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Proinflammatory Mediators (proinflammatory + mediator)
Selected AbstractsProinflammatory mediator,induced reversal of CD4+,CD25+ regulatory T cell,mediated suppression in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 3 2007Jocea M. R. van Amelsfort Objective We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg,mediated suppression. Methods Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25, and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor , (TNF,), or IL-7. Results Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25, and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg,mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNF,, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg,mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression. Conclusion Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA. [source] The proinflammatory activity of recombinant serum amyloid A is not shared by the endogenous protein in the circulationARTHRITIS & RHEUMATISM, Issue 6 2010Lena Björkman Objective Elevated serum levels of the acute-phase protein serum amyloid A (SAA) are a marker for active rheumatoid arthritis (RA), and SAA can also be found in the tissues of patients with active RA. Based on a number of studies with recombinant SAA (rSAA), the protein has been suggested to be a potent proinflammatory mediator that activates human neutrophils, but whether endogenous SAA shares these proinflammatory activities has not been directly addressed. The present study was undertaken to investigate whether SAA in the plasma of patients with RA possesses proinflammatory properties and activates neutrophils in a manner similar to that of the recombinant protein. Methods Neutrophil activation was monitored by flow cytometry, based on L-selectin shedding from cell surfaces. Whole blood samples from healthy subjects and from RA patients with highly elevated SAA levels were studied before and after stimulation with rSAA as well as purified endogenous SAA. Results Recombinant SAA potently induced cleavage of L-selectin from neutrophils and in whole blood samples. Despite highly elevated SAA levels, L-selectin was not down-regulated on RA patient neutrophils as compared with neutrophils from healthy controls. Spiking SAA-rich whole blood samples from RA patients with rSAA, however, resulted in L-selectin shedding. In addition, SAA purified from human plasma was completely devoid of neutrophil- or macrophage-activating capacity. Conclusion The present findings show that rSAA is proinflammatory but that this activity is not shared by endogenous SAA, either when present in the circulation of RA patients or when purified from plasma during an acute-phase response. [source] Hypoxia and glucocorticoid signaling converge to regulate macrophage migration inhibitory factor gene expressionARTHRITIS & RHEUMATISM, Issue 8 2009Laura M. Elsby Objective Macrophage migration inhibitory factor (MIF) is a proinflammatory mediator involved in the pathogenesis of rheumatoid arthritis. This study was undertaken to identify the MIF promoter elements responsible for regulating gene expression. Methods Luciferase reporter gene assays were used to identify the MIF promoter sequence responsible for basal activity. Bioinformatic analysis was used to predict transcription factor binding sites, and electrophoretic mobility shift assay (EMSA) was used to demonstrate transcription factor binding. Chromatin immunoprecipitation (ChIP) was used to demonstrate transcription factor loading on the MIF promoter. Results We identified the minimal promoter sequence required for basal MIF promoter activity that was also capable of conferring glucocorticoid-dependent inhibition in a T lymphocyte model cell line. Deletion studies and EMSA revealed 2 elements in the MIF promoter that were responsible for basal promoter activity. The 5, element binds CREB/activating transcription factor 1, and the 3, element is a functional hypoxia-responsive element binding hypoxia-inducible factor 1,. Further studies demonstrated that the cis elements are both required for glucocorticoid-dependent inhibition. ChIP demonstrated glucocorticoid-dependent recruitment of glucocorticoid receptor , to the MIF promoter in lymphocytes within 1 hour of treatment and a concomitant decrease in acetylated histone H3. Conclusion Our findings indicate