strains were able to improve resistance against the intestinal pathogen. Only Lr05 was able to induce a significant decrease in the number of S. pneumoniae in the lung, prevent its dissemination into the blood and induce a significant increase in Th1 (INF-gamma) and Th2 (IL-6, IL-4 and IL-10) cytokine levels in the bronchoalveolar lavages (BAL). The changes in the cytokines profiles in BAL were associated with an increase in the number and activity of phagocytic cells and with the increase in specific antibodies in serum and BAL, which would explain the increased resistance to the challenge. The administration of Lr06 did not induce significant effects at the respiratory mucosal level. The results described in the present paper showed that certain LAB strains can share certain functional properties, although some of them can perform a functional role better than others, so that it is important to perform careful studies on specific strains, according to their therapeutic use. PMID:20395002

Salva, Susana; Villena, Julio; Alvarez, Susana

2010-06-30

233

In vitro killing of Ehrlichia risticii by activated and immune mouse peritoneal macrophages.  

PubMed Central

Normal resident murine peritoneal macrophages inoculated in vitro with Ehrlichia risticii readily phagocytized the organism but were unable to suppress ehrlichial replication as determined by indirect fluorescent-antibody staining of the inoculated cells. In contrast, macrophages from Corynebacterium parvum-inoculated and E. risticii-recovered mice rapidly eliminated the ehrlichiae. Macrophages from E. risticii-recovered mice were as effective as the C. parvum-activated cells in phagocytizing and eliminating the organism. Opsonization of E. risticii with homologous antiserum prior to inoculation of macrophage cultures resulted in enhancement of phagocytosis and greater suppression of E. risticii replication in all macrophage groups. These findings indicate that the pathogenesis of E. risticii infection centers on the ability of the organism to enter and replicate within the macrophage with avoidance of macrophage antimicrobial effects. An immune response results in macrophage activation with enhancement of the macrophage's ability to eliminate E. risticii. Opsonization of E. risticii with anti-E. risticii serum renders E. risticii more susceptible to macrophage destruction.

Williams, N M; Timoney, P J

1993-01-01

234

IVIG treatment of adenovirus infection-associated macrophage activation syndrome in a two-year-old boy: case report and review of the literature.  

PubMed

A 2-year-old boy with severe multiorgan disease (i.e., otitis, enteritis, bilateral pneumonia, encephalopathy, myocarditis, rash) was diagnosed with adenovirus-associated macrophage activation syndrome according to clinical and laboratory parameters (fever, hepatosplenomegaly, bicytopenia, hyperferritinemia, hypertriglyceridemia). He had no unusual history of earlier infections or a family history of hemophagocytic syndrome or immune defects. Intravenous immunoglobulin was administered to prevent exacerbation of the suspected incipient hemophagocytic syndrome. Clarithromycin, a macrolide with immunomodulatory effect, was included in the antibiotic regimen of the progressive pneumonia, followed by rapid amelioration and remission of clinical and laboratory findings. Causal links between treatment and clinical improvement are discussed and a brief review of the recent literature is included. PMID:14631618

Seidel, Markus G; Kastner, Ulrike; Minkov, Milen; Gadner, Helmut

2003-09-01

235

CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation.  

PubMed

Macrophages play pivotal roles in development, homeostasis, tissue repair and immunity. Macrophage proliferation is promoted by macrophage colony-stimulating factor (M-CSF)-induced Akt signaling; yet, how this process is terminated remains unclear. Here, we identify casein kinase 2-interacting protein-1 (CKIP-1) as a novel inhibitor of macrophage proliferation. In resting macrophages, CKIP-1 was phosphorylated at Serine 342 by constitutively active GSK3?, the downstream target of Akt. This phosphorylation triggers the polyubiquitination and proteasomal degradation of CKIP-1. Upon M-CSF stimulation, Akt is activated by CSF-1R-PI3K and then inactivates GSK3?, leading to the stabilization of CKIP-1 and ?-catenin proteins. ?-catenin promotes the expression of proliferation genes including cyclin D and c-Myc. CKIP-1 interacts with TRAF6, a ubiquitin ligase required for K63-linked ubiquitination and plasma membrane recruitment of Akt, and terminates TRAF6-mediated Akt activation. By this means, CKIP-1 inhibits macrophage proliferation specifically at the late stage after M-CSF stimulation. Furthermore, CKIP-1 deficiency results in increased proliferation and decreased apoptosis of macrophages in vitro and CKIP-1(-/-) mice spontaneously develop a macrophage-dominated splenomegaly and myeloproliferation. Together, these data demonstrate that CKIP-1 plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated Akt activation. PMID:24777252

Zhang, Luo; Wang, Yiwu; Xiao, Fengjun; Wang, Shaoxia; Xing, Guichun; Li, Yang; Yin, Xiushan; Lu, Kefeng; Wei, Rongfei; Fan, Jiao; Chen, Yuhan; Li, Tao; Xie, Ping; Yuan, Lin; Song, Lei; Ma, Lanzhi; Ding, Lujing; He, Fuchu; Zhang, Lingqiang

2014-06-01

236

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

237

IL-16 promotes T. whipplei replication by inhibiting phagosome conversion and modulating macrophage activation.  

PubMed

The replication of Tropheryma whipplei (the agent of Whipple's disease) within human macrophages is associated with the expression of IL-16, a cytokine known for its chemotactic and inflammatory properties. In this study, we asked whether IL-16 acts on T. whipplei replication by interfering with the endocytic pathway. We observed that in macrophages, T. whipplei was located within late phagosomes that were unable to fuse with lysosomes; in monocytes, T. whipplei was eliminated in phagolysosomes. Moreover, adding IL-16 to monocytes induced bacterial replication and inhibited phagolysosome formation. On the other hand, blocking IL-16 activity, either with anti-IL-16 antibodies in human macrophages or by using murine IL-16(-/-) bone marrow-derived macrophages, inhibited T. whipplei replication and rescued phagolysosome biogenesis. Furthermore, we propose that IL-16-mediated interference with the endocytic pathway is likely related to macrophage activation. First, IFN? induced T. whipplei elimination and phagolysosome formation and inhibited IL-16 production by macrophages. Second, the full transcriptional response of murine macrophages to T. whipplei showed that T. whipplei specifically modulated the expression of 231 probes in IL-16(-/-) macrophages. Gene Ontology analysis revealed that 10 of 13 over-represented terms were linked to immune responses, including proinflammatory transcriptional factors of the NF-?B family. Our results demonstrated a previously unreported function for IL-16 in promoting bacterial replication through inhibited phagolysosome biogenesis and modulated macrophage activation program. PMID:21042409

Ghigo, Eric; Barry, Abdoulaye Oury; Pretat, Lionel; Al Moussawi, Khatoun; Desnues, Benoît; Capo, Christian; Kornfeld, Hardy; Mege, Jean-Louis

2010-01-01

238

Host defenses in experimental scrub typhus: role of normal and activated macrophages.  

PubMed

Resident peritoneal macrophage from BALB/c mice were infected in vitro with Rickettsia tsutsugamushi strain Gilliam, and rickettsial growth was estimated by microscopic examination of Giemsa-stained cells. Both number of infected macrophage per culture and number of intracellular rickettsiae per cell increased with time during culture. Treatment of rickettsiae with immune serum before infection macrophage cultures reduced the number of infected macrophage by 50%. Macrophage treated in vitro with lymphokines were able to suppress rickettsial growth in the absence of detectable antibody and exhibited a 75% reduction in infection compared with normal macrophage. We also obtained activated macrophage from immune mice and found that they were refractory to in vitro rickettsial infection. Macrophage populations activated in vitro or in vivo contained a small percentage of cells which supported unrestrained growth of rickettsiae. These data suggest that an early immunological event in experimental scrub typhus infection may be the development of activated macrophage capable of suppressing rickettsial proliferation before the appearance of circulating antibody. PMID:121116

Nacy, C A; Osterman, J V

1979-11-01

239

Host defenses in experimental scrub typhus: role of normal and activated macrophages.  

PubMed Central

Resident peritoneal macrophage from BALB/c mice were infected in vitro with Rickettsia tsutsugamushi strain Gilliam, and rickettsial growth was estimated by microscopic examination of Giemsa-stained cells. Both number of infected macrophage per culture and number of intracellular rickettsiae per cell increased with time during culture. Treatment of rickettsiae with immune serum before infection macrophage cultures reduced the number of infected macrophage by 50%. Macrophage treated in vitro with lymphokines were able to suppress rickettsial growth in the absence of detectable antibody and exhibited a 75% reduction in infection compared with normal macrophage. We also obtained activated macrophage from immune mice and found that they were refractory to in vitro rickettsial infection. Macrophage populations activated in vitro or in vivo contained a small percentage of cells which supported unrestrained growth of rickettsiae. These data suggest that an early immunological event in experimental scrub typhus infection may be the development of activated macrophage capable of suppressing rickettsial proliferation before the appearance of circulating antibody. Images

Nacy, C A; Osterman, J V

1979-01-01

240

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.

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

2013-01-01

241

Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility  

PubMed Central

Crescentic glomerulonephritis is an important cause of human kidney failure for which the underlying molecular basis is largely unknown. In previous studies, we mapped several susceptibility loci, Crgn1–Crgn7, for crescentic glomerulonephritis in the Wistar Kyoto (WKY) rat1. Here we show by combined congenic, linkage and microarray studies that the activator protein-1 (AP-1) transcription factor JunD is a major determinant of macrophage activity and is associated with glomerulonephritis susceptibility. Introgression of Crgn2 from the nonsusceptible Lewis strain onto the WKY background leads to significant reductions in crescent formation, macrophage infiltration, Fc receptor–mediated macrophage activation and cytokine production. Haplotype analysis restricted the Crgn2 linkage interval to a 430-kb interval containing Jund, which is markedly overexpressed in WKY macrophages and glomeruli. Jund knockdown in rat and human primary macrophages led to significantly reduced macrophage activity and cytokine secretion, indicating conservation of JunD function in macrophage activation in rats and humans and suggesting in vivo inhibition of Jund as a possible new therapeutic strategy for diseases characterized by inflammation and macrophage activation.

Behmoaras, Jacques; Bhangal, Gurjeet; Smith, Jennifer; McDonald, Kylie; Mutch, Brenda; Lai, Ping Chin; Domin, Jan; Game, Laurence; Salama, Alan; Foxwell, Brian M; Pusey, Charles D; Cook, H Terence; Aitman, Timothy J

2009-01-01

242

Regulation of murine macrophage Ia antigen expression by a lymphokine with immune interferon activity  

PubMed Central

A culture supernatant of concanavalin A-activated spleen cells (Con A supernatant) induced murine macrophages to express Ia antigens in vitro. Biochemical characterization of the Con A supernatant indicated that the macrophage Ia antigen regulatory activity shares molecular weight, pI, and hydrophobic and affinity characteristics with immune interferon (IFN-gamma). Antiserum to mouse IFN-gamma neutralized both the macrophage Ia antigen regulatory and IFN-gamma bioactivities of the Con A supernatant. Furthermore, both partially purified murine IFN- gamma (10(7) U/mg protein sp act) and IFN-containing culture supernatants of the murine BFS T cell line-induced macrophage Ia antigen expression in vitro. Culture supernatants containing colony- stimulating factor, interleukin 1, interleukin 2, macrophage migration inhibitory factor, and a macrophage-activating activity that were distinct from IFN-gamma did not induce macrophage Ia antigen expression. Taken together, the data indicate that the in vitro expression of Ia antigens on macrophages is regulated by an activity that has the characteristics of interferon.

1982-01-01

243

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.

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

2013-01-01

244

Combination of alphavirus replicon particle-based vaccination with immunomodulatory antibodies: therapeutic activity in the b16 melanoma mouse model and immune correlates.  

PubMed

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-CTL antigen-4 (CTLA-4) or agonist anti-glucocorticoid-induced TNF family-related gene (GITR) immunomodulatory monoclonal antibodies (mAb). In the challenging therapeutic setting, VRP-TRP2 plus anti-GITR or anti-CTLA-4 mAb induced complete tumor regression in 90% and 50% of mice, respectively. These mAbs had similar adjuvant effects in priming an adaptive immune response against the vaccine-encoded antigen, augmenting, respectively, approximately 4- and 2-fold the TRP2-specific CD8(+) T-cell response and circulating Abs, compared with 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 intratumor CD4(+)Foxp3(-) T cells expressing the negative costimulatory 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 anticancer vaccines can provide therapeutic antitumor 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. Cancer Immunol Res; 2(5); 448-58. ©2014 AACR. PMID:24795357

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

2014-05-01

245

Regulation of IFN and TLR Signaling During Macrophage Activation by Opposing Feedforward and Feedback Inhibition Mechanisms  

PubMed Central

Summary Activated macrophages and their inflammatory products play a key role in innate immunity and in pathogenesis of autoimmune/inflammatory diseases. Macrophage activation needs to be tightly regulated to rapidly mount responses to infectious challenges but to avoid toxicity associated with excessive activation. Rapid and potent macrophage activation is driven by cytokine-mediated feedforward loops, while excessive activation is prevented by feedback inhibition. Here we discuss feedforward mechanisms that augment macrophage responses to Toll-like receptor (TLR) ligands and cytokines that are mediated by signal transducer and activator of transcription 1 (STAT1) and induced by interferon-? (IFN-?). IFN-? also drives full macrophage activation by inactivating feedback inhibitory mechanisms, such as those mediated by IL-10 and STAT3. Priming of macrophages with IFN-? reprograms cellular responses to other cytokines, such as type I IFNs and IL-10, with a shift toward pro-inflammatory STAT1-dominated responses. Similar but partially distinct priming effects are induced by other cytokines that activate STAT1, including type I IFNs and interleukin-27. We propose a model whereby opposing feedforward and feedback inhibition loops crossregulate each other to fine tune macrophage activation. In addition, we discuss how dysregulation of the balance between feedforward and feedback inhibitory mechanisms can contribute to the pathogenesis of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus.

Hu, Xiaoyu; Chakravarty, Soumya D.; Ivashkiv, Lionel B.

2008-01-01

246

An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile.  

PubMed

Cardiac tissue macrophages (cTMs) are a previously uncharacterised cell type that we have identified and characterise here as an abundant GFP(+) population within the adult Cx(3)cr1(GFP/+) knock-in mouse heart. They comprise the predominant myeloid cell population in the myocardium, and are found throughout myocardial interstitial spaces interacting directly with capillary endothelial cells and cardiomyocytes. Flow cytometry-based immunophenotyping shows that cTMs exhibit canonical macrophage markers. Gene expression analysis shows that cTMs (CD45(+)CD11b(+)GFP(+)) are distinct from mononuclear CD45(+)CD11b(+)GFP(+) cells sorted from the spleen and brain of adult Cx(3)cr1(GFP/+) mice. Gene expression profiling reveals that cTMs closely resemble alternatively-activated anti-inflammatory M2 macrophages, expressing a number of M2 markers, including Mrc1, CD163, and Lyve-1. While cTMs perform normal tissue macrophage homeostatic functions, they also exhibit a distinct phenotype, involving secretion of salutary factors (including IGF-1) and immune modulation. In summary, the characterisation of cTMs at the cellular and molecular level defines a potentially important role for these cells in cardiac homeostasis. PMID:22590615

Pinto, Alexander R; Paolicelli, Rosa; Salimova, Ekaterina; Gospocic, Janko; Slonimsky, Esfir; Bilbao-Cortes, Daniel; Godwin, James W; Rosenthal, Nadia A

2012-01-01

247

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

248

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

249

Activation of macrophages by silicones: phenotype and production of oxidant metabolites  

Microsoft Academic Search

BACKGROUND: The effect of silicones on the immune function is not fully characterized. In clinical and experimental studies, immune alterations associated with silicone gel seem to be related to macrophage activation. In this work we examined in vivo, phenotypic and functional changes on peritoneal macrophages early (24 h or 48 h) and late (45 days) after the intraperitoneal (i.p.) injection

Pablo Iribarren; Silvia G Correa; Natalia Sodero; Clelia M Riera

2002-01-01

250

Alginates from wound dressings activate human macrophages to secrete tumour necrosis factor- ?  

Microsoft Academic Search

Alginates are used to manufacture a number of wound dressings. Clinical observations indicate that they may initiate or accelerate healing of chronic wounds after treatment of underlying pathology. Wound granulation tissue contains large numbers of macrophages and they are thought to regulate the healing process. As purified alginates have been demonstrated to activate macrophages this study was initiated to determine

A Thomas; K. G Harding; K Moore

2000-01-01

251

Regulation of Macrophage Activation and Human Immunodeficiency Virus Production by InvasiveSalmonellaStrains  

Microsoft Academic Search

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 mech- anisms 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

STEVEN B. MIZEL; LOUIS S. KUCERA; STEPHEN H. RICHARDSON; FEDERICA CIACCI; ANDNATHAN P. IYER

252

Virulizin, a novel immunotherapy agent, activates NK cells through induction of IL12 expression in macrophages  

Microsoft Academic Search

Virulizin, a novel biological response modifier, has demonstrated significant antitumor efficacy in a variety of human tumor xenograft models including melanoma, pancreatic cancer, breast cancer, ovarian cancer and prostate cancer. The significant role of macrophages and NK (Natural killer) cells was implicated in the antitumor mechanism of Virulizin where expansion as well as increased activity of macrophages and NK cells

Hui Li; Ming Y. Cao; Yoon Lee; Vivian Lee; Ningping Feng; Tania Benatar; Hongnan Jin; Ming Wang; Sandy Der; Jim A. Wright; Aiping H. Young

2005-01-01

253

Platelet Phagocytosis and Processing of Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis  

Microsoft Academic Search

In human occluded saphenous vein grafts, we previously demonstrated cytotoxic foam cells, presumably derived from macrophages engulfing platelets. In the present study, we investigated whether platelet phagocytosis occurs in human atherosclerotic plaques, whether this activates macrophages, and whether the platelet constituent, amyloid precursor protein (APP), was involved. Immunohistochemistry documented the presence of APP, -amyloid peptide (A, cleaved from APP), and

Guido R. Y. De; Dieter Meyer; Susan Cooper; Michiel W. M. Knaapen; Dominique M. Jans; Wim Martinet; Arnold G. Herman; Hidde Bult; Mark M. Kockx

254

Cooperation between Reactive Oxygen and Nitrogen Intermediates in Killing of Rhodococcus equi by Activated Macrophages  

Microsoft Academic Search

Rhodococcus equi is a facultative intracellular bacterium of macrophages which can infect immunocompro- mised humans and young horses. In the present study, we examine the mechanism of host defense against R. equi by using a murine model. We show that bacterial killing is dependent upon the presence of gamma interferon (IFN-g), which activates macrophages to produce reactive nitrogen and oxygen

PATRICIA A. DARRAH; MARY K. HONDALUS; QUIPING CHEN; HARRY ISCHIROPOULOS; DAVID M. MOSSER

2000-01-01

255

Toll-Like Receptor 9Dependent Macrophage Activation by Entamoeba histolytica DNA  

Microsoft Academic Search

Activation of the innate immune system by bacterial DNA and DNA of other invertebrates represents a pathogen recognition mechanism. In this study we investigated macrophage responses to DNA from the intestinal protozoan parasite Entamoeba histolytica. E. histolytica genomic DNA was purified from log-phase trophozoites and tested with the mouse macrophage cell line RAW 264.7. RAW cells treated with E. histolytica

Catherine P. A. Ivory; Michael Prystajecky; Christian Jobin; Kris Chadee

2008-01-01

256

Immunomodulatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) at the clinically available doses.  

PubMed

Non-steroidal anti-inflammatory drugs (NSAIDs) with cyclooxygenase (COX) inhibitory activity are commonly used in various inflammatory diseases. In this study, to examine the immunomodulatory effects of well known NSAIDs at clinically available doses, macrophage- and T cell-mediated immune responses such as tumor necrosis factor (TNF)-alpha release and nitric oxide (NO) production, cell-cell adhesion, phagocytic uptake and lymphocyte proliferation were investigated. NSAIDs tested significantly enhanced TNF-alpha release from lipopolysaccharide (LPS)-activated RAW264.7 cells at certain concentrations (fenoprofen, indomethacin, piroxicam, aceclofenac, diclofenac and sulindac) or in a dose-dependent manner (aspirin and phenylbutazone). Of NSAIDs, phenylbutazone and aspirin most potently attenuated NO production, although sulindac was the only compound with cytoprotective activity against LPS-induced cytotoxicity. Most NSAIDs used displayed weak or no modulatory effects on phagocytic uptake and CD29- or CD43-mediated cell-cell adhesion. Interestingly, however, phenylbutazone itself triggered cell-cell clustering under normal culture conditions and enhanced the phagocytic activity. Aspirin and phenylbutazone also dose-dependently attenuated CD4+ T cell proliferation stimulated by concanavalin A (Con A) and CD8+ CTLL-2 cell proliferation induced by interleukin (IL)-2. Sulindac only blocked CTLL-2 cell proliferation. These results suggest that NSAIDs may differentially exert immunomodulatory effects on activated macrophages and lymphocytes, and some of the effects may enforce NSAID's therapeutic effect against inflammatory symptoms. PMID:17328244

Cho, Jae Youl

2007-01-01

257

Antitumor and Immunomodulatory Effects of Polysaccharides from Broken-Spore of Ganoderma lucidum  

PubMed Central

The antitumor and immunomodulatory activity of broken-spore of Ganoderma lucidum polysaccharides (Gl-BSP) were investigated in vivo and in vitro. It was showed that Gl-BSP (50, 100, and 200?mg?kg?1) exhibited antitumor effect against Sarcoma 180 (S180) in BALB/c mice. The Gl-BSP was not cytotoxicity in S180 cells and PG cells (human lung carcinoma cell) in vitro. However, serum from Gl-BSP-treated S180-bearing mice significantly inhibited S180 and PG cells proliferation in vitro. Moreover, Gl-BSP promoted the splenic lymphocyte proliferation induced by Con A or LPS, enhanced nature killer cell (NK cell) cytotoxic activity, augmented the percentage of neutral red phagocytosis by macrophages, and increased the percentage of the CD4+ or CD8+ subset in S180-bearing mice. The serum level of IFN-?, TNF-?, and nitric oxide was increased by Gl-BSP. Gl-BSP also showed immunomodulatory activities in tumor-bearing mice. Furthermore, neutralization with anti-TNF-? and/or anti-IFN-? significantly diminished growth inhibition induced by Gl-BSP-treated serum of S180-bearing mice in S180 or PG cells. These observations suggest that the antitumor activity of Gl-BSP may be mainly related to the activation of the immune response of the host organism by the stimulation of NK cells, T cells, and macrophages.

Wang, Peng-Yun; Zhu, Xiao-Ling; Lin, Zhi-Bin

2012-01-01

258

Guinea Pig Neutrophils Infected with Mycobacterium tuberculosis Produce Cytokines Which Activate Alveolar Macrophages in Noncontact Cultures?  

PubMed Central

The early influx of neutrophils to the site of infection may be an important step in host resistance against Mycobacterium tuberculosis. In this study, we investigated the effect of M. tuberculosis infection on the ability of guinea pig neutrophils to produce interleukin-8 (IL-8; CXCL8) and tumor necrosis factor alpha (TNF-?) and to activate alveolar macrophages. Neutrophils and alveolar macrophages were isolated from naïve guinea pigs, cultured together or alone, and infected with virulent M. tuberculosis for 3, 12, and 24 h. IL-8 protein production in cocultures, as measured by using an enzyme-linked immunosorbent assay, was found to be additive at 24 h and significantly greater in M. tuberculosis-infected cocultures than in uninfected cocultures and in cultures of the infected neutrophils or macrophages alone. The IL-8 mRNA levels, determined by real-time reverse transcription-PCR, were elevated at 24 h in infected cocultures and infected cells cultured alone. In order to elucidate the contributions of neutrophils and their soluble mediators to the activation of alveolar macrophages, neutrophils and alveolar macrophages were cultured in a contact-independent manner by using a Transwell insert system. Neutrophils were infected with virulent M. tuberculosis in the upper wells, and alveolar macrophages were cultured in the lower wells. The release of hydrogen peroxide from alveolar macrophages exposed to soluble products from infected neutrophils was significantly increased compared to that from unexposed alveolar macrophages. Significant up-regulation of IL-1? and TNF-? mRNA levels in alveolar macrophages was observed at 24 and 30 h, respectively, compared to those in cells not exposed to soluble neutrophil products. Treatment with anti-guinea pig TNF-? polyclonal antibody completely abolished the response of alveolar macrophages to neutrophil products. This finding suggests that TNF-? produced by infected neutrophils may be involved in the activation of alveolar macrophages and hence may contribute to the containment of M. tuberculosis infection during the early period of infection.

Sawant, Kirti V.; McMurray, David N.

2007-01-01

259

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.

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

2006-01-01

260

Macrophage activation by factors released from acetaminophen-injured hepatocytes: Potential role of HMGB1  

SciTech Connect

Toxic doses of acetaminophen (AA) cause hepatocellular necrosis. Evidence suggests that activated macrophages contribute to the pathogenic process; however, the factors that activate these cells are unknown. In these studies, we assessed the role of mediators released from AA-injured hepatocytes in macrophage activation. Treatment of macrophages with conditioned medium (CM) collected 24 hr after treatment of mouse hepatocytes with 5 mM AA (CM-AA) resulted in increased production of reactive oxygen species (ROS). Macrophage expression of heme oxygenase-1 (HO-1) and catalase mRNA was also upregulated by CM-AA, as well as cyclooxygenase (COX)-2 and 12/15-lipoxygenase (LOX). CM-AA also upregulated expression of the proinflammatory chemokines, MIP-1{alpha} and MIP-2. The effects of CM-AA on expression of COX-2, MIP-1{alpha} and MIP-2 were inhibited by blockade of p44/42 MAP kinase, suggesting a biochemical mechanism mediating macrophage activation. Hepatocytes injured by AA were found to release HMGB1, a potent macrophage activator. This was inhibited by pretreatment of hepatocytes with ethyl pyruvate (EP), which blocks HMGB1 release. EP also blocked CM-AA induced ROS production and antioxidant expression, and reduced expression of COX-2, but not MIP-1{alpha} or MIP-2. These findings suggest that HMGB1 released by AA-injured hepatocytes contributes to macrophage activation. This is supported by our observation that expression of the HMGB1 receptor RAGE is upregulated in macrophages in response to CM-AA. These data indicate that AA-injured hepatocytes contribute to the inflammatory environment in the liver through the release of mediators such as HMGB1. Blocking HMGB1/RAGE may be a useful approach to limiting classical macrophage activation and AA-induced hepatotoxicity. - Research Highlights: > These studies analyze macrophage activation by mediators released from acetaminophen-damaged hepatocytes. > Factors released from acetaminophen-injured hepatocytes induce macrophage ROS production and expression of COX-2, chemokines, and RAGE. > Hepatocyte-mediated macrophage activation involves p44/42 MAP kinase signaling. > HMGB1 is released from acetaminophen-injured hepatocytes and contributes to macrophage activation.

Dragomir, Ana-Cristina [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 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)

2011-06-15

261

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

262

Superinduction of interleukin 8 mRNA in activated monocyte derived macrophages from rheumatoid arthritis patients  

PubMed Central

OBJECTIVE—Synovial inflammation in patients with rheumatoid arthritis (RA) is characterised by the presence of large numbers of highly activated monocytes and macrophages. The importance of these cells in the aethiopathogenesis and prognosis of RA is increasingly recognised. The object of this report is to determine whether monocytes and monocyte derived macrophages of RA patients produce increased cytokine mRNA levels.?METHODS—Monocyte derived macrophages from RA patients and healthy controls were cultured either in the absence or presence of lipopolysaccharide. The expression levels of the mRNAs encoding GAPDH, interleukin 1? (IL1?), IL8, and ?2 macroglobulin in these cells were analysed by reverse transcriptase-polymerase chain reaction (RT-PCR).?RESULTS—Activated monocyte derived macrophages from RA patients produce significantly higher IL8 mRNA levels than activated macrophages from healthy controls. By contrast, resting RA and control macrophages produce similar levels of IL8 mRNA. Culturing of activated macrophages in the presence of RA or control sera has no effect on the expression levels of IL8 mRNA. No significant differences between RA and control macrophages were observed in the expression levels of IL1? and ?2 macroglobulin mRNAs.?CONCLUSION—These data indicate that the increased IL8 mRNA production capacity of RA macrophages upon activation is an intrinsic property of these cells, and is not attributable to factors present in the circulation. Based on these observations, it is postulated that this innate hyper-responsiveness of RA macrophages contributes to the high IL8 levels present in the synovial fluid of rheumatoid joints, and is implicated in the chemotactic gradient leading to the homing of leucocytes to the joints.??

Rodenburg, R.; van den Hoogen, F. H J; Barrera, P.; van Venrooij, W. J; van de Putte, L. B A

1999-01-01

263

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.

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

264

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

PubMed

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; Nagy, Gergely; 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

2014-07-15

265

Potentiated macrophage activation by acid sensing under low adiponectin levels.  

PubMed

Adiponectin can protect against inflammation; one of the mechanisms involves direct, inhibition of macrophages (M?). We postulated that adiponectin anti-sense transgenic (AsTg) mice raised in our laboratory are prone to inflammation because of systemic low adiponectin levels. The writhing response to acetic acid was utilized as an in vivo inflammatory model, and using Ca(2)(+), response to the acid was exploited in vitro to evaluate the function of resident peritoneal M?. The in vivo response to the acid was increased and the Ca(2)(+) response of M? was enhanced in AsTg mice, compared with those in wild type (WT) mice. In parallel with these enhanced responses, M? from AsTg mice augmented TNF-? and IL-6 mRNA expression. We further analyzed the enhancement in activity of M? from AsTg mice by acid sensing using specific inhibitors, amiloride for acid-sensing ion channels (ASICs) and KB-R7943 for Na(+)/Ca(2)(+) exchangers (NCXs). Our results indicated that in AsTg mice, the Ca(2)(+) response to the acid was facilitated in M? by a low threshold of ASIC1 and NCX1 molecules and the activity of these channel was possibly regulated by adiponectin. PMID:24084100

Negoro, Takaharu; Kin, Masaoki; Takuma, Akitoshi; Saito, Kiyomi; Shimizu, Shunichi; Nakano, Yasuko

2014-02-01

266

Surfactant therapy of newborn rabbits impairs lung macrophage bactericidal activity.  

PubMed

Because in vitro studies indicate that pulmonary alveolar macrophages (PAM's) filled with phospholipid vesicles have depressed microbicidal capacity, we tested the intrapulmonary bactericidal activity of newborn PAM's after surfactant treatment. Term newborn rabbits received intratracheally either homologous surfactant or one of two artificial phospholipid vesicle preparations followed by pulmonary aerosol infection with group B streptococci (GBS). Four hours after lung infection, phagocytic killing of GBS was reduced by 70-90% in animals treated with the homologous and one of the artificial surfactants compared with untreated animals or animals that received intrapulmonary injections of the surfactant vehicle (P less than 0.02). The other artificial phospholipid preparation decreased intrapulmonary inactivation of GBS by 30-40% compared with the controls. The phospholipid vesicles in the three preparations were avidly ingested and processed by newborn PAM's. The diminished in vivo killing of GBS was not attributed to decreased viability or phagocytic behavior of the PAM's toward GBS. The bactericidal defect that was evident in the newborn PAM's appeared related to the uptake of large phospholipid vesicles in the preparations rather than to the phospholipid content of the surfactants themselves. When in vitro conditions that stimulated the alveolar environment were used, the natural surfactant preparation promoted GBS proliferation, whereas the artificial preparations did not. Our findings indicate that surfactant administration reduces the bactericidal activity of neonatal PAM's. We conclude that additional investigations are needed to ascertain the effect of surfactant replacement therapy on lost defenses of the lung. PMID:3042738

Sherman, M P; D'Ambola, J B; Aeberhard, E E; Barrett, C T

1988-07-01

267

Immunomodulatory Activity and Protective Effects of Polysaccharide from Eupatorium adenophorum Leaf Extract on Highly Pathogenic H5N1 Influenza Infection.  

PubMed

The development of novel broad-spectrum, antiviral agents against H5N1 infection is urgently needed. In this study, we evaluated the immunomodulatory activities and protective effect of Eupatorium adenophorum polysaccharide (EAP) against the highly pathogenic H5N1 subtype influenza virus. EAP treatment significantly increased the production of IL-6, TNF- ? , and IFN- ? both in vivo and in vitro as measured by qPCR and ELISA. In a mouse infection model, intranasal administration of EAP at a dose of 25?mg/kg body weight prior to H5N1 viral challenge efficiently inhibited viral replication, decreased lung lesions, and increased survival rate. We further evaluated the innate immune recognition of EAP, as this process is regulated primarily Dectin-1 and mannose receptor (MR). These results indicate that EAP may have immunomodulatory properties and a potential prophylactic effect against H5N1 influenza infection. Our investigation suggests an alternative strategy for the development of novel antiinfluenza agents and benefits of E. adenophorum products. PMID:24159339

Jin, Yi; Zhang, Yuewei; Wan, Chunyan; Wang, Hongjun; Hou, Lingyu; Chang, Jianyu; Fan, Kai; Xie, Xiangming

2013-01-01

268

Aspartic protease and caspase 3\\/7 activation are central for macrophage apoptosis following infection with Escherichia coli  

Microsoft Academic Search

Macrophages are vital for host defense against microbial infections. We have previously shown that infection of macrophages with a non- pathogenic strain of Escherichia coli induces apo- ptosis rapidly. Here, we demonstrate that infection of macrophages results in the activation of caspases prior to the induction of the intrinsic apoptosis pathway. Caspases 9 and 3 are activated prior to the

Lee Albee; Bo Shi; Harris Perlman

2006-01-01

269

Zinc Finger Transcription Factor Egr1 Activates Flt1 Gene Expression in THP1 Cells on Induction for Macrophage Differentiation  

Microsoft Academic Search

Activation of macrophages is a hallmark of atherosclerosis. Stimulation of human monocytic leukemia THP-1 cells with phorbol 12-myristate 13-acetate (PMA) is known to induce a variety of genes whose function is relevant to activated macrophages. Flt-1, a receptor tyrosine kinase for vascular endothelial growth factor, is expressed in macrophages as well as in endothelial cells and mediates the biological response

Nobuhiro Akuzawa; Masahiko Kurabayashi; Yoshio Ohyama; Masashi Arai; Ryozo Nagai

2010-01-01

270

Effect of Glucocorticoids and Catecholamiens on Macrophage Antimicrobial Activity.  