that hypoxia and glucocorticoid signaling converge on a single element regulating MIF; this regulatory unit is a potential interacting node for microenvironment sensing of oxygen tension and glucocorticoid action in foci of inflammation. [source] High mobility group box chromosomal protein 1: A novel proinflammatory mediator in synovitisARTHRITIS & RHEUMATISM, Issue 10 2002R. Kokkola Objective High mobility group box chromosomal protein 1 (HMGB-1) is a ubiquitous chromatin component expressed in nucleated mammalian cells. It has recently and unexpectedly been demonstrated that stimulated live mononuclear phagocytes secrete HMGB-1, which then acts as a potent factor that causes inflammation and protease activation. Macrophages play pivotal roles in the pathogenesis of arthritis. The aim of this study was to determine whether synovial macrophage expression of HMGB-1 is altered in human and experimental synovitis. Methods Intraarticular tissue specimens were obtained from healthy Lewis rats, Lewis rats with Mycobacterium tuberculosis,induced adjuvant arthritis, and from patients with rheumatoid arthritis (RA). Specimens were immunohistochemically stained for cellular HMGB-1. Extracellular HMGB-1 levels were assessed in synovial fluid samples from RA patients by Western blotting. Results Immunostaining of specimens from normal rats showed that HMGB-1 was primarily confined to the nucleus of synoviocytes and chondrocytes, with occasional cytoplasmic staining and no extracellular matrix deposition. In contrast, inflammatory synovial tissue from rats with experimental arthritis as well as from humans with RA showed a distinctly different HMGB-1 staining pattern. Nuclear HMGB-1 expression was accompanied by a cytoplasmic staining in many mononuclear cells, with a macrophage-like appearance and an extracellular matrix deposition. Analysis of synovial fluid samples from RA patients further confirmed the extracellular presence of HMGB-1; 14 of 15 samples had HMGB-1 concentrations of 1.8,10.4 ,g/ml. Conclusion The proinflammatory mediator HMGB-1 was abundantly expressed as a nuclear, cytoplasmic, and extracellular component in synovial tissues from RA patients and from rats with experimental arthritis. These findings suggest a pathogenetic role for HMGB-1 in synovitis and indicate a new potential therapeutic target molecule. [source] Ex vivo TCR-induced leukocyte gene expression of inflammatory mediators is increased in type 1 diabetic patients but not in overweight childrenDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2010Jaime S. Rosa Abstract Background Abnormal systemic concentrations of proinflammatory cytokines/chemokines have been implicated in the development of long-term cardiovascular complications in type 1 diabetes (T1DM) and obesity. Whether leukocyte white blood cell (WBC) gene expression of these proinflammatory mediators contributes to their increased systemic levels, however, remains unclear, especially in the pediatric patient populations. This study examines mRNA changes of 9 cytokines and chemokines in WBCs following ex vivo immunostimulation from 9 T1DM (13.4 ± 0.5 year, 4F/5 M), 23 overweight (OW, 12.3 ± 0.5 year, 10F/13M, BMI% 97.1 ± 0.5 and > 90.0), and 21 healthy (CL, 13.8 ± 0.7 year, 9F/12 M, BMI% 59.6 ± 4.6 and < 85.0) children. Methods All subjects had been maintained in euglycemic conditions for at least 90 min before blood draws. Whole blood was then sampled and incubated with anti-T-cell receptor (TCR) antibody or heat-aggregated IgG (HAG) to stimulate T-cell and Fc receptors (FcR), respectively. After lysis of leukocytes, mRNA levels of six tumor necrosis factor superfamily cytokines (TNFSF2, 5, 6, 7, 9, 14) and three chemokines (CCL8, 20, and CXCL10) were measured using RT-PCR. Results Following TCR stimulation, T1DM displayed significantly greater mRNA responses than CL for TNFSF5, 7, 9, and CCL8, and CXCL10; TNFSF9, CCL8, and CXCL10 were also significantly higher in T1DM than OW; no difference was observed between OW and CL. FcR stimulation induced similar responses across groups. Conclusions Leukocytes of T1DM children displayed exaggerated gene expression in response to ex vivo TCR induction of five key proinflammatory cytokines/chemokines. This elevated leukocyte gene expression may be one of the pathophysiological contributors to the development of vascular complications in T1DM. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effects of co-culture of amoebae with indoor microbes on their cytotoxic and proinflammatory potentialENVIRONMENTAL TOXICOLOGY, Issue 4 2007Terhi Yli-Pirilä Abstract Free-living amoebae are ubiquitous environmental protozoa found in both natural and man-made environments, including moisture-damaged buildings. Furthermore, the interaction between amoebae and bacteria has been shown to enhance the virulence and pathogenicity of some bacteria. While the inhabitants of moisture damaged buildings are known to be at risk of suffering adverse health effects, the exact causative agents and mechanisms are still obscure. To examine the possible role of amoebae in the health effects associated with moisture damages, the effects of amoebae on the cytotoxicity and proinflammatory potential of nonpathogenic microbes common in moisture-damaged buildings were investigated. First, two bacterial and three fungal strains were cultured both individually and in coculture with Acanthamoeba polyphaga. Then, mouse RAW264.7 macrophages were exposed to the cocultures as well as the individually grown bacteria, fungi, and amoebae. Finally, cell viability and production of proinflammatory mediators, i.e., nitric oxide (NO), tumor necrosis factor , (TNF-,), and interleukin 6 (IL-6), were measured in macrophages after the exposure. The results revealed that cocultivation with amoebae increased the cytotoxicity of the bacterium Streptomyces californicus and the fungus Penicillium spinulosum. Moreover, the macrophages produced up to 10 times higher concentrations of NO after the exposure to these cocultures than after the exposure to individually grown microbes. Finally, the production of the cytokines was up to two orders of magnitude higher (IL-6) and up to four times higher (TNF-,) after exposure to the cocultures when compared to individually grown microbes. We conclude that amoebae are able to potentiate the cytotoxicity and proinflammatory properties of certain microbes associated with moisture damages. © 2007 Wiley Periodicals, Inc. Environ Toxicol 22: 357,367, 2007. [source] Role of the pro-inflammatory cytokines TNF-, and IL-1, in HIV-associated dementiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2006N. A. C. H. Brabers Abstract Human immunodeficiency virus-1 (HIV-1)-infected and immune-activated macrophages and microglia secrete neurotoxins. Two of these neurotoxins are the pro-inflammatory cytokines tumour necrosis factor-, (TNF-,) and interleukin-1, (IL-1,), which are thought to play a major role in inducing neuronal death. Both TNF-, and IL-1, increase the permeability of the blood,brain barrier, through which subsequently HIV-infected monocytes can enter the brain. They both induce over-stimulation of the NMDA-receptor via several pathways, resulting in a lethal neuronal increase in Ca2+ levels. Additionally, TNF-, co-operates with several other proinflammatory mediators to enhance their toxic effects. Although most research has focused on the neurotoxic effects of TNF-, and IL-1, in HAD, there is also evidence that these cytokines can be neuroprotective. In this paper the effect of TNF-, and IL-1, on neuronal life and death in HAD is discussed. [source] AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase-2 mRNA by inhibiting mitogen-activated protein kinase p38EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2004Pilar Alcaide Abstract Secretion of proinflammatory mediators by activated macrophages plays an important role in the immune response to Trypanosoma cruzi. We have previously reported that AgC10, a glycosylphosphatidylinositol-anchored mucin from T. cruzi, inhibits TNF secretion by activated macrophages (de Diego, J., Punzon, C., Duarte, M. and Fresno, M., Alteration of macrophage function bya Trypanosoma cruzi membrane mucin. J. Immunol. 1997. 