National Technical Information Service (NTIS)

The effects of stress hormones on antibacterial and antiviral functions of resident peritoneal macrophages (MO) were determined. All studies were performed using a serum-free, chemically defined, medium, which eliminates complications which may arise as t...

P. S. Morahan W. L. Dempsey

1989-01-01

271

Biochemical and functional characterization of three activated macrophage populations  

PubMed Central

We generated three populations of macrophages (M?) in vitro and characterized each. Classically activated M? (Ca-M?) were primed with IFN-? and stimulated with LPS. Type II-activated M? (M?-II) were similarly primed but stimulated with LPS plus immune complexes. Alternatively activated M? (AA-M?) were primed overnight with IL-4. Here, we present a side-by-side comparison of the three cell types. We focus primarily on differences between M?-II and AA-M?, as both have been classified as M2 M?, distinct from Ca-M?. We show that M?-II more closely resemble Ca-M? than they are to AA-M?. M?-II and Ca-M?, but not AA-M?, produce high levels of NO and have low arginase activity. AA-M? express FIZZ1, whereas neither M?-II nor Ca-M? do. M?-II and Ca-M? express relatively high levels of CD86, whereas AA-M? are virtually devoid of this costimulatory molecule. Ca-M? and M?-II are efficient APC, whereas AA-M? fail to stimulate efficient T cell proliferation. The differences between Ca-M? and M?-II are more subtle. Ca-M? produce IL-12 and give rise to Th1 cells, whereas M?-II produce high levels of IL-10 and thus, give rise to Th2 cells secreting IL-4 and IL-10. M?-II express two markers that may be used to identify them in tissue. These are sphingosine kinase-1 and LIGHT (TNF superfamily 14). Thus, Ca-M?, M-II, and AA-M? represent three populations of cells with different biological functions. J. Leukoc. Biol. 80: 1298–1307; 2006.

Edwards, Justin P.; Zhang, Xia; Frauwirth, Kenneth A.; Mosser, David M.

2008-01-01

272

Chemotactic activity of culture supernatants of free and encapsulated pancreatic rat islets towards peritoneal macrophages.  

PubMed

Longterm efficiency of encapsulated pancreatic islet transplantation is limited by macrophagic reaction at the surface of biocompatible membrane. The aim of this work was to investigate the influence of soluble factors released by free and encapsulated islets on macrophage chemotaxis. The culture mediums conditioned for 6 days by free and encapsulated rat islets were incubated with peritoneal murine, rat allo and syngenic macrophages to study their migration. Culture supernatants of rat fibroblasts and acinar cells, glucose-stimulated free rat islets and supernatants of free rat islets treated by heat and proteinase K were also tested for their chemotactic activity. Islets encapsulation decreased the chemotactic activity of culture medium conditioned for 6 days by free rat islets on murine (1.66 +/- 0.20 vs. 3.10 +/- 0.23; p < 0.001, n = 5) and rat allogenic macrophages (1.63 +/- 0.21 vs. 4.70 +/- 0.36; p < 0.001, n = 9). There was no migration of rat macrophages towards syngenic islets. Fibroblasts exhibited a very strong chemotactic effect as compared to acinar cells. Insulin was not involved in macrophage migration. Proteinase K treatment of culture supernatant of free rat islets totally inhibited the chemotactic activity. After heating at 56 degrees C and 100 degrees C, this activity was reduced to 41 +/- 7% and 32 +/- 5% of the initial activity, respectively. In conclusion, pancreatic islet stimulated macrophage migration by release of immunological specific proteins partly retained by macroencapsulation. PMID:10494869

Karsten, V; Lencioni, C; Tritschler, S; Marchetti, P; Belcourt, A; Navalesi, R; Alexandre, E; Poindron, P; Pinget, M; Kessler, L

1999-08-01

273

Macrophages as a source of tumoricidal activity (tumor-necrotizing factor).  

PubMed Central

Macrophage-enriched peritoneal exudate cells from mice infected with Mycobacterium bovis BCG, macrophage-like tumor cells (PU 5-1.8), and peritoneal macrophages propagated in vitro with macrophage growth factor released tumoricidal activity into the culture medium within 2 to 3 h after stimulation with nanogram quantities of bacterial lipopolysaccharide. The cytotoxic activities from each of the macrophage culture supernatants eluted from diethylaminoethyl-Sephacel columns at a sodium chloride concentration of 200 mM exhibited a molecular weight of 50,000 to 60,000 as estimated by gel filtration, were stable at 56 degrees C for 30 min, and were active at a pH range of 6 to 10. A rabbit antiserum directed against serum-derived cytotoxic activity (tumor-necrotizing factor) from BCG-infected and lipopolysaccharide-challenged mice inhibited all of the cytotoxic activities generated in vitro. This suggests that the macrophage-derived cytotoxins are identical with serum-derived cytotoxic factor, which further implies that the macrophage is the cellular source of tumor-necrotizing factor.

Mannel, D N; Moore, R N; Mergenhagen, S E

1980-01-01

274

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

275

Accelerated cerebral ischemic injury by activated macrophages\\/microglia after lipopolysaccharide microinjection into rat corpus callosum  

Microsoft Academic Search

In cerebral ischemic insults, activated inflammatory cells such as microglia and macrophages may be implicated in the pattern and degree of ischemic injury by producing various bioactive mediators. In the present study, we provide the evidence that activated microglia\\/macrophages accelerate cerebral ischemic injury by overexpression of inducible nitric oxide synthase (iNOS). To activate microglia\\/macro- phages, a potent inflammation inducer lipopolysaccharide

Jae-Chul Lee; Geum-Sil Cho; Hye Jin Kim; Ji-Hye Lim; Yu-Kyoung Oh; Wonwoo Nam; Jang-Hyun Chung; Won-Ki Kim

2005-01-01

276

Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages  

PubMed Central

Tuberculosis remains one of the major infectious causes of morbidity and mortality in the world, yet the mechanisms by which macrophages defend against Mycobacterium tuberculosis have remained obscure. Results from this study show that murine macrophages, activated by interferon gamma, and lipopolysaccharide or tumor necrosis factor alpha, both growth inhibit and kill M. tuberculosis. This antimycobacterial effect, demonstrable both in murine macrophage cell lines and in peritoneal macrophages of BALB/c mice, is independent of the macrophage capacity to generate reactive oxygen intermediates (ROI). Both the ROI-deficient murine macrophage cell line D9, and its ROI-generating, parental line J774.16, expressed comparable antimycobacterial activity upon activation. In addition, the oxygen radical scavengers superoxide dismutase (SOD), catalase, mannitol, and diazabicyclooctane had no effect on the antimycobacterial activity of macrophages. These findings, together with the results showing the relative resistance of M. tuberculosis to enzymatically generated H2O2, suggest that ROI are unlikely to be significantly involved in killing M. tuberculosis. In contrast, the antimycobacterial activity of these macrophages strongly correlates with the induction of the L-arginine- dependent generation of reactive nitrogen intermediates (RNI). The effector molecule(s) that could participate in mediating this antimycobacterial function are toxic RNI, including NO, NO2, and HNO2, as demonstrated by the mycobacteriocidal effect of acidified NO2. The oxygen radical scavenger SOD adventitiously perturbs RNI production, and cannot be used to discriminate between cytocidal mechanisms involving ROI and RNI. Overall, our results provide support for the view that the L-arginine-dependent production of RNI is the principal effector mechanism in activated murine macrophages responsible for killing and growth inhibiting virulent M. tuberculosis.

1992-01-01

277

Microcystin-LR exhibits immunomodulatory role in mouse primary hepatocytes through activation of the NF-?B and MAPK signaling pathways.  

PubMed

Microcystin-leucine-arginine (MCLR) is an environmental toxin from harmful algae, which has been linked to hepatotoxicity with high risks associated with liver disease. In this study, we explored the role of MCLR in NF-?B and mitogen-activated protein kinase (MAPK) signaling pathways, which are important in regulating inflammatory and immune responses, in human hepatoma cell line HepG2 and primary mouse hepatocytes (PMHs). By in vitro cell-free and luciferase reporter systems, Western blotting with antiphospho-inhibitory protein of NF-?B (I?B?)/c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase 1/2 (ERK1/2) antibody, it was found that at noncytotoxic concentrations (? 20 nM MCLR in PMHs, 1-1000 nM in HepG2), MCLR treatment alone promoted activation of NF-?B and MAPK pathways and modulated TNF-?-induced activation of the 2 pathways in both cell models. By ELISA assay, MCLR was found to induce production of proinflammatory cytokine IL-6 in PMHs. At cytotoxic concentrations (? 50 nM MCLR in PMHs), MCLR dramatically reduced cell viability and damaged cell morphology in PMHs, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transmission electron microscopy analysis. These results suggest that MCLR below 20 nM has significant immunomodulatory activities through activation of NF-?B and MAPK signaling pathways, and PMHs are more sensitive to MCLR-induced cytotoxicity than HepG2. To our knowledge, this is the first report showing the immunomodulatory role of MCLR in hepatocytes. Our results provide a better understanding of the molecular mechanisms underlying MCLR-induced hepatotoxicity. PMID:23970801

Zhang, Jianying; Chen, Jin; Xia, Zongping

2013-11-01

278

Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences.  

PubMed

The molecular repertoire of macrophages in health and disease can provide novel biomarkers for diagnosis, prognosis, and treatment. Th2-IL-4–activated macrophages (M2) have been associated with important diseases in mice, yet no specific markers are available for their detection in human tissues. Although mouse models are widely used for macrophage research, translation to the human can be problematic and the human macrophage system remains poorly described. In the present study, we analyzed and compared the transcriptome and proteome of human and murine macrophages under resting conditions (M0) and after IL-4 activation (M2). We provide a resource for tools enabling macrophage detection in human tissues by identifying a set of 87 macrophage-related genes. Furthermore, we extend current understanding of M2 activation in different species and identify Transglutaminase 2 as a conserved M2 marker that is highly expressed by human macrophages and monocytes in the prototypic Th2 pathology asthma. PMID:23293084

Martinez, Fernando O; Helming, Laura; Milde, Ronny; Varin, Audrey; Melgert, Barbro N; Draijer, Christina; Thomas, Benjamin; Fabbri, Marco; Crawshaw, Anjali; Ho, Ling Pei; Ten Hacken, Nick H; Cobos Jiménez, Viviana; Kootstra, Neeltje A; Hamann, Jörg; Greaves, David R; Locati, Massimo; Mantovani, Alberto; Gordon, Siamon

2013-02-28

279

[Prospects for pharmacological regulation of macrophage activity by modulation of intracellular signal cascade].  

PubMed

This article is devoted to classical and alternative macrophage activation, and intracellular transmission of external signals onto genes. It presents data on postreceptor events resulting in the formation of classical or alternative properties of macrophages. The role of some molecules of intracellular signaling pathways (STAT1, NF-kappaB, IRAK, TRAF6, Jak1, Tyk2, STAT3, c-Maf, Sp1, C/EBP, CREB, STAT6, MAP-kinase, PI3-kinase, c P) in the development of proinflammatory and anti-inflammatory activities of macrophages is discussed. PMID:20017403

Bel'ski?, Iu P; Bel'skaia, N V; Danilets, M G; Trofimova, E S; Uchasova, E G; Ligacheva, A A; Agafonov, V I

2009-01-01

280

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.

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

2011-01-01

281

Gallium arsenide modulates proteolytic cathepsin activities and antigen processing by macrophages.  

PubMed

Gallium arsenide (GaAs) is a semiconductor utilized in the electronics industry. Chemical exposure of animals causes a local inflammatory reaction, but systemic immunosuppression. Mice were administered i.p. 200 mg/kg GaAs crystals or latex beads, or vehicle. Five days after exposure, splenic macrophages were defective, whereas thioglycolate-elicited peritoneal macrophages (PEC) were more efficient in processing the Ag, pigeon cytochrome c, than vehicle control macrophages. Various aspects of the MHC class II Ag-processing pathway were examined. Both macrophage populations normally presented a peptide fragment to the CD4+ T cells. Surface MHC class II expression on the PEC was up-regulated, but splenic cells had normal MHC class II expression. PEC had elevated levels of glutathione and cysteine, major physiologic reducing thiols. However, the cysteine content of splenic macrophages was diminished. Proteolytic activities of aspartyl cathepsin D, and thiol cathepsins B and L were decreased significantly in splenic macrophages. On the other hand, thiol cathepsin activities were increased selectively in PEC. Latex bead-exposed PEC were not more potent APC, and their thiol cathepsin activities were unchanged, indicating that phagocytosis and nonspecific irritation were not responsible. The phenotype of PEC directly exposed to GaAs mirrored cytokine-activated macrophages, in contrast to splenic macrophages from a distant site. Therefore, GaAs exposure differentially modulated cathepsin activities in splenic macrophages and PEC, which correlated with their Ag-processing efficiency. Perhaps such distinct alterations may contribute to the local inflammation and systemic immunotoxicity caused by chemical exposure. PMID:9725206

Lewis, T A; Hartmann, C B; McCoy, K L

1998-09-01

282

Cot/tpl2 participates in the activation of macrophages by adiponectin.  

PubMed

Whereas the main function of APN is to enhance insulin activity, it is also involved in modulating the macrophage phenotype. Here, we demonstrate that at physiological concentrations, APN activates Erk1/2 via the IKK?-p105/NF-??1-Cot/tpl2 intracellular signal transduction cassette in macrophages. In peritoneal macrophages stimulated with APN, Cot/tpl2 influences the ability to phagocytose beads. However, Cot/tpl2 did not modulate the known capacity of APN to decrease lipid content in peritoneal macrophages in response to treatment with oxLDL or acLDL. A microarray analysis of gene-expression profiles in BMDMs exposed to APN revealed that APN modulated the expression of ?3300 genes; the most significantly affected biological functions were the inflammatory and the infectious disease responses. qRT-PCR analysis of WT and Cot/tpl2 KO macrophages stimulated with APN for 0, 3, and 18 h revealed that Cot/tpl2 participated in the up-regulation of APN target inflammatory mediators included in the cytokine-cytokine receptor interaction pathway (KEGG ID 4060). In accordance with these data, macrophages stimulated with APN increased secretion of cytokines and chemokines, including IL-1?, IL-1?, TNF-?, IL-10, IL-12, IL-6, and CCL2. Moreover, Cot/tpl2 also played an important role in the production of these inflammatory mediators upon stimulation of macrophages with APN. It has been reported that different types of signals that stimulate TLRs, IL-1R, TNFR, Fc?R, and proteinase-activated receptor-1 activate Cot/tpl2. Here, we demonstrate that APN is a new signal that activates the IKK?-p105/NF-??1-Cot/tpl2-MKK1/2-Erk1/2 axis in macrophages. Furthermore, this signaling cassette modulates the biological functions triggered by APN in macrophages. PMID:24532642

Sanz-Garcia, Carlos; Nagy, Laura E; Lasunción, Miguel A; Fernandez, Margarita; Alemany, Susana

2014-06-01

283

New immunomodulatory drugs in myeloma.  

PubMed

Multiple myeloma (MM) is an incurable malignancy of plasma cells. The introduction of thalidomide was a milestone in the treatment of MM. Thalidomide analogues termed immunomodulatory drugs (IMiDs) have been developed that are more effective and have less toxicity than thalidomide. The role of lenalidomide in relapsed MM has been well defined. This review discusses the data regarding the upfront use of lenalidomide with dexamethasone or in multidrug combinations, as well as its potential role as maintenance therapy. It also reviews our experience with pomalidomide, a new IMid with remarkable activity in relapsed, refractory MM. PMID:21327565

Lacy, Martha Q

2011-06-01

284

Polyclonal activation of B lymphocytes by lipopolysaccharide requires macrophage-derived interleukin-1.  

PubMed Central

Lipopolysaccharide (LPS) is a potent murine polyclonal B-cell activator which induces cellular proliferation and IgM secretion. The precise role of activated macrophages in the induction of LPS-dependent, B-cell responses has been unclear. Although early reports concluded that the LPS effect occurs independently of other cell types, other studies have suggested that adherent macrophages exert either potentiating or inhibitory effects. In the present study, B-cell mitogenesis and IgM production were measured in primary spleen cell cultures after removing adherent cells by a variety of experimental procedures. B-cell activation by LPS was found to be strictly dependent on the presence of adherent macrophages. Antibody neutralization and cytokine reconstitution studies demonstrated that macrophage-derived interleukin- (IL-1) is a necessary co-factor for LPS-induced polyclonal activation.