159: 4983,4989). In this report we have further investigated the molecular mechanisms underlying this inhibition. AgC10 inhibited TNF, IL-10 and cyclooxygenase-2 (COX-2) synthesis by macrophages activated with LPS or LPS plus IFN-, in a dose-dependent manner. AgC10 did not affect other aspects of macrophage activation induced by LPS, such as inducible nitric oxide synthase (iNOS) expression. AgC10 also had no effect on TNF or COX-2 transcription or the induction of their promoters but inhibited the stability of TNF and COX-2 mRNA, which are regulated post-transcriptionally by the mitogen-activated protein kinase (MAPK) p38 pathway. AgC10 was found to inhibit both the activation and the activity of p38 MAPK, since MAPK activated protein kinase-2 (MAPKAP-K2 or MK-2) phosphorylation was also strongly inhibited. This led to TNF and COX-2 mRNA destabilization. In contrast, AgC10 did not affect p38 activation induced by TNF. Furthermore, AgC10 inhibition must lie upstream in the MAPK activation pathway by LPS, since this mucin also inhibited extracellularly regulated kinase (ERK) and Jun kinase (JNK)activation. [source] Rhinovirus increases human ,-defensin-2 and -3 mRNA expression in cultured bronchial epithelial cellsFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 1 2003Louise A Duits Abstract Human ,-defensins (hBDs) are antimicrobial peptides that play important roles in host defense against infection, inflammation and immunity. Previous studies showed that micro-organisms and proinflammatory mediators regulate the expression of these peptides in airway epithelial cells. The aim of the present study was to investigate the modulation of expression of hBDs in cultured primary bronchial epithelial cells (PBEC) by rhinovirus-16 (RV16), a respiratory virus responsible for the common cold and associated with asthma exacerbations. RV16 was found to induce expression of hBD-2 and -3 mRNA in PBEC, but did not affect hBD-1 mRNA. Viral replication appeared essential for rhinovirus-induced ,-defensin mRNA expression, since UV-inactivated rhinovirus did not increase expression of hBD-2 and hBD-3 mRNA. Exposure to synthetic double-stranded RNA (dsRNA) molecule polyinosinic:polycytidylic acid had a similar effect as RV16 on mRNA expression of these peptides in PBEC. In line with this, PBEC were found to express TLR3, a Toll-like receptor involved in recognition of dsRNA. This study shows that rhinovirus infection of PBEC leads to increased hBD-2 and hBD-3 mRNA expression, which may play a role in both the uncomplicated common cold and in virus-associated exacerbations of asthma. [source] Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injuryGLIA, Issue 3 2008Aaron Y. Lai Abstract Microglial activation has been reported to promote neurotoxicity and also neuroprotective effects. A possible contributor to this dichotomy of responses may be the degree to which proximal neurons are injured. The aim of this study was to determine whether varying the severity of neuronal injury influenced whether microglia were neuroprotective or neurotoxic. We exposed cortical neuronal cultures to varying degrees of hypoxia thereby generating mild (<20% death, 30min hypoxia), moderate (40,60% death, 2 h hypoxia), or severe (>70% death, 6 h hypoxia) injuries. Twenty-four hours after hypoxia, the media from the neuronal cultures was collected and incubated with primary microglial cultures for 24 h. Results showed that the classic microglial proinflammatory mediators including inducible nitric oxide synthase, tumor necrosis factor ,, and interleukin-1-, were upregulated only in response to mild neuronal injuries, while the trophic microglial effectors brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor were upregulated in response to all degrees of neuronal injury. Microglia stimulated with media from damaged neurons were co-cultured with hypoxic neurons. Microglia stimulated by moderate, but not mild or severe damage were neuroprotective in these co-cultures. We also showed that the severity-dependent phenomenon was not related to autocrine microglial signaling and was dependent on the neurotransmitters released by neurons after injury, namely glutamate and adenosine 5,-triphosphate. Together our results show that severity of neuronal injury is an important factor in determining microglial release of "toxic" versus "protective" effectors and the resulting neurotoxicity versus neuroprotection. © 2007 Wiley-Liss, Inc. [source] Tumor necrosis factor is required for RANTES-induced astrocyte monocyte chemoattractant protein-1 productionGLIA, Issue 2 2003Yi Luo Abstract Astrocytes respond to stimulation with the chemokine RANTES (regulated on activation, normal T cell expressed) by production of a series of cytokines and chemokines, including tumor necrosis factor-, (TNF-,) and monocyte chemoattractant protein-1 (MCP-1). In the present study we demonstrate that RANTES induces TNF, which in turn stimulates subsequent