Bucala, R

1992-01-01

285

Acute Ethanol Exposure Attenuates Pattern Recognition Receptor Activated Macrophage Functions  

PubMed Central

Both clinical and experimental data have linked acute ethanol exposure to increased susceptibility to infection as well as increased morbidity and mortality after injury. Macrophages play an integral role in the innate immune system and are important in priming the adaptive immune system. In this study, we investigated the effect of a single in vivo exposure of macrophages to physiologically relevant levels of ethanol (1.2 and 2.9?g/kg) followed by ex vivo stimulation with lipopolysaccharide (LPS) or bacteria. Our study confirms the work of others showing that a single administration of ethanol suppresses the production of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), and IL-12 in response to LPS. There was no effect of ethanol on LPS induction of cytokine production at 30?min after treatment. In contrast, at 3?h, both doses of ethanol exposure decreased ex vivo TNF-? production by splenic and alveolar macrophages. Interestingly, the higher dose of ethanol resulted in sustained suppression of LPS-induced TNF-? production at 3 and 6?h after ethanol administration, as well as decreased IL-6 and IL-12 production after 6?h, as compared to control (saline-treated groups). Alveolar macrophages behaved similarly at 3?h after ethanol treatment. LPS-stimulated production of TNF-? and IL-6 was reduced at 3?h after ethanol administration, when compared with the saline-treated animals. Alveolar macrophages stimulated for 3?h with bacteria also showed decreased TNF-? and IL-6 production after harvested from mice given 2.9?g/kg ethanol for 3?h. This time point and high dose of ethanol also resulted in decreased Pseudomonas aeruginosa phagocytosis by alveolar macrophages. Taken together, we conclude that the effects of physiological levels of ethanol are dose dependent, have effects that last after ethanol is cleared from the circulation, and can affect multiple macrophage functions.

Karavitis, John; Murdoch, Eva L.; Gomez, Christian R.; Ramirez, Luis

2008-01-01

286

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2  

Microsoft Academic Search

Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV rep-

Kazuo Nakamichi; Satoshi Inoue; Tomohiko Takasaki; Kinjiro Morimoto; Ichiro Kurane

2004-01-01

287

Re-evaluation of anti-inflammatory activity of mastic using activated macrophages.  

PubMed

Mastic is a resinous exudate obtained from the stem and the main leaves of Pistacia lentiscus. Mastic has shown several beneficial pharmaceutical properties such as antibacterial and apoptosis-modulating activities. The aim of this study was to investigate whether mastic affects the function of activated macrophages. Both solid and liquid types of mastic inhibited the production of pro-inflammatory substances such as nitric oxide (NO) and prostaglandin (PG)E(2) by lipopolysaccharide (LPS)-activated mouse macrophage-like RAW264.7 cells. This was accompanied by the decline of viable cell number. Western blot and RT-PCR analyses showed that mastic inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 at both protein and mRNA levels. ESR spectroscopy revealed that mastic scavenged NO and superoxide radicals very poorly, in contrast to its potent hydroxyl radical scavenging activity. These data demonstrate that mastic inhibits the production of both NO and PGE(2) by activated macrophages mostly via its cytotoxic action. The narrow range of effective concentration of mastic due to its cytotoxicity may limit its potential application as an anti-inflammatory agent. PMID:19567394

Zhou, Li; Satoh, Kazue; Takahashi, Keiso; Watanabe, Shuji; Nakamura, Wataru; Maki, Jun; Hatano, Hajime; Takekawa, Fumihiro; Shimada, Chiyako; Sakagami, Hiroshi

2009-01-01

288

Nonpathogenic Lactobacillus rhamnosus activates the inflammasome and antiviral responses in human macrophages.  

PubMed

In this study, we have utilized global gene expression profiling to compare the responses of human primary macrophages to two closely related, well-characterized Lactobacillus rhamnosus strains GG and LC705, since our understanding of the responses elicited by nonpathogenic bacteria in human innate immune system is limited. Macrophages are phagocytic cells of the innate immune system that perform sentinel functions to initiate appropriate responses to surrounding stimuli. Macrophages that reside on gut mucosa encounter ingested and intestinal bacteria. Bacteria of Lactobacillus genus are nonpathogenic and used in food and as supplements with health-promoting probiotic potential. Our results demonstrate that live GG and LC705 induced quantitatively different gene expression profiles in macrophages. A gene ontology analysis revealed functional similarities and differences in responses to GG and LC705 that were reflected in host defense responses. Both GG and LC705 induced interleukin-1? production in macrophages that required caspase-1 activity. LC705, but not GG, induced type I interferon -dependent gene activation that correlated with its ability to prevent influenza A virus replication and production of viral proteins in macrophages. Our results indicate that nonpathogenic bacteria are able to activate the inflammasome. In addition, our results suggest that L. rhamnosus may prime the antiviral potential of human macrophages. PMID:22895087

Miettinen, Minja; Pietilä, Taija E; Kekkonen, Riina A; Kankainen, Matti; Latvala, Sinikka; Pirhonen, Jaana; Österlund, Pamela; Korpela, Riitta; Julkunen, Ilkka

2012-01-01

289

Nonpathogenic Lactobacillus rhamnosus activates the inflammasome and antiviral responses in human macrophages  

PubMed Central

In this study, we have utilized global gene expression profiling to compare the responses of human primary macrophages to two closely related, well-characterized Lactobacillus rhamnosus strains GG and LC705, since our understanding of the responses elicited by nonpathogenic bacteria in human innate immune system is limited. Macrophages are phagocytic cells of the innate immune system that perform sentinel functions to initiate appropriate responses to surrounding stimuli. Macrophages that reside on gut mucosa encounter ingested and intestinal bacteria. Bacteria of Lactobacillus genus are nonpathogenic and used in food and as supplements with health-promoting probiotic potential. Our results demonstrate that live GG and LC705 induced quantitatively different gene expression profiles in macrophages. A gene ontology analysis revealed functional similarities and differences in responses to GG and LC705 that were reflected in host defense responses. Both GG and LC705 induced interleukin-1? production in macrophages that required caspase-1 activity. LC705, but not GG, induced type I interferon -dependent gene activation that correlated with its ability to prevent influenza A virus replication and production of viral proteins in macrophages. Our results indicate that nonpathogenic bacteria are able to activate the inflammasome. In addition, our results suggest that L. rhamnosus may prime the antiviral potential of human macrophages.

Miettinen, Minja; Pietila, Taija E.; Kekkonen, Riina A.; Kankainen, Matti; Latvala, Sinikka; Pirhonen, Jaana; Osterlund, Pamela; Korpela, Riitta; Julkunen, Ilkka

2012-01-01

290

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.

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

2014-01-01

291

Hyponatremia, hypophosphatemia, and hypouricemia in a girl with macrophage activation syndrome.  

PubMed

Macrophage activation syndrome, a life-threatening complication of rheumatic disorders, is accompanied by the overproduction of cytokines. We describe a girl with macrophage activation syndrome complicating systemic-onset juvenile arthritis who developed hyponatremia, hypophosphatemia, and hypouricemia associated with a high level of serum tumor necrosis factor alpha. Renal proximal tubule dysfunction was considered to be the cause, which may be attributable to tumor necrosis factor alpha. PMID:17142545

Yamazawa, Kazuki; Kodo, Kazuki; Maeda, Jun; Omori, Sayu; Hida, Mariko; Mori, Tetsuya; Awazu, Midori

2006-12-01

292

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.

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

2014-01-01

293

The in vitro phagocytic activity of guinea-pig macrophages to Salmonella typhi and Salmonella enteritidis  

Microsoft Academic Search

The engulfing, bactericidal and degrading activities toSalmonella typhi, strain ty2-4446 and 0-901 and toSalmonella enteritidis of guinea pig macrophages obtained from peritoneal exudate, spleen and bone marrow that were cultivated for 2–7 days, were\\u000a studied. The phagocytic activity was expressed as a total number of phagocytosed microbes and the number of viable bacteria,\\u000a released from mechanically disrupted macrophages. The ratio

N. B. Kamzolkina; N. S. Zakharova

1973-01-01

294

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

2013-01-01

295

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

296

Impaired activation of Stat1 and c-Jun as a possible defect in macrophages of patients with active tuberculosis  

PubMed Central

Studies of patients with active tuberculosis (TB) and infected healthy individuals have shown that interferon (IFN)-? is present in sites of Mycobacterium tuberculosis infection in comparable levels. This suggests that there is a deficiency in the macrophage response to IFN-? in TB patients. We used recombinant human IFN-? to stimulate adherent monocyte-derived macrophages from three groups of people: patients with active tuberculosis (TBP), their healthy household contacts (HHC) and healthy uninfected controls from the community (CC). We then evaluated the ability of the macrophages to inhibit the growth of M. tuberculosis H37Rv as well as their cytokine profile at early in infection (48 h). After IFN-? treatment, macrophages of healthy individuals (HHC and CC) controlled M. tuberculosis growth and produced mainly nitric oxide (NO) and interleukin (IL)-12p70, whereas TBP macrophages did not kill M. tuberculosis. Additionally, TBP macrophages produced low levels of NO and IL-12p70 and high levels of tumour necrosis factor (TNF)-? and IL-10. Transforming growth factor (TGF)-? levels were similar among all three groups. M. tuberculosis infection had little effect on the cytokine response after IFN-? stimulus, but infection alone induced more IL-10 and TGF-? in TBP macrophages. There were no differences in Stat1 nuclear translocation and DNA binding between the groups. However, the phosphorylated Stat1 and c-Jun (AP-1) in nuclear protein extracts was diminished in TBP macrophages compared to macrophages of healthy individuals. These results indicate an impairment of Stat1-dependent and Stat1-independent IFN-? signalling in macrophages of people with active tuberculosis, suggesting a different molecular regulation that could impact macrophage functionality and disease outcome.

Esquivel-Solis, H; Quinones-Falconi, F; Zarain-Herzberg, A; Amieva-Fernandez, R I; Lopez-Vidal, Y

2009-01-01

297

RP105 involved in activation of mouse macrophages via TLR2 and TLR4 signaling.  

PubMed

RP105 is a member of the toll-like receptor family of proteins that transmits an activation signal in B cells, playing a role in regulation of B cell growth and death; in macrophages and dendritic cells, RP105 is a specific inhibitor of TLR4 signaling. RP105 is uniquely important for regulating TLR4-dependent signaling. It also proved that RP105 is closely related to TLR2 in macrophage activation by Mycobacterium tuberculosis lipoproteins. The aim of our study is to investigate the role of RP105 in mouse macrophages activation of TLR4 and TLR2 signaling by lipopolysaccharides (LPS) and Pam3CysSerLys4 (Pam3CSK4) alone or in combination, and the interaction between TLR2 and TLR4 signaling through RP105. Our results indicate that besides exhibiting negative regulation of TNF-? and IL12-p40 secretion in macrophage activated by LPS, RP105 is also involved in macrophages activation by Pam3CSK4 through TLR2 signaling and exhibited regulation to IL-10 and RANTES production by mouse peritoneal macrophage activated by Pam3CSK4. In macrophages activation by LPS and Pam3CSK4 in combination, TLR2 signaling can overcome RP105-mediated regulation of TLR4 signaling. Thus, our data demonstrate that not only TLR4 signaling, but also RP105 appears to be an essential accessory for immune responses through TLR2 signaling. The function of TLR2 and TLR4 in response to TLR ligands could be associated with each other by RP105. These results can help us understanding the unique role of RP105 in macrophages response to TLR ligands. PMID:23483427

Liu, Bo; Zhang, Naisheng; Liu, Zhicheng; Fu, Yunhe; Feng, Shuang; Wang, Shan; Cao, Yongguo; Li, Depeng; Liang, Dejie; Li, Fengyang; Song, Xiaojing; Yang, Zhengtao

2013-06-01

298

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.

Henderson, Samantha

2008-01-01

299

Molecular imaging of macrophage protease activity in cardiovascular inflammation in vivo  

PubMed Central

Summary Macrophages contribute pivotally to cardiovascular diseases (CVD), notably to atherosclerosis. Imaging of macrophages in vivo could furnish new tools to advance evaluation of disease and therapies. Proteolytic enzymes serve as key effectors of many macrophage contributions to CVD. Therefore, intravital imaging of protease activity could aid evaluation of the progress and outcome of atherosclerosis, aortic aneurysm formation, or rejection of cardiac allografts. Among the large families of proteases, matrix metalloproteinases (MMPs) and cysteinyl cathepsins have garnered the most interest because of their participation in extracellular matrix remodeling. These considerations have spurred the development of dedicated imaging agents for protease activity detection. Activatable fluorescent probes, radiolabeled inhibitors, and nanoparticles are currently under exploration for this purpose. While some agents and technologies may soon see clinical use, others will require further refinement. Imaging of macrophages and protease activity should provide an important adjunct to understanding pathophysiology in vivo, evaluating the effects of interventions, and ultimately aiding clinical care.

Quillard, Thibaut; Croce, Kevin; Jaffer, Farouc A.; Weissleder, Ralph; Libby, Peter

2011-01-01

300

Infection of macrophages by Theiler's murine encephalomyelitis virus is highly dependent on their activation or differentiation state.  

PubMed Central

Macrophages are the main targets of Theiler's murine encephalomyelitis virus (TMEV) during persistent demyelinating infection of mice. Replication of TMEV in macrophages was previously shown to depend on their activation state. Here, we show that the quality of the serum used for culture drastically influences viral entry in RAW264.7 macrophages.

Shaw-Jackson, C; Michiels, T

1997-01-01

301

Lung Collagens Perpetuate Pulmonary Fibrosis via CD204 and M2 Macrophage Activation  

PubMed Central

Idiopathic pulmonary fibrosis is characterized by abundant collagen production and accumulation of alternatively activated macrophages (M2) in the lower respiratory tract. Mechanisms as to how alveolar macrophages are activated by collagen breakdown products are unknown. Alveolar macrophages were obtained by bronchoalveolar lavage from 30 patients with idiopathic pulmonary fibrosis (IPF) and 37 healthy donors (HD). Alveolar macrophages were cultured in the presence of collagen type I, III, IV and V monomers w/wo a neutralizing antibody against scavenger receptor I class A (CD204). Culture supernatants were assayed for the M2 markers CCL18, CCL2, and interleukin-1 receptor antagonist (IL-1ra) by ELISA. Furthermore, expression of phospho-Akt was measured using ELISA and expression of CD204 by RT-PCR and flow cytometry. Stimulation with collagen type I and III monomers significantly up-regulated CCL18, IL-1ra production of alveolar macrophages. Furthermore, expression of CCL2 and CD204 were up-regulated by collagen type I exposure. In addition, collagen type I stimulation increased pospho-Akt expression. Collagen type I effects were abrogated by neutralizing antiCD204 and a non-selective Phosphatidylinositide 3-kinase inhibitor (LY294002). Spontaneous CD204 expression of alveolar macrophages was significantly increased in patients with IPF. In conclusion, our findings demonstrate that monomeric collagen type I via CD204 induces phospho-Akt expression shifting alveolar macrophages to the profibrotic M2 type. Innate immune responses induced by collagen monomers might perpetuate pulmonary fibrosis.

Stahl, Mirjam; Schupp, Jonas; Jager, Benedikt; Schmid, Michael; Zissel, Gernot; Muller-Quernheim, Joachim; Prasse, Antje

2013-01-01

302

Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization.  

PubMed

Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9(-/-)) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies. PMID:24722209

Yang, M; Shao, J-H; Miao, Y-J; Cui, W; Qi, Y-F; Han, J-H; Lin, X; Du, J

2014-08-01

303

Structurally well-defined macrophage activating factor derived from vitamin D3-binding protein has a potent adjuvant activity for immunization  

Microsoft Academic Search

Freund's adjuvant produced severe inflammation that augments development of antibodies. Thus, mixed administration of antigens with adjuvant was not required as long as inflammation was induced in the hosts. Since macrophage activation for phagocytosis and antigen processing is the first step of antibody development, inflammation-primed macrophage activation plays a major role in immune development. Therefore, macrophage activating factor should act

Nobuto Yamamoto; Venkateswara R Naraparaju

1998-01-01

304

Anthrax Lethal Factor Activates K+ Channels To Induce IL-1? Secretion in Macrophages  

PubMed Central

Anthrax lethal toxin (LeTx) is a virulence factor of Bacilillus anthracis that is a bivalent toxin, containing lethal factor (LF) and protective Ag proteins, which causes cytotoxicity and altered macrophage function. LeTx exposure results in early K+ efflux from macrophages associated with caspase-1 activation and increased IL-1? release. The mechanism of this toxin-induced K+ efflux is unknown. The goals of the current study were to determine whether LeTx-induced K+ efflux from macrophages is mediated by toxin effects on specific K+ channels and whether altered K+-channel activity is involved in LeTx-induced IL-1? release. Exposure of macrophages to LeTx induced a significant increase in the activities of two types of K+ channels that have been identified in mouse macrophages: Ba2+-sensitive inwardly rectifying K+ (Kir) channels and 4-aminopyridine–sensitive outwardly rectifying voltage-gated K+ (Kv) channels. LeTx enhancement of both Kir and Kv required the proteolytic activity of LF, because exposure of macrophages to a mutant LF-protein (LFE687C) combined with protective Ag protein had no effect on the currents. Furthermore, blocking Kir and Kv channels significantly decreased LeTx-induced release of IL-1?. In addition, retroviral transduction of macrophages with wild-type Kir enhanced LeTx-induced release of IL-1?, whereas transduction of dominant-negative Kir blocked LeTx-induced release of IL-1?. Activation of caspase-1 was not required for LeTx-induced activation of either of the K+ channels. These data indicate that a major mechanism through which LeTx stimulates macrophages to release IL-1? involves an LF-protease effect that enhances Kir and Kv channel function during toxin stimulation.

Thomas, Johnson; Epshtein, Yulia; Chopra, Arun; Ordog, Balazs; Ghassemi, Mahmood; Christman, John W.; Nattel, Stanley; Cook, James L.; Levitan, Irena

2012-01-01

305

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

PubMed

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 Egfr(fl/fl)LysM-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 Egfr(fl/fl)LysM-Cre mice. An anti-IL-10 neutralizing Ab abolished these effects of macrophage-specific EGFR deletion on DSS-induced colitis in Egfr(fl/fl)LysM-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 proinflammatory 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

2014-02-01

306

The insect peptide CopA3 inhibits lipopolysaccharide-induced macrophage activation.  

PubMed

We recently demonstrated that the insect peptide CopA3 (LLCIALRKK), a disulfide-linked dimeric peptide, exerts antimicrobial and anti-inflammatory activities in a mouse colitis model. Here, we examined whether CopA3 inhibited activation of macrophages by LPS. Exposure of an unseparated mouse peritoneal cell population or isolated peritoneal macrophages to LPS markedly increased secretion of IL-6 and TNF-?; these effects were significantly inhibited by CopA3 treatment. The inhibitory effect of CopA3 was also evident in murine macrophage cell line, RAW 264.7. Western blotting revealed that LPS-induced activation of STAT1 and STAT5 in macrophages was significantly inhibited by CopA3. Inhibition of JAK (STAT1/STAT5 kinase) with AG490 markedly reduced the production of IL-6 and TNF-? in macrophages. Collectively, these observations suggest that CopA3 inhibits macrophage activation by inhibiting activating phosphorylations of the transcription factors, STAT1 and STAT5, and blocking subsequent production of IL-6 and TNF-? and indicate that CopA3 may be useful as an immune-modulating agent. PMID:22969062

Nam, Hyo Jung; Oh, Ah Reum; Nam, Seung Taek; Kang, Jin Ku; Chang, Jong Soo; Kim, Dae Hong; Lee, Ji Hye; Hwang, Jae Sam; Shong, Ko Eun; Park, Mi Jung; Seok, Heon; Kim, Ho

2012-10-01

307

Functional Roles of p38 Mitogen-Activated Protein Kinase in Macrophage-Mediated Inflammatory Responses  

PubMed Central

Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs) are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-? (TNF-?) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases.

Yang, Yanyan; Yu, Tao; Sung, Gi-Ho; Yoo, Byong Chul

2014-01-01

308

Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages.  

PubMed

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor activated by fatty acid derivatives and hypolipidemic drugs of the fibrate class. PPARalpha is expressed in monocytes, macrophages, and foam cells, suggesting a role for this receptor in macrophage lipid homeostasis with consequences for atherosclerosis development. Recently, it was shown that PPARalpha activation promotes cholesterol efflux from macrophages via induction of the ABCA1 pathway. In the present study, the influence of PPARalpha activators on intracellular cholesterol homeostasis was investigated. In human macrophages and foam cells, treatment with fibrates, synthetic PPARalpha activators, led to a decrease in the cholesteryl ester (CE):free cholesterol (FC) ratio. In these cells, PPARalpha activation reduced cholesterol esterification rates and Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) activity. However, PPARalpha activation did not alter ACAT1 gene expression, whereas mRNA levels of carnitine palmitoyltransferase type 1 (CPT-1), a key enzyme in mitochondrial fatty acid catabolism, were induced. Finally, PPARalpha activation blocked CE formation induced by TNF-alpha, possibly due to the inhibition of neutral sphingomyelinase activation by TNF-alpha. In conclusion, our results identify a role for PPARalpha in the control of cholesterol esterification in macrophages, resulting in an enhanced availability of FC for efflux through the ABCA1 pathway. PMID:12574149

Chinetti, G; Lestavel, S; Fruchart, J-C; Clavey, V; Staels, B

2003-02-01

309

Effect of low extracellular pH on NF-?B activation in macrophages?  

PubMed Central

Objective Many diseases, including atherosclerosis, involve chronic inflammation. The master transcription factor for inflammation is NF-?B. Inflammatory sites have a low extracellular pH. Our objective was to demonstrate the effect of pH on NF-?B activation and cytokine secretion. Methods Mouse J774 macrophages or human THP-1 or monocyte-derived macrophages were incubated at pH 7.0–7.4 and inflammatory cytokine secretion and NF-?B activity were measured. Results A pH of 7.0 greatly decreased pro-inflammatory cytokine secretion (TNF or IL-6) by J774 macrophages, but not THP-1 or human monocyte-derived macrophages. Upon stimulation of mouse macrophages, the levels of I?B?, which inhibits NF-?B, fell but low pH prevented its later increase, which normally restores the baseline activity of NF-?B, even though the levels of mRNA for I?B? were increased. pH 7.0 greatly increased and prolonged NF-?B binding to its consensus promoter sequence, especially the anti-inflammatory p50:p50 homodimers. Human p50 was overexpressed using adenovirus in THP-1 macrophages and monocyte-derived macrophages to see if it would confer pH sensitivity to NF-?B activity in human cells. Overexpression of p50 increased p50:p50 DNA-binding and in THP-1 macrophages inhibited considerably TNF and IL-6 secretion, but there was still no effect of pH on p50:p50 DNA binding or cytokine secretion. Conclusion A modest decrease in pH can sometimes have marked effects on NF-?B activation and cytokine secretion and might be one reason to explain why mice normally develop less atherosclerosis than do humans.

Gerry, A.B.; Leake, D.S.

2014-01-01

310

The M1 and M2 paradigm of macrophage activation: time for reassessment.  

PubMed

Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response. PMID:24669294

Martinez, Fernando O; Gordon, Siamon

2014-01-01

311

The M1 and M2 paradigm of macrophage activation: time for reassessment  

PubMed Central

Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response.

2014-01-01

312

Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide  

PubMed Central

Taxol, a plant-derived antitumor agent, stabilizes microtubules. Taxol also elicits cell signals in a manner indistinguishable from bacterial lipopolysaccharide (LPS). LPS-like actions of Taxol are controlled by the lps gene and are independent of binding to the known Taxol target, ?-tubulin. Using biotin-labeled Taxol, avidin-agarose affinity chromatography, and peptide mass fingerprinting, we identified two Taxol targets from mouse macrophages and brain as heat shock proteins (Hsps) of the 70- and 90-kDa families. Geldanamycin, a specific inhibitor of the Hsp 90 family, blocked the nuclear translocation of NF-?B and expression of tumor necrosis factor in macrophages treated with Taxol or with LPS. Geldanamycin did not block microtubule bundling by Taxol or macrophage activation by tumor necrosis factor. Thus, Taxol binds Hsps, and Hsp 90 helps mediate the activation of macrophages by Taxol and by LPS.

Byrd, Cynthia A.; Bornmann, William; Erdjument-Bromage, Hediye; Tempst, Paul; Pavletich, Nikola; Rosen, Neal; Nathan, Carl F.; Ding, Aihao

1999-01-01

313

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

PubMed Central

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.

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

2014-01-01

314

Differential Macrophage Activation Alters the Expression Profile of NTPDase and Ecto-5?-Nucleotidase  

PubMed Central

Macrophages are key elements in the inflammatory process, whereas depending on the micro-environmental stimulation they exhibit a pro-inflammatory (classical/M1) or an anti-inflammatory/reparatory (alternative/M2) phenotype. Extracellular ATP can act as a danger signal whereas adenosine generally serves as a negative feedback mechanism to limit inflammation. The local increase in nucleotides communication is controlled by ectonucleotidases, such as members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family and ecto-5?-nucleotidase/CD73 (ecto-5?-NT). In the present work we evaluated the presence of these enzymes in resident mice M1 (macrophages stimulated with LPS), and M2 (macrophages stimulated with IL-4) macrophages. Macrophages were collected by a lavage of the mice (6–8 weeks) peritoneal cavity and treated for 24 h with IL-4 (10 ng/mL) or LPS (10 ng/mL). Nitrite concentrations were measured using the Greiss reaction. Supernatants were harvested to determine cytokines and the ATPase, ADPase and AMPase activities were determined by the malachite green method and HPLC analysis. The expression of selected surface proteins was evaluated by flow cytometry. The results reveal that M1 macrophages presented a decreased ATP and AMP hydrolysis in agreement with a decrease in NTPDase1, -3 and ecto-5?-nucleotidase expression compared to M2. In contrast, M2 macrophages showed a higher ATP and AMP hydrolysis and increased NTPDase1, -3 and ecto-5?-nucleotidase expression compared to M1 macrophages. Therefore, macrophages of the M1 phenotype lead to an accumulation of ATP while macrophages of the M2 phenotype may rapidly convert ATP to adenosine. The results also showed that P1 and P2 purinoreceptors present the same mRNA profile in both phenotypes. In addition, M2 macrophages, which have a higher ATPase activity, were less sensitive to cell death. In conclusion, these changes in ectoenzyme activities might allow macrophages to adjust the outcome of the extracellular purinergic cascade in order to fine-tune their functions during the inflammatory set.

Zanin, Rafael Fernandes; Braganhol, Elizandra; Bergamin, Leticia Scussel; Campesato, Luis Felipe Ingrassia; Filho, Alfeu Zanotto; Moreira, Jose Claudio Fonseca; Morrone, Fernanda Bueno; Sevigny, Jean; Schetinger, Maria Rosa Chitolina; de Souza Wyse, Angela Terezinha; Battastini, Ana Maria Oliveira

2012-01-01

315

Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages.  

PubMed Central

The microbiostatic action of macrophages was studied in vitro employing peritoneal cytotoxic macrophages (CM) from mice acting against Cryptococcus neoformans cultured in Dulbecco's medium with 10% dialyzed fetal bovine serum. Fungistasis was measured using electronic particle counting after lysis of macrophages with detergent. Macrophage fungistasis failed in medium lacking only L-arginine. Complete fungistasis was restored by L-arginine; restoration was concentration dependent, maximal at 200 microM. Deletion of all other essential amino acids did not abrogate fungistasis provided that L-arginine was present. Of twenty guanido compounds, including D-arginine, only three (L-arginine, L-homoarginine, and L-arginine methylester) supported fungistasis. Known activators or mediators of macrophage cytotoxicity (endotoxin, interferon gamma, tumor necrosis factor) did not replace L-arginine for CM-mediated fungistasis. The guanido analogue NG-monomethyl-L-arginine was a potent competitive inhibitor of CM-mediated fungistasis giving 50% inhibition at an inhibitor/L-arginine ratio of 1:27. Although CM completely blocked fungal reproduction via an L-arginine-dependent mechanism, the majority of the dormant fungi remained viable. Thus, this mechanism is viewed as a microbiostatic process similar or identical to the tumoristatic effect of macrophages. This suggests the production of a broad spectrum biostatic metabolite(s) upon consumption of L-arginine by cytotoxic macrophages.

Granger, D L; Hibbs, J B; Perfect, J R; Durack, D T

1988-01-01

316

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.

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

317

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

318

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

Microsoft Academic Search

Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, because 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

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

2005-01-01

319

Induction of Macrophage Antitumor Activity by Acetylated Low Density Lipoprotein Containing Lipophilic Muramyl Tripeptide  

Microsoft Academic Search

A method has been developed for the selective delivery of lipophilic immunomodulators to macrophages, which results in the induction of antitumor activity. This method utilizes exhaustively acetylated low density lipoprotein (acetyl-LDL) to deliver the lipophilic immunomodulator, muramyl tripeptide phosphatidylethanolamine (MTP-PtdEtn; amide composed of N-acetylmuramyl-L-alanyl-D-isoglutamyl-L-alanine and dipalmitoyl phosphatidylethanolamine) to macrophages (Mphi ) by means of a scavenger lipoprotein receptor pathway. The

J. Michael Shaw; William S. Futch; Lawrence B. Schook

1988-01-01

320

Microarray analysis of activated mixed glial (microglia) and monocyte-derived macrophage gene expression.  

PubMed

Since macrophage activation can now be studied at a global level using modern microarray and proteomic analyses, discovery of novel macrophage activation genes is inevitable and important for understanding HIV-associated dementia (HAD). We isolated two different types of primary human macrophages: microglia and monocyte-derived macrophages (MDM) from brain tissue and whole blood, respectively. The microarray analysis of differentially regulated macrophage activation genes reported here supports our previous assertions that the mixed glia (MIX) cultured in starvation conditions (DMEM alone) are a non-activated, or "quiescent", tissue culture model for studying macrophage activation in the brain. Transcript levels from these quiescent cultures provided a background level of gene expression and allowed for the identification of upregulated macrophage activation genes in the MIX brain cultures upon treatment with an array of soluble activation factors: serum components, cytokines, and growth factors. We found that 914 genes in the MIX cultures and 734 genes in the MDM cultures had a greater than twofold increase in expression. We discovered 180 genes with expression that was increased more than twofold in both culture types. Microarray-specific statistical analyses were performed to complement fold change analysis: significance analysis of microarrays (SAM) and Partek Pro. In the MIX cultures, we detected over a 100-fold increase in IL-1beta and TIMP1 transcription; Caspase 9, S100A8 and 9, MMP12, IL-8, monocyte chemotactic protein 1 (MCP1), MRC-1, and IL-6 were also upregulated. Activation of starved MDM cultures resulted in fewer upregulated genes compared to MIX cultures. Genes upregulated in both MIX and MDM included CCL2 (MCP1), CCL7, CXCL5, TNFSF14, kinases, and phosphatases. These microarray data may provide leads for identifying previously unknown neurotoxins, disease biomarkers, and pathways responsible for the neuronal apoptosis observed in HAD and for the eventual identification of therapeutic targets and treatments. PMID:15579277

Albright, Andrew V; González-Scarano, Francisco

2004-12-01

321

[Studies on the activities of peptidases from human leucocytes, and human and guinea pig alveolar macrophages (author's transl)].  

PubMed

Peptidases activities were compared in human leucocytes, guinea pig and human alveolar macrophages. Seversl endo- and exopeptides were characterized; some of them were active at acid pH and others at neutral and alkaline pH. Leucocytes and alveolar macrophages had proteolygic activity for hemoglobin, fibrinogen, collagen and elastin. Using synthetic substrates, several enzymes were characterized: arylamidase, aminopeptidase, carboxypeptidases A and B and cathepsins A and C. The enzymatic activities were much higher in alveolar macrophages than in leucocytes. PMID:2398

Scharfman, A; Roussel, P; Biserte, G; Aerts, C; Tonnel, A B; Voisin, C

1976-02-01

322

Fisetin inhibits lipopolysaccharide-induced macrophage activation and dendritic cell maturation.  

PubMed

Macrophages and dendritic cells are required for initiating innate immunity and adaptive immunity. Aberrant activation of macrophages and dendritic cells can cause detrimental immune responses; thus, agents effectively modulating their functions are of great clinical value. We herein investigated whether fisetin, a flavonoid prevalently present in fruits and vegetables, could inhibit macrophage activation and dendritic cell maturation. Fisetin suppressed LPS-induced NF-?B activation, expression of pro-inflammatory proteins (TNF-? and iNOS), MMP-9 activity, and phagocytic activity in macrophages. Furthermore, upon LPS-induced dendritic cell maturation, fisetin at nontoxic concentrations suppressed the expression of costimulatory molecules (CD80 and CD86), the production of cytokines (IL-12, IL-6, and TNF-?), and the endocytic activity of dendritic cells. Fisetin treatment significantly attenuated migration of dendritic cells into spleens and dendritic cell-mediated T cell activation in LPS-treated mice. Collectively, our data reveal that fisetin inhibits macrophage activation and impairs functional maturation of dendritic cells. PMID:20923145

Liu, Sheng-Hung; Lin, Chao-Hsiung; Hung, Shih-Kai; Chou, Jen-Hwey; Chi, Chin-Wen; Fu, Shu-Ling

2010-10-27

323

Progranulin promotes activation of microglia/macrophage after pilocarpine-induced status epilepticus.  