production of MCP-1. TNF-R1 (p55) serves as the principal receptor responsible for MCP-1 synthesis. The results define an astrocyte proinflammatory cascade that amplifies synthesis of proinflammatory mediators. The implications of these findings to inflammatory diseases of the central nervous system are discussed. © 2003 Wiley-Liss, Inc. [source] RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytesGLIA, Issue 1 2002Yi Luo Abstract Cultured mouse astrocytes respond to the CC chemokine RANTES by production of chemokine and cytokine transcripts. Stimulation of astrocytes with 1 nM RANTES or 3,10 nM of the structurally related chemokines (eotaxin, macrophage inflammatory protein-1, and -, [MIP-1,, MIP-1,]) induced transcripts for KC, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-, (TNF-,), MIP-1,, MIP-2, and RANTES in a chemokine and cell-specific fashion. Synthesis of chemokine (KC and MCP-1) and cytokine (TNF-,) proteins was also demonstrated. RANTES-mediated chemokine synthesis was specifically inhibited by pertussis toxin, indicating that G-protein-coupled chemokine receptors participated in astrocyte signaling. Astrocytes expressed CCR1 and CCR5 (the redundant RANTES receptors). Astrocytes derived from mice with targeted mutations of either CCR1 or CCR5 respond after RANTES stimulation, suggesting multiple chemokine receptors may separately mediate RANTES responsiveness in astrocytes. Preliminary data suggest activation of the MAP kinase pathway is also critical for RANTES-mediated signaling in astrocytes. Treatment with RANTES specifically modulated astrocyte receptors upregulating intercellular adhesion molecule 1 (ICAM-1) and downregulating CX3CR1 expression. Thus, after chemokine treatment, astrocytes release proinflammatory mediators and reprogram their surface molecules. The combined effects of RANTES may serve to amplify inflammatory responses within the central nervous system. GLIA 39:19,30, 2002. © 2002 Wiley-Liss, Inc. [source] Nitric oxide suppresses transforming growth factor-,1,induced epithelial-to-mesenchymal transition and apoptosis in mouse hepatocytes,HEPATOLOGY, Issue 5 2009Xinchao Pan Nitric oxide (NO) is a multifunctional regulator that is implicated in various physiological and pathological processes. Here we report that administration of NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibited transforming growth factor-,1 (TGF-,1)-induced epithelial-to-mesenchymal transition (EMT) and apoptosis in mouse hepatocytes. Overexpression of inducible NO synthase (iNOS) by transfection of the iNOS-expressing vector, which increased NO production, also inhibited the TGF-,1-induced EMT and apoptosis in these cells. Treatment of cells with proinflammatory mediators, including tumor necrosis factor (TNF)-,, interleukin (IL)-1,, and interferon (IFN)-,, which increased the endogenous NO production, produced the same inhibitory effect. Furthermore, exogenous NO donor SNAP treatment caused a decrease in the intracellular adenosine triphosphate (ATP) levels. Consistently, depletion of intracellular ATP by mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) inhibited the TGF-,1-induced EMT and apoptosis, suggesting that an NO-induced decrease of ATP involved in the NO-mediated inhibition of TGF-,1-induced EMT and apoptosis. NO and FCCP also inhibited TGF-,1-induced STAT3 activation, suggesting that signal transducer and activator of transcription 3 inactivation is involved in the NO-induced effects on TGF-,1-induced EMT and apoptosis. Conclusion: Our study indicates that NO plays an important role in the inhibition of TGF-,1-induced EMT and apoptosis in mouse hepatocytes through the downregulation of intracellular ATP levels. The data provide an insight into the in vivo mechanisms on the function of NO during the processes of both EMT and apoptosis. (HEPATOLOGY 2009.) [source] Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogueIMMUNOLOGY, Issue 2 2003Mark A. Wortinger Summary Fas ligand (FasL)-induced lung inflammation has recently been suggested to play an important role in the pathogenesis of acute respiratory disease syndrome (ARDS). In order to further explore this connection, we established a FasL-induced murine model of pulmonary inflammation. Instillation of recombinant FasL (rFasL) into the lung induced neutrophil infiltration and increased pulmonary permeability, as evidenced by increased total protein