PubMed

Progranulin (PGRN) haploinsufficiency accounts for up to 10% of frontotemporal lobe dementia. PGRN has also been implicated in neuroinflammation in acute and chronic neurological disorders. Here we report that both protein and mRNA levels of cortical and hippocampal PGRN are significantly enhanced following pilocarpine-induced status epilepticus. We also identify intense PGRN immunoreactivity that colocalizes with CD11b in seizure-induced animals, suggesting that PGRN elevation occurs primarily in activated microglia and macrophages. To test the role of PGRN in activation of microglia/macrophages, we apply recombinant PGRN protein directly into the hippocampal formation, and observe no change in the number of CD11b(+) microglia/macrophages in the dentate gyrus. However, with pilocarpine-induced status epilepticus, PGRN application significantly increases the number of CD11b(+) microglia/macrophages in the dentate gyrus, without affecting the extent of hilar cell death. In addition, the number of CD11b(+) microglia/macrophages induced by status epilepticus is not significantly different between PGRN knockout mice and wildtype. Our findings suggest that status epilepticus induces PGRN expression, and that PGRN potentiates but is not required for seizure-induced microglia/macrophage activation. PMID:23887054

Zhu, Shanshan; Tai, Chao; Petkau, Terri L; Zhang, Si; Liao, Chengyong; Dong, Zhifang; Wen, Wendy; Chang, Qing; Tian Wang, Yu; MacVicar, Brian A; Leavitt, Blair R; Jia, William; Cynader, Max S

2013-09-12

324

Attenuated expression of interferon-? and interferon-?1 by human alternatively activated macrophages.  

PubMed

Macrophages can be polarized into classically (CAM) or alternatively (AAM) activated macrophages with IFN-? or IL-4, respectively. CAM are associated with type 1 immune responses and are implicated in autoimmunity; AAM are associated with type 2 responses and are implicated in allergic diseases. An impediment in investigating macrophage biology using primary human monocyte derived macrophages is the wide inter-donor heterogeneity and the limited quantity of cells that survive in vitro polarization. To overcome this impediment, we established a protocol to generate CAM and AAM cultures derived from the THP-1 human promonocytic cell line. In this report, we demonstrate that THP-CAM and -AAM express gene and protein markers that define their primary human monocyte derived counterparts, such as IL-1?, CXCL10, and CXCL11 for CAM, and MRC1, IL-4 and CCL22 for AAM. In addition, we demonstrate that STAT6 is selectively activated in THP-AAM which, upon LPS stimulation, have an attenuated or delayed expression of IFN-?, IFN-?1, and IFN ?/? pathway genes compared to their CAM counterparts. Taken together, these findings may help further investigate human diseases associated with the alternatively activated macrophage phenotype using this reproducible in vitro macrophage model. PMID:23993990

El Fiky, Ashraf; Perreault, Roger; McGinnis, Gwendolyn J; Rabin, Ronald L

2013-12-01

325

Differential gene expression in LPS/IFN? activated microglia and macrophages: in vitro versus in vivo  

PubMed Central

Two different macrophage populations contribute to CNS neuroinflammation: CNS-resident microglia and CNS-infiltrating peripheral macrophages. Markers distinguishing these two populations in tissue sections have not been identified. Therefore, we compared gene expression between LPS (lipopolysaccharide)/interferon (IFN)?-treated microglia from neonatal mixed glial cultures and similarly treated peritoneal macrophages. Fifteen molecules were identified by quantative PCR (qPCR) as being enriched from 2-fold to 250-fold in cultured neonatal microglia when compared with peritoneal macrophages. Only three of these molecules (C1qA, Trem2, and CXCL14) were found by qPCR to be also enriched in adult microglia isolated from LPS/IFN?-injected CNS when compared with infiltrating peripheral macrophages from the same CNS. The discrepancy between the in vitro and in vivo qPCR data sets was primarily because of induced expression of the ‘microglial’ molecules (such as the tolerance associated transcript, Tmem176b) in CNS-infiltrating macrophages. Bioinformatic analysis of the ?19000 mRNAs detected by TOGA gene profiling confirmed that LPS/IFN?-activated microglia isolated from adult CNS displayed greater similarity in total gene expression to CNS-infiltrating macrophages than to microglia isolated from unmanipulated healthy adult CNS. In situ hybridization analysis revealed that nearly all microglia expressed high levels of C1qA, while subsets of microglia expressed Trem2 and CXCL14. Expression of C1qA and Trem2 was limited to microglia, while large numbers of GABA+ neurons expressed CXCL14. These data suggest that (i) CNS-resident microglia are heterogeneous and thus a universal microglia-specific marker may not exist; (ii) the CNS micro-environment plays significant roles in determining the phenotypes of both CNS-resident microglia and CNS-infiltrating macrophages; (iii) the CNS microenvironment may contribute to immune privilege by inducing macrophage expression of anti-inflammatory molecules.

Schmid, Christoph D; Melchior, Benoit; Masek, Kokoechat; Puntambekar, Shweta S; Danielson, Patria E; Lo, David D; Gregor Sutcliffe, J; Carson, Monica J

2009-01-01

326

IFN-?-activated lymphocytes boost nitric oxide production in grass carp monocytes/macrophages.  

PubMed

It is well known that IFN-? is a prime activator of nitric oxide (NO) production by monocytes/macrophages in mammals and fish. In parallel, whether IFN-?-activated lymphocytes are associated with NO production remains unclear. In this study, grass carp monocytes/macrophages and lymphocytes from head kidney were isolated and effects of recombinant grass carp IFN-? (rgcIFN-?) on NO releases by these two cell populations were determined. Results showed that rgcIFN-? time- and dose-dependently increased NO production by monocytes/macrophages but not lymphocytes, which are consistent with the findings in mammals. Interestingly, rgcIFN-? displayed a greater stimulation on NO production in the co-cultures of monocytes/macrophages and lymphocytes when compared with that in the culture of monocytes/macrophages alone. Furthermore, the media harvested from rgcIFN-?-treated lymphocytes were effective in boosting NO release in monocytes/macrophages. These data suggest that secretions from rgcIFN-?-treated lymphocytes may be involved in the NO release by monocytes/macrophages. To address this hypothesis, effect of rgcIFN-? on the gene expression of inflammatory cytokines in grass carp lymphocytes was examined, showing that it consistently stimulated the mRNA expression of grass carp TNF-? and IL-1? but not IFN-?. Furthermore, treatment of rgcIFN-? combined with recombinant grass carp IL-1? (rgcIL-1?) induced a NO production by monocytes/macrophages, which was significantly higher than those induced by either cytokine alone. It provides the evidence that the cytokines secreted by the activated lymphocytes may facilitate the NO production by monocytes/macrophages. Taken together, our findings point out a new mechanism for the involvement of IFN-?-activated lymphocytes in the NO production by monocytes/macrophages in fish. This knowledge not only strengthens the role of IFN-? in immune system but also provides the evidence for the existence of a close relationship between lymphocytes and monocytes/macrophages in fish. PMID:24056277

Yang, Kun; Zhang, Shengnan; Chen, Danyan; Zhang, Anying; Wang, Xinyan; Zhou, Hong

2013-11-01

327

Pyrrolidine dithiocarbamate inhibits induction of nitric oxide synthase activity in rat alveolar macrophages.  

PubMed

Since nuclear factor kappa B (NF-kappa B) is activated during many inflammatory conditions, we assessed its role in expression of the L-arginine-nitric oxide pathway by rat alveolar macrophages. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappa B activation, was added to cultured macrophages stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN gamma). Inducible nitric oxide synthase (iNOS) activity was determined by measuring the stable nitrogen oxide end products of L-arginine oxidation: nitrite (NO2-) and nitrate (NO3-). Ten, 25 and 50 microM PDTC progressively inhibited iNOS activity by macrophages. When 50 microM PDTC was added 2 h before LPS + IFN gamma, L-arginine oxidation by macrophages was inhibited by > 99%; L-arginine oxidation was reduced by 70% if 50 microM PDTC and the stimuli were introduced together; NO2- and NO3- were not decreased significantly if 50 microM PDTC was added 6 h after LPS + IFN gamma. Cycloheximide added along with LPS + IFN gamma totally inhibits iNOS activity, while cycloheximide added 6 h after LPS + IFN gamma did not reduce NO2- and NO3- in tissue culture supernatants. These findings suggest iNOS activity in macrophages treated with LPS + IFN gamma requires NF-kappa B activation. PMID:7682068

Sherman, M P; Aeberhard, E E; Wong, V Z; Griscavage, J M; Ignarro, L J

1993-03-31

328

Swainsonine modulation of protein kinase C activity in murine peritoneal macrophages.  

PubMed

The level of Ca2+, phospholipid-dependent, protein kinase C (PKC) activity in murine peritoneal macrophages treated with swainsonine, an indolizidine alkaloid, has been investigated. The present studies are based on our recent report that murine peritoneal macrophages are activated by swainsonine (Grzegorzewski, K.; Newton, S.A.; Akiyama, S.K.; Sharrow, S.; Olden, K.; White, S.L., Cancer Commun. 1:373-379, 1989). Presently, we have demonstrated that macrophages treated with swainsonine exhibited a substantial increase in PKC activity. The activity was enhanced as much as 4- to 5-fold over that obtained in untreated macrophages and was inhibited by H-7 (1-[5-isoquinoline sulphonyl]-2-methylpiperazine), D-sphingosine, or a monoclonal antibody specific for the active site of PKC. This represents the first report to demonstrate an effect of swainsonine on a second messenger system known to be involved in tumor promotion and macrophage activation. Elevation of PKC activity occurred much more slowly in swainsonine-treated cells than in cells treated with agents known to activate PKC directly, e.g., PMA (4-beta-phorbol-12-beta-myristate-13-gamma-acetate) or gamma-interferon (IFN-gamma). Furthermore the increase in PKC activity was inhibited by alpha-amanitine and cycloheximide, inhibitors of RNA and protein synthesis, respectively. These results suggest that swainsonine enhancement of PKC activity occurred by an indirect and possibly protein-synthesis-dependent mechanism. Whatever its precise mechanism of action, swainsonine provides a potentially important new probe to evaluate PKC mediated events. Selective enhancement of PKC activity may be important not only in elucidating the role of PKC in tumor promotion or macrophage activation but, also, in contributing to development of therapeutic regimens. PMID:2119676

Breton, P; Asseffa, A; Grzegorzewski, K; Akiyama, S K; White, S L; Cha, J K; Olden, K

1990-01-01

329

Macrophages in resistance to rickettsial infection: strains of mice susceptible to the lethal effects of Rickettsia akari show defective macrophage Rickettsicidal activity in vitro.  

PubMed Central

Activation of macrophages was assessed in strains of mice inoculated intraperitoneally with 1,000 times the 50% lethal dose of Rickettsia akari. Macrophages from mice resistant to R. akari infection (C3H/HeN, C57BL/10J, and BALB/cN) were nonspecifically tumoricidal 2 to 4 days after rickettsial inoculation. Moreover, these macrophages were microbial for R. akari in vitro; cells were resistant to infection with the bacterium and were capable of killing intracellular rickettsiae. In contrast, macrophages from strains of mice susceptible to R. akari (C3H/HeJ, C57BL/10SnCR, and A/J) failed to develop nonspecific tumoricidal activity over the course of lethal disease and became infected with R. akari in vivo within 2 days of rickettsial inoculation. Macrophages from uninfected mice of strains susceptible to R. akari also could not be activated for rickettsicidal or tumoricidal activities by treatment with macrophage-activating agents (Mycobacterium bovis BCG) in vivo or by treatment with lymphokines in vitro.

Nacy, C A; Meltzer, M S

1982-01-01

330

M2 Macrophages Activate WNT Signaling Pathway in Epithelial Cells: Relevance in Ulcerative Colitis  

PubMed Central

Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of ?-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, ?-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of ?-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation.

Cosin-Roger, Jesus; Ortiz-Masia, Dolores; Calatayud, Sara; Hernandez, Carlos; Alvarez, Angeles; Hinojosa, Joaquin; Esplugues, Juan V.; Barrachina, Maria D.

2013-01-01

331

Analysis of the primed intermediate stage in the macrophage tumoricidal activation pathway  

SciTech Connect

Model systems were developed for the analysis of macrophage activation for tumor cell killing using established murine macrophage-like tumor cell lines. This activation process is currently understood as consisting of sequential priming and triggering steps. Treatment with interferon-gamma resulted in the acquisition of a primed activation state by some, but not all, of the macrophage populations studied. A dissociation of the modulation of cell surface major histocompatibility complex (MHC) Class II (Ia) antigen expression and priming for tumor cytolysis by interferon-gamma was observed in the macrophage cell lines, indicating that the primed intermediate in the macrophage tumoricidal activation pathway was not necessarily Ia antigen-positive. Examination of the tumor cytolytic activity of cycloheximide-treated cells indicated that protein synthesis was required for priming by interferon-gamma. A novel priming stimulus, gamma irradiation, was identified using the RAW 264.7 cell line. Treatment of the RAW 264.7 cell line with doses of gamma radiation > 1000 rads resulted in the acquisition of the primed intermediate activation state, as evidenced by the expression of maximum tumor cell killing following incubation of irradiated cells with the triggering stimulus alone.

Lambert, L.E.

1987-01-01

332

Macrophage Inflammatory Protein-lc Activates Basophlh and Mast Cells  

Microsoft Academic Search

Summary Macrophage inflammatory protein-1 (MIP) is a recently cloned cytokine that causes neutrophilic infiltration and induces an inflammatory response. We studied the effect of MIP-lo~ on histamine secretion from basophils and mast cells. Leukocytes from allergic and normal subjects were studied. MIP-loe caused dose-dependent release of histamine from basophils of 14 of 20 allergic donors at concentrations of 10-9-10 -7

Rafeul Alam; Patricia A. Forsythe; Susan Stafford; Michael A. Lett-Brown; J. Andrew Grant

333

Targeting GGTase-I Activates RHOA, Increases Macrophage Reverse Cholesterol Transport, and Reduces Atherosclerosis in Mice  

PubMed Central

Background Statins have antiinflammatory and antiatherogenic effects that have been attributed to inhibition of RHO protein geranylgeranylation in inflammatory cells. The activity of protein geranylgeranyltransferase type I (GGTase-I) is widely believed to promote membrane association and activation of RHO family proteins. However, we recently showed that knockout of GGTase-I in macrophages activates RHO proteins and proinflammatory signaling pathways, leading to increased cytokine production and rheumatoid arthritis. In this study, we asked whether the increased inflammatory signaling of GGTase-I–deficient macrophages would influence the development of atherosclerosis in low-density lipoprotein receptor–deficient mice. Methods and Results Aortic lesions in mice lacking GGTase-I in macrophages (Pggt1b?/?) contained significantly more T lymphocytes than the lesions in controls. Surprisingly, however, mean atherosclerotic lesion area in Pggt1b?/? mice was reduced by ?60%. GGTase-I deficiency reduced the accumulation of cholesterol esters and phospholipids in macrophages incubated with minimally modified and acetylated low-density lipoprotein. Analyses of GGTase-I–deficient macrophages revealed upregulation of the cyclooxygenase 2–peroxisome proliferator-activated-? pathway and increased scavenger receptor class B type I– and CD36-mediated basal and high-density lipoprotein–stimulated cholesterol efflux. Lentivirus-mediated knockdown of RHOA, but not RAC1 or CDC42, normalized cholesterol efflux. The increased cholesterol efflux in cultured cells was accompanied by high levels of macrophage reverse cholesterol transport and slightly reduced plasma lipid levels in vivo. Conclusions Targeting GGTase-I activates RHOA and leads to increased macrophage reverse cholesterol transport and reduced atherosclerosis development despite a significant increase in inflammation.

Khan, Omar M.; Akula, Murali K.; Skalen, Kristina; Karlsson, Christin; Stahlman, Marcus; Young, Stephen G.; Boren, Jan; Bergo, Martin O.

2013-01-01

334

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

335

Effect of macrophage colony-stimulating factor on anticryptococcal activity of bronchoalveolar macrophages: synergy with fluconazole for killing.  

PubMed Central

The anticryptococcal activity of murine bronchoalveolar macrophages (BAM) and their synergy with fluconazole (FCZ) was studied. BAM cultured with tissue culture medium for 48 to 72 h were fungicidal (24 to 39%) in a 3-h killing assay. However, net killing of Cryptococcus neoformans did not continue when culture time was extended to 24 h, although BAM were fungistatic (88 to 98%). Treatment with macrophage colony-stimulating factor (M-CSF; 5,000 U/ml, 48 h) did not significantly increase BAM killing of a low challenge dose in 3-h assays compared with control BAM. However, M-CSF-treated BAM were significantly more fungistatic against higher challenge doses in the 3-h assays. FCZ was not fungicidal at 5 micrograms/ml but was highly fungistatic (98 and 99% at 24 and 48 h, respectively). M-CSF-treated BAM acted synergistically with FCZ (2.5 micrograms/ml) for significantly greater killing than control BAM, 55% versus 20% and 96% versus 45% at 24 h and 48 h, respectively. Killing by M-CSF BAM and FCZ (5.0 micrograms/ml) was significantly (P < 0.01) greater than that by control BAM and FCZ at 48 h. These findings indicate an important collaborative role for BAM and FCZ in killing C. neoformans, and this is enhanced by M-CSF.

Brummer, E; Nassar, F; Stevens, D A

1994-01-01

336

IL-2/CD40-activated macrophages rescue age and tumor-induced T cell dysfunction in elderly mice.  

PubMed

The role of macrophages and their interactions with T cells during aging is not well understood. We determined if activating elderly-derived macrophages could rescue age-related and tumor-induced T cell dysfunction. Healthy elderly (18-24 months) Balb/c contained significantly more splenic IL-10-secreting M2-macrophages and myeloid-derived suppressor cells than young (6-8 weeks) mice. Exposure to syngeneic mesothelioma or lung carcinoma-conditioned media polarized peritoneal macrophages into suppressive M2-macrophages regardless of age. Tumor-exposed, elderly, but not young-derived, macrophages produced high levels of IL-4 and could not induce T cell IFN-? production. We attempted to rescue tumor-exposed macrophages with LPS/IFN-? (M1 stimulus) or IL-2/agonist anti-CD40 antibody. Tumor-exposed, M1-stimulated macrophages retained high CD40 expression, yet TNF-? and IFN-? production were diminished relative to non-tumor-exposed, M1-stimulated controls. These macrophages induced young and elderly-derived T cell proliferation however, T cells did not secrete IFN-?. In contrast, tumor-exposed, IL-2/CD40-stimulated macrophages rescued elderly-derived T cell IFN-? production, suggesting that IL-2/CD40-activated macrophages could rescue T cell immunity in aging hosts. PMID:24744051

Jackaman, C; Dye, D E; Nelson, D J

2014-06-01

337

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

338

Role of the programmed Death-1 pathway in the suppressive activity of alternatively activated macrophages in experimental cysticercosis.  

PubMed

We characterised a population of macrophages potentially involved in the immunoregulation induced by experimental cysticercosis. Following Taenia crassiceps infection, macrophages recruited in the peritoneal cavity were isolated and co-cultured at different ratios with T cells from naïve mice previously stimulated with anti-CD3/CD28 antibodies; these macrophages inhibited naïve T cell proliferation. This suppressive effect was Interleukin (IL)-10, Interferon-gamma (IFN-gamma), and nitric oxide (NO) independent. In contrast, macrophage-T cell contact was necessary to maintain anergy of T cells. Reverse transcriptase-PCR analysis of these macrophages showed higher transcripts of IL-10, chitinases Fizz1 and Ym1, and arginase-1 compared with naïve macrophages; by contrast, IL-12p40, and inducible nitric oxide synthase (iNOS) transcripts were undetected, whereas C-C chemokine ligand 5 (CCL5) was unchanged. Analysis of the membrane molecules expressed on Taenia-induced macrophages showed an up-regulation of several markers, mainly programmed death ligand 1 (PD-L1) and PD-L2. Blockade of PD-L1, PD-L2 or their receptor PD-1, but not of another marker, eliminated their ability to inhibit T-cell proliferation. Parallel experiments using ovalbumin (OVA)-peptide as a model antigen displayed similar results. Additionally, the same mechanism appears to be functional in splenocytes of T. crassiceps-infected mice given that blockade of PD-1, PD-L1 or PD-L2 re-established their ability to proliferate in response to parasite antigens. Moreover, Taenia-induced macrophages were able to suppress a mixed lymphocyte reaction in a PD-1-dependent manner. Thus, cestode infections induce macrophages alternatively activated with strong suppressive activity involving the PD-1/PD-L's pathway. PMID:16126211

Terrazas, Luis I; Montero, Daniel; Terrazas, César A; Reyes, José L; Rodríguez-Sosa, Miriam

2005-11-01

339

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

340

Alternatively activated RAW264.7 macrophages enhance tumor lymphangiogenesis in mouse lung adenocarcinoma.  

PubMed

Tumor-associated macrophages (TAMs) have been implicated in promoting tumor progression and invasion. The onset and maintenance of tumor angiogenesis and lymphangiogenesis also seem to be partly driven by a group of polarized alternatively activated macrophages (aaMphi) in lung adenocarcinoma. Here, the aaMphi and classically activated macrophages (caMphi) were obtained using RAW264.7 cells via IL-4 and IFN-gamma + LPS treatment, respectively. Co-inoculation of aaMphi with Lewis lung carcinoma (LLC) cells promoted tumor growth, increased lymph node metastasis, and reduced the survival in C57BL/6 mice bearing LLC. Furthermore, the effects of the activated macrophages on the lymphangiogenesis-related properties of lymphatic endothelial cells (LECs) were investigated in vitro. When LECs were cultured in macrophages conditioned medium or in a co-culture system of macrophages and LECs, aaMphi significantly promoted proliferation, migration, and tube-like formation of LECs. We identified high VEGF-C expression in aaMphi and low expression in caMphi as well as unactivated macrophages by ELISA and Western blotting. In LECs, co-culture with aaMphi resulted in a significant increase of mRNA levels of specific lymphatic marker VEGF receptor-3 and the homeobox gene Prox-1, as well as lymphangiogenic factor VEGF-C rather than VEGF-D by quantitative RT-PCR. Furthermore, enhanced LECs migration and capillary formation by co-culture with aaMphi were significantly inhibited by rVEGF receptor-3/Fc chimera. In conclusion, these data show that aaMphi play a critical role in tumor-induced lymphangiogenesis through up-regulating VEGF-C and increasing lymphangiogenesis-related behavior of LECs, which may contribute to lymphatic invasion in lung adenocarcinoma. PMID:19241443

Zhang, Bicheng; Wang, Jun; Gao, Juan; Guo, Yan; Chen, Xi; Wang, Baocheng; Gao, Jianfei; Rao, Zhiguo; Chen, Zhengtang

2009-05-01

341

Dihydro-CDDO-trifluoroethyl amide suppresses inflammatory responses in macrophages via activation of Nrf2.  

PubMed

Nuclear factor erythroid 2-related factor (Nrf2) is the major regulator of cellular defenses against various pathological stresses in a variety of organ systems, thus Nrf2 has evolved to be an attractive drug target for the treatment and/or prevention of human disease. Several synthetic oleanolic triterpenoids including dihydro-CDDO-trifluoroethyl amide (dh404) appear to be potent activators of Nrf2 and exhibit chemopreventive promises in multiple disease models. While the pharmacological efficacy of Nrf2 activators may be dependent on the nature of Nrf2 activation in specific cell types of target organs, the precise role of Nrf2 in mediating biological effects of Nrf2 activating compounds in various cell types remains to be further explored. Herein we report a unique and Nrf2-dependent anti-inflammatory profile of dh404 in inflamed macrophages. In lipopolysaccharide (LPS)-inflamed RAW264.7 macrophages, dh404 dramatically suppressed the expression of pro-inflammatory cytokines including inducible nitric oxide synthase (iNOS), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1?), while minimally regulating the expression of interleulin-6 (IL-6), IL-1?, and tumor necrosis factor alpha (TNF?). Dh404 potently activated Nrf2 signaling; however, it did not affect LPS-induced NF-?B activity. Dh404 did not interrupt the interaction of Nrf2 with its endogenous inhibitor Kelch-like ECH associating protein 1 (Keap1) in macrophages. Moreover, knockout of Nrf2 blocked the dh404-induced anti-inflammatory responses in LPS-inflamed macrophages. These results demonstrated that dh404 suppresses pro-inflammatory responses in macrophages via an activation of Nrf2 independently of Keap1 and NF-?B, suggesting a unique therapeutic potential of dh404 for specific targeting a Nrf2-mediated resolution of inflammation. PMID:24486487

Li, Bin; Abdalrahman, Akram; Lai, Yimu; Janicki, Joseph S; Ward, Keith W; Meyer, Colin J; Wang, Xing Li; Tang, Dongqi; Cui, Taixing

2014-02-21

342

Macrophage activation induced by different carbon fiber-epoxy resin composites.  

PubMed

The activation of cells by interaction with solid surfaces is important in many settings, including the response of tissue to implanted materials. However, few comprehensive studies of both cell migration and activation have been performed so that the connection between these events and immunological activation against foreign material is not well understood. In the present study, synthesis and expression of Ia antigens by peritoneal exudate macrophages after implantation of different carbon fiber composites in the rat peritoneal cavity have been investigated in order to determine whether the type of material implanted affected the composition of Ia-bearing cells of the exudate. The results have confirmed the low level of expression of Ia on resident peritoneal macrophages; while we have found that macrophages, harvested after implantation, express a different amount of Ia related to the different cure cycles of the composite material used. PMID:1869579

Peluso, G; Ambrosio, L; Cinquegrani, M; Nicolais, L; Tajana, G

1991-05-01

343

Induction of Rapid T Cell Death and Phagocytic Activity by Fas-Deficient lpr Macrophages  

PubMed Central

Peripheral T cells are maintained by the apoptosis of activated T cells through the Fas–Fas ligand system. Although it is well known that normal T cells fail to survive in the Fas-deficient immune condition, the molecular mechanism for the phenomenon has yet to be elucidated. In this study, we demonstrate that rapid cell death and clearance of normal T cells were induced by Fas-deficient lpr macrophages. Transfer of normal T cells into lpr mice revealed that Fas expression on donor T cells was promptly enhanced through the IFN-?/IFN-?R. In addition, Fas ligand expression and phagocytic activity of lpr macrophages were promoted through increased NF-?B activation. Controlling Fas expression on macrophages plays an essential role in maintaining T cell homeostasis in the peripheral immune system. Our data suggest a critical implication to the therapeutic strategies such as transplantation and immunotherapy for immune disorder or autoimmunity related to abnormal Fas expression.

Oura, Ritsuko; Arakaki, Rieko; Yamada, Akiko; Kudo, Yasusei; Tanaka, Eiji; Hayashi, Yoshio

2013-01-01

344

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.

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

2013-01-01

345

Paracrine IL33 Stimulation Enhances Lipopolysaccharide-Mediated Macrophage Activation  

Microsoft Academic Search

BackgroundIL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes

Tatsukuni Ohno; Keisuke Oboki; Hideaki Morita; Naoki Kajiwara; Ken Arae; Shizuko Tanaka; Masako Ikeda; Motoyasu Iikura; Taishin Akiyama; Jun-Ichiro Inoue; Kenji Matsumoto; Katsuko Sudo; Miyuki Azuma; Ko Okumura; Thomas Kamradt; Hirohisa Saito; Susumu Nakae; Lena Alexopoulou

2011-01-01

346

HMGB1 modulates inflammatory responses in LPS-activated macrophages  

Microsoft Academic Search

.\\u000a Objective:  As a late mediator of inflammation, high mobility group box 1 protein (HMGB1) amplifies the inflammatory responses to tissue\\u000a injury and infection by inducing and extending the production of proinflammaory cytokines. The aim was to investigate whether\\u000a HMGB1 mediates such effects by affecting the production of anti-inflammatory mediators.\\u000a \\u000a \\u000a \\u000a Materials and methods:  The murine macrophage RAW 264.7 cells were stimulated with

M. El Gazzar

2007-01-01

347

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

348

Contrasting Effects of Steroids and Mizoribine on Macrophage Activation and Glomerular Lesions in Rat Thy1 Mesangial Proliferative Glomerulonephritis  

Microsoft Academic Search

Background: Macrophages with a pro-inflammatory (M1) phenotype mediate renal injury in proliferative forms of glomerulonephritis, while alternatively activated (M2) macrophages are thought to be anti-inflammatory and promote repair. Glucocorticoids, the mainstay therapy for proliferative glomerulonephritis, can induce alternative macrophage activation in vitro, but it is unknown whether this occurs in vivo and if this is required for glucocorticoid responsiveness. In

Yohei Ikezumi; Toshiaki Suzuki; Tamaki Karasawa; Hiroya Hasegawa; Hiroshi Kawachi; David J. Nikolic-Paterson; Makoto Uchiyama

2010-01-01

349

Diminishment of  MSH anti-inflammatory activity in MC1r siRNA-transfected RAW264.7 macrophages  

Microsoft Academic Search

The neuropeptide -melanocyte-stimu- lating hormone (-MSH) is a powerful suppressor of inflammation mediated by macrophages, which express at least two receptors, melanocortin 1 and 3 receptors (MC1r and MC3r) that bind -MSH. Albeit, the anti-inflammatory activity of -MSH has been well documented in macrophages, the mech- anisms of -MSH activity in macrophages are not clearly understood. This study is to

Dayu Li; Andrew W. Taylor

2008-01-01

350

Genetic Loci Modulate Macrophage Activity and Glomerular Damage in Experimental Glomerulonephritis  

PubMed Central

The Wistar Kyoto (WKY) rat is uniquely susceptible to experimentally induced crescentic glomerulonephritis. Two major quantitative trait loci (QTLs) on chromosomes 13 (Crgn1) and 16 (Crgn2) with logarithm of odds >8, as well as five other loci (Crgn3 through 7), largely explain this genetic susceptibility. To understand further the effects of Crgn1 and Crgn2, we generated a double-congenic strain by introgressing these loci from glomerulonephritis-resistant Lewis rats onto the WKY genetic background. Induction of nephrotoxic nephritis in the double-congenic rats (WKY.LCrgn1,2) produced markedly fewer glomerular crescents, reduced macrophage infiltration, and decreased expression of glomerular TNF-? and inducible nitric oxide synthase expression compared with control animals. Bone marrow and kidney transplantation studies between parental and WKY.LCrgn1,2 strains, together with in vitro experiments, demonstrated that Crgn1 and Crgn2 contribute exclusively to circulating cell-related glomerular injury by regulating macrophage infiltration and activation. The residual genetic susceptibility to crescentic glomerulonephritis in WKY.LCrgn1,2 rats associated with macrophage activity (especially with enhanced metalloelastase expression) rather than macrophage infiltration. Taken together, these results demonstrate that a genetic influence on macrophage activation, rather than number, determines glomerular damage in immune-mediated glomerulonephritis.

Smith, Jennifer; D'Souza, Zelpha; Bhangal, Gurjeet; Chawanasuntoropoj, Ratana; Tam, Frederick W.K.; Pusey, Charles D.; Aitman, Timothy J.; Cook, H. Terence

2010-01-01

351

Gene Deficiency in Activating Fc? Receptors Influences the Macrophage Phenotypic Balance and Reduces Atherosclerosis in Mice  

PubMed Central

Immunity contributes to arterial inflammation during atherosclerosis. Oxidized low-density lipoproteins induce an autoimmune response characterized by specific antibodies and immune complexes in atherosclerotic patients. We hypothesize that specific Fc? receptors for IgG constant region participate in atherogenesis by regulating the inflammatory state of lesional macrophages. In vivo we examined the role of activating Fc? receptors in atherosclerosis progression using bone marrow transplantation from mice deficient in ?-chain (the common signaling subunit of activating Fc? receptors) to hyperlipidemic mice. Hematopoietic deficiency of Fc? receptors significantly reduced atherosclerotic lesion size, which was associated with decreased number of macrophages and T lymphocytes, and increased T regulatory cell function. Lesions of Fc? receptor deficient mice exhibited increased plaque stability, as evidenced by higher collagen and smooth muscle cell content and decreased apoptosis. These effects were independent of changes in serum lipids and antibody response to oxidized low-density lipoproteins. Activating Fc? receptor deficiency reduced pro-inflammatory gene expression, nuclear factor-?B activity, and M1 macrophages at the lesion site, while increasing anti-inflammatory genes and M2 macrophages. The decreased inflammation in the lesions was mirrored by a reduced number of classical inflammatory monocytes in blood. In vitro, lack of activating Fc? receptors attenuated foam cell formation, oxidative stress and pro-inflammatory gene expression, and increased M2-associated genes in murine macrophages. Our study demonstrates that activating Fc? receptors influence the macrophage phenotypic balance in the artery wall of atherosclerotic mice and suggests that modulation of Fc? receptor-mediated inflammatory responses could effectively suppress atherosclerosis.

Mallavia, Benat; Oguiza, Ainhoa; Lopez-Franco, Oscar; Recio, Carlota; Ortiz-Munoz, Guadalupe; Lazaro, Iolanda; Lopez-Parra, Virginia; Egido, Jesus; Gomez-Guerrero, Carmen

2013-01-01

352

Characterization of a water-soluble polysaccharide from Boletus edulis and its antitumor and immunomodulatory activities on renal cancer in mice.  

PubMed

A polysaccharide (BEP, Mw=113,432Da) was purified from Boletus edulis, which had a backbone consisting of (1?6)-linked-?-d-glucopyranosyl, (1?2,6)-linked-?-d-galactopyranosyl, (1?6)-linked-?-d-galactopyranosyl, and (1?3)-linked-?-d-rhamnopyranosyl residues, which were branched at O-2 position of (1?2,6)-linked-?-d-galactopyranosyl residue with a single terminal (1?)-linked-?-l-arabinofuranosyl residue. After 32 days' BEP administration to Renca tumor bearing mice, the tumor mass of Renca transplanted in mice was significantly repressed. Furthermore, BEP could significantly increase the spleen and thymus indices, stimulate splenocytes proliferation, augment NK cell and CTL activities in spleen, and promote the secretion of the cytokines IL-2 and TNF-? in Renca tumor bearing mice. Meanwhile oral administration of BEP (100 and 400mg/kg) restored all the altered hematological and biochemical parameters of tumor-bearing mice to normal levels. Thus, these data demonstrate that BEP possesses potential immunomodulatory activity and might be employed as effective therapeutic agents for the prevention of renal caner. PMID:24708961

Wang, Dong; Sun, Shu-Qing; Wu, Wei-Zhen; Yang, Shun-Liang; Tan, Jian-Ming

2014-05-25

353

Immunomodulatory activity of the water extract of Thymus vulgaris, Thymus daenensis, and Zataria multiflora on dendritic cells and T cells responses.  

PubMed

Thymus vulgaris (thyme), Thymus daenensis, and Zataria multiflora are medicinal plants being used widely for infections and inflammatory diseases in folk medicine. In this study, the effects of the water extract of these plants on the activation of dendritic cells (DCs) and T cells was investigated. Both T. vulgaris and Z. multiflora decreased the proliferation of mitogen-stimulated lymphocytes, whereas T. daenensis induced cell proliferation in a dose-dependent manner (p < 0.001). All the three plants increased the CD40 expression on DCs (p < 0.04). The extent of allogenic T cell proliferation in the presence of T. vulgaris and Z. multiflora extracts was significantly decreased (p < 0.02). The effect of the extracts on secretion of IFN-? and IL-4 cytokines showed that none of the extracts influenced the pattern of cytokine production by T helper (Th) cells toward a Thl or Th2 profile. In conclusion, all the extracts had the ability to activate DCs. Whereas Z. multiflora and T. vulgaris extracts showed immunoihibitory effects on allogenic T cell proliferation, the main effect of T. daenensis was on mitogenic T cell response. These data may partly explain the mechanisms underlying the beneficial immunomodulatory effects of these extracts in infections and immune-related diseases. PMID:22963488

Amirghofran, Zahra; Ahmadi, Hossein; Karimi, Mohammad Hossein

2012-01-01

354

Effects of IFN-? on intracellular trafficking and activity of macrophage NADPH oxidase flavocytochrome b558  

PubMed Central

Flavocytochrome b558, the catalytic core of the phagocyte NADPH oxidase (NOX2), mediates electron transfer from NADPH to molecular oxygen to generate superoxide, the precursor of highly ROS for host defense. Flavocytochrome b558 is an integral membrane heterodimer consisting of a large glycosylated subunit, gp91phox, and a smaller subunit, p22phox. We recently showed in murine macrophages that flavocytochrome b558 localizes to the PM and Rab11-positive recycling endosomes, whereas in primary hMDMs, gp91phox and p22phox reside in the PM and the ER. The antimicrobial activity of macrophages, including ROS production, is greatly enhanced by IFN-?, but how this is achieved is incompletely understood. To further define the mechanisms by which IFN-? enhances macrophage NADPH oxidase activity, we evaluated changes in flavocytochrome b558 expression and localization, along with NADPH oxidase activity, in IFN-? stimulated RAW 264.7 cells and primary murine BMDMs and hMDMs. We found that enhanced capacity for ROS production is, in part, a result of increased protein expression of gp91phox and p22phox but also demonstrate that IFN-? induced a shift in the predominant localization of gp91phox and p22phox from intracellular membrane compartments to the PM. Our results are the first to show that a cytokine can change the distribution of macrophage flavocytochrome b558 and provide a potential, new mechanism by which IFN-? modulates macrophage antimicrobial activity. Altogether, our data suggest that the mechanisms by which IFN-? regulates antimicrobial activity of macrophages are more complex than previously appreciated.

Casbon, Amy-Jo; Long, Matthew E.; Dunn, Kenneth W.; Allen, Lee-Ann H.; Dinauer, Mary C.

2012-01-01

355

Adipose Tissue Exosome-Like Vesicles Mediate Activation of Macrophage-Induced Insulin Resistance  

PubMed Central

OBJECTIVE We sought to determine whether exosome-like vesicles (ELVs) released from adipose tissue play a role in activation of macrophages and subsequent development of insulin resistance in a mouse model. RESEARCH DESIGN AND METHODS ELVs released from adipose tissue were purified by sucrose gradient centrifugation and labeled with green fluorescent dye and then intravenously injected into B6 ob/ob mice (obese model) or B6 mice fed a high-fat diet. The effects of injected ELVs on the activation of macrophages were determined through analysis of activation markers by fluorescence-activated cell sorter and induction of inflammatory cytokines using an ELISA. Glucose tolerance and insulin tolerance were also evaluated. Similarly, B6 mice with different gene knockouts including TLR2, TLR4, MyD88, and Toll-interleukin-1 receptor (TIR) domain–containing adaptor protein inducing interferon-? (TRIF) were also used for testing their responses to the injected ELVs. RESULTS ELVs are taken up by peripheral blood monocytes, which then differentiate into activated macrophages with increased secretion of tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6). Injection of obELVs into wild-type C57BL/6 mice results in the development of insulin resistance. When the obELVs were intravenously injected into TLR4 knockout B6 mice, the levels of glucose intolerance and insulin resistance were much lower. RBP4 is enriched in the obELVs. Bone marrow–derived macrophages preincubated with recombinant RBP4 led to attenuation of obELV-mediated induction of IL-6 and TNF-?. CONCLUSIONS ELVs released by adipose tissue can act as a mode of communication between adipose tissues and macrophages. The obELV-mediated induction of TNF-? and IL-6 in macrophages and insulin resistance requires the TLR4/TRIF pathway.

Deng, Zhong-bin; Poliakov, Anton; Hardy, Robert W.; Clements, Ronald; Liu, Cunren; Liu, Yuelong; Wang, Jianhua; Xiang, Xiaoyu; Zhang, Shuangqin; Zhuang, Xiaoying; Shah, Spandan V.; Sun, Dongmei; Michalek, Sue; Grizzle, William E.; Garvey, Timothy; Mobley, Jim; Zhang, Huang-Ge

2009-01-01

356

Involvement of protein kinase C and tyrosin kinase in tumoricidal activation of macrophage induced by Streptococcus pneumoniae type II capsular polysaccharide  

Microsoft Academic Search

Capsular polysaccharide type 2 (PS) from Streptococcus pnemoniae induced the secretory and cellular macrophage response. However, the exact mechanism by which PS regulates the macrophage functions remains unclear. In this study, we examined signal molecules which may participate in PS-elicited responses by macrophages. Our data demonstrated that tumoricidal activation of macrophages induced by PS was inhibited by either protein kinase

Sung-Hee Um; Dong-Kwon Rhee; Suhkneung Pyo

2002-01-01

357

Gut-derived substances in activation of hepatic macrophages after partial hepatectomy in rats.  

PubMed

When liver perfusion with nitro blue tetrazolium and phorbol myristate acetate was performed in rats 24 h after two-thirds liver resection, there were marked deposits of formazan converted from nitro blue tetrazolium in hepatic macrophages throughout the liver, indicating macrophage activity. The extent of the deposits was significantly reduced when perfusion was performed following oral administration of polymyxin B sulfate, a non-absorbable bacteriocidal agent against gram-negative bacilli which can also bind endotoxin lipopolysaccharides. Polymyxin B sulfate administration also attenuated the derangements of SGPT and the histological liver injury provoked by endotoxin administration after partial hepatectomy. These results suggests that gut-derived substances sensitive to polymyxin B sulfate may contribute to activation of hepatic macrophages after partial hepatectomy in rats. PMID:1487602

Mochida, S; Ohta, Y; Ogata, I; Fujiwara, K

1992-11-01

358

Signaling events during macrophage activation with Betula pendula roth pectic polysaccharides.  

PubMed

We studied the effect of two pectic polysaccharides PS-B1-AG and PS-B2-RG that were contained in total polysaccharides extracted from Betula pendula leaves on NO production by mouse macrophages and the contribution of signaling molecules to macrophage activation by the test substances. Unlike the total sample, pectins produced a NO-stimulating effect on macrophages. The effect of PS-B2-RG (10 ?g/ml) did not differ from the effect of LPS, while PS-B1-AG produced this effect only in a concentration of 20 ?g/ml, which was probably due to differences in the chemical structure of the test substances. The studied pectin polysaccharides activated transcription factor NF-?B, kinases p38 and PI3, and cAMP as a negative regulator. These results indicate that Betula pendula polysaccharides are promising substances for creation of immunomodulating drugs. PMID:24771428

Ligacheva, A A; Danilets, M G; Trofimova, E S; Belsky, Y P; Belska, N V; Zyuz'kov, G N; Zhdanov, V V; Ivanova, A N; Guriev, A M; Belousov, M V; Yusubov, M S; Dygai, A M

2014-02-01

359

Impairment of alternative macrophage activation delays cutaneous leishmaniasis in nonhealing BALB/c mice.  

PubMed

Expressed on various cell types, the IL-4Ralpha is a component of both receptors for IL-4 and IL-13. Susceptibility of BALB/c mice to Leishmania major is believed to be dependent on the development of IL-4- and IL-13-producing Th2 cells, while IFN-gamma secretion by Th1 cells is related to resistance. Despite a sustained development of Th2 cells, IL-4Ralpha-deficient BALB/c mice are able to control acute cutaneous leishmaniasis, suggesting that IL-4Ralpha-bearing cells other than Th2 cells contribute to susceptibility. To analyze the contribution of the IL-4Ralpha on macrophages, recently generated macrophage/neutrophil-specific IL-4Ralpha-deficient mice on a susceptible BALB/c genetic background were infected with L. major. Strikingly, macrophage/neutrophil-specific IL-4Ralpha-deficient mice showed a significantly delayed disease progression with normal Th2 and type 2 Ab responses but improved macrophage leishmanicidal effector functions and reduced arginase activity. Together, these results suggest that alternative macrophage activation contributes to susceptibility in cutaneous leishmaniasis. PMID:16394000

Hölscher, Christoph; Arendse, Berenice; Schwegmann, Anita; Myburgh, Elmarie; Brombacher, Frank

2006-01-15

360

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.

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

2013-01-01

361

Activation of Toll-like receptor 2 increases macrophage resistance to HIV-1 infection.  

PubMed

Patients infected with HIV-1, the etiological agent of AIDS, have increased intestinal permeability, which allows for the passage of microbial products, including Toll-like receptor (TLR) ligands, into circulation. The exposure of HIV-1-infected cells to certain TLR agonists affects viral replication, but studies associating viral production with the activation of TLR2 in HIV-1-infected cells are rare and controversial. Here, we report that the TLR2 ligands Zymosan and Pam3CSK4 potently inhibit HIV-1 replication in acutely infected monocyte-derived macrophages and the exposure to TLR2 ligands prior to infection renders macrophages refractory to HIV-1 production. Macrophage treatment with Pam3CSK4 did not change the cellular expression of the HIV-1 entry receptors CD4 and CCR5. Both TLR2 ligands increased the macrophage production of ?-chemokines and IL-10, and the blockage of these soluble factors prevented the inhibitory effect of TLR2 activation on HIV-1 replication. Our findings show that the direct engagement of TLR2 in HIV-1-infected macrophages increase cellular resistance to HIV-1 infection, and that controlling HIV-1 replication with agonists for TLR2 might have implications for the development of antiretroviral therapies. PMID:23891328

Victoria, Sabina; Temerozo, Jairo R; Gobbo, Livia; Pimenta-Inada, Haynna K; Bou-Habib, Dumith Chequer

2013-12-01

362

A novel compound, RS-1178, specifically inhibits neuronal cell death mediated by beta-amyloid-induced macrophage activation in vitro.  

PubMed

beta-Amyloid peptide (Abeta), a major component of senile plaques, the formation of which is characteristic of Alzheimer's disease (AD), is believed to induce inflammation in the brain leading to cell loss and cognitive decline. Accumulating evidence shows Abeta activates microglia, which play the role of the brain's immune system, and mediates inflammatory responses in the brain. Thus, a compound inhibiting Abeta-induced activation of microglia may lead to a novel therapy for AD. However, the compound should not inhibit natural immune responses during events such as bacterial infections. We investigated the effect of a synthesized compound, 7,8-dihydro-5-methyl-8-(1-phenylethyl)-6H-pyrrolo [3,2-e] [1,2,4] triazolo [1,5-a] pyrimidine (RS-1178) on macrophage activation induced by various stimulants. The activation of macrophages was determined by nitric oxide or tumor necrosis factor alpha production. RS-1178 inhibited Abeta-induced macrophage activation but did not inhibit zymosan A- nor lipopolysaccharide (LPS)-induced macrophage activation. Moreover, RS-1178 attenuated neurotoxicity due to Abeta-induced macrophage activation in neuron-macrophage co-cultures but not neurotoxicity due to zymosan A- or LPS-induced macrophage activation. In conclusion, RS-1178 showed a specific inhibitory effect on Abeta-induced macrophage activation. Although the exact mechanisms of this effect remain unknown, RS-1178 may provide a novel therapy for AD. PMID:12137934

Uryu, Shigeko; Tokuhiro, Shinya; Murasugi, Takako; Oda, Tomiichiro

2002-08-16

363

Macrophage activation induces formation of the anti-inflammatory lipid cholesteryl-nitrolinoleate  

PubMed Central

Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPAR? (peroxisome-proliferator-activated receptor ? ) ligand activity and electrophilic reactivity with proteins, including transcription factors. Although free or esterified lipid nitroalkene derivatives have been detected in human plasma and urine, their generation by inflammatory stimuli has not been reported. In the present study, we show increased nitration of cholesteryl-linoleate by activated murine J774.1 macrophages, yielding the mononitrated nitroalkene CLNO2 (cholesteryl-nitrolinoleate). CLNO2 levels were found to increase ~20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide plus interferon-? ; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the •NO (nitric oxide) inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO2 or LNO2 (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPAR? and •NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-?B (nuclear factor ?B) activation. Overall, these results suggest that lipid nitration occurs as part of the response of macrophages to inflammatory stimuli involving NOS2 induction and that these by-products of nitro-oxidative reactions may act as novel adaptive down-regulators of inflammatory responses.

FERREIRA, Ana M.; FERRARI, Mariana I.; TROSTCHANSKY, Andres; BATTHYANY, Carlos; SOUZA, Jose M.; ALVAREZ, Maria N.; LOPEZ, Gloria V.; BAKER, Paul R. S.; SCHOPFER, Francisco J.; O'DONNELL, Valerie; FREEMAN, Bruce A.; RUBBO, Homero

2012-01-01

364

Adiponectin Suppresses Angiotensin II-Induced Inflammation and Cardiac Fibrosis through Activation of Macrophage Autophagy.  

PubMed

Previous studies have indicated that adiponectin (APN) protects against cardiac remodeling, but the underlying mechanism remains unclear. The present study aimed to elucidate how APN regulates inflammatory responses and cardiac fibrosis in response to angiotensin II (Ang II). Male APN knockout (APN KO) mice and wild-type (WT) C57BL/6 littermates were sc infused with Ang II at 750 ng/kg per minute. Seven days after Ang II infusion, both APN KO and WT mice developed equally high blood pressure levels. However, APN KO mice developed more severe cardiac fibrosis and inflammation compared with WT mice. This finding was demonstrated by the up-regulation of collagen I, ?-smooth muscle actin, IL-1?, and TNF-? and increased macrophage infiltration in APN KO mice. Moreover, there were substantially fewer microtubule-associated protein 1 light chain 3-positive autophagosomes in macrophages in the hearts of Ang II-infused APN KO mice. Additional in vitro studies also revealed that globular APN treatment induced autophagy, inhibited Ang II-induced nuclear factor-?B activity, and enhanced the expression of antiinflammatory cytokines, including IL-10, macrophage galactose N-acetyl-galactosamine specific lectin 2, found in inflammatory zone 1, and type-1 arginase in macrophages. In contrast, APN-induced autophagy and antiinflammatory cytokine expression was diminished in Atg5-knockdown macrophages or by Compound C, an inhibitor of adenosine 5'-monophosphate-activated protein kinase. Our study indicates that APN activates macrophage autophagy through the adenosine 5'-monophosphate-activated protein kinase pathway and suppresses Ang II-induced inflammatory responses, thereby reducing the extent of cardiac fibrosis. PMID:24684303

Qi, Guan-Ming; Jia, Li-Xin; Li, Yu-Lin; Li, Hui-Hua; Du, Jie

2014-06-01

365

Incorporation of recombinant gamma interferon into liposomes enhances its ability to induce peritoneal macrophage antitoxoplasma activity.  

PubMed Central

In this study we compared the ability of free- and liposome-incorporated murine recombinant gamma interferon (rIFN-gamma) to enhance peritoneal macrophage H2O2 release and antitoxoplasma activity in vitro. rIFN-gamma was efficiently (37 to 47%) incorporated into multilamellar vesicles composed of phosphatidylglycerol/cholesterol in a 2:1 molar ratio. The amount of rIFN-gamma incorporated into multilamellar vesicles and added to macrophages (0.1 to 1,000 U/ml) was quantitated with [3H]rIFN-gamma. The concentration of liposomal rIFN-gamma required to enhance macrophage H2O2 release (1 U/ml) and maximally inhibit Toxoplasma gondii growth (10 U/ml) was one-tenth the concentration required for free rIFN-gamma (10 and 100 U/ml, respectively). This increase in potency was observed in both thioglycolate-elicited and resident peritoneal macrophages. Control liposomes containing encapsulated buffer had no effect on the potency of free rIFN-gamma. The duration of macrophage activation induced by 24 h of liposomal rIFN-gamma treatment was also considerably longer than that induced by free rIFN-gamma (2 days versu