in the airspace; both occur in patients with ARDS. These effects were accompanied with a rapid induction of proinflammatory mediators: cytokine granulocyte,macrophage colony-stimulating factor (GM-CSF) and the chemokines macrophage inflammatory protein-2 (MIP-2) and KC. Pretreatment with a FasL antagonist, a decoy receptor 3 analogue (DcR3 analogue), reduced neutrophil infiltration into the airspace and resulted in a highly significant reduction in the levels of GM-CSF, MIP-2 and KC in bronchoalveolar lavage (BAL) fluid. We postulate that rFasL may be responsible for induction of proinflammatory chemokines and cytokines in the lung, which in turn attract neutrophil infiltration into the airspace. This proinflammatory process and the associated pulmonary permeability may, in part, explain the association of FasL with severe pulmonary inflammation, such as ARDS, and shed new light on FasL and its role in lung injury. [source] Mechanisms by which inflammation may increase intestinal cancer risk in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 8 2010Pamela M. O'Connor PhD Abstract Patients with ulcerative colitis and Crohn's disease are at increased risk of developing intestinal cancers via mechanisms that remain incompletely understood. However, chronic inflammation and repeated events of inflammatory relapse in inflammatory bowel disease (IBD) expose these patients to a number of signals known to have tumorigenic effects including persistent activation of the nuclear factor-,B and cyclooxygenase-2/prostaglandin pathways, release of proinflammatory mediators such as tumor necrosis factor-, and interleukin-6, and enhanced local levels of reactive oxygen and nitrogen species. These inflammatory signals can contribute to carcinogenesis via 3 major processes: 1) by increasing oxidative stress, which promotes DNA mutagenesis thus contributing to tumor initiation; 2) by activating prosurvival and antiapoptotic pathways in epithelial cells, thereby contributing to tumor promotion; and 3) by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of tumor cells, thus supporting tumor progression and metastasis. The present review integrates clinical and basic research observations in an attempt to provide a comprehensive understanding of how inflammatory processes may contribute to intestinal cancer development in IBD patients. (Inflamm Bowel Dis 2010) [source] Carcinoid tumors are 15 times more common in patients with Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 9 2007N.E. West Abstract Background: The coexistence of intestinal neoplasms with Crohn's disease (CD) has been reported, but the evidence of an increased risk of carcinoid tumor with Crohn's disease has been mixed. We present 4 patients with CD with associated carcinoid tumor. Methods: The charts of 111 patients with CD who had undergone resection between June 2001 and March 2005 were reviewed. The number of incidental carcinoid tumors in patients who underwent an appendectomy was used as a control. Results: Four cases of carcinoid tumor discovered in patients at resection for CD were identified. None had metastatic disease or carcinoid syndrome. These included 1 cecal (1 mm), 2 appendiceal (3 and 7mm), and 1 transverse colon (7 mm) carcinoid tumors. None of the carcinoid tumors were identified in regions of active Crohn's disease. The incidence of carcinoid tumor in patients with Crohn's disease was 4 of 111 (3.6%). In comparison, 3 of 1199 patients (0.25%) who had appendectomies were identified as having appendiceal carcinoid tumor. Crohn's disease was associated with an increased incidence of carcinoid tumor; OR 14.9 (95% CI 2.5,102.5), P < 0.0001. Conclusions: There was a significantly increased incidence of carcinoid tumor in our Crohn's patients compared to the control patients. None of the carcinoid tumors developed in areas of Crohn's disease. This suggests that the development of carcinoid tumors may be secondary to distant proinflammatory mediators, rather than a local inflammatory effect from adjacent Crohn's disease. Patients with CD may be at increased risk of developing a carcinoid tumor. (Inflamm Bowel Dis 2007) [source] Downregulation of inducible nitric oxide synthetase by neurotrophin-3 in microgliaJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2003Shun-Fen Tzeng Abstract Microglia activated after many neurological degeneration of the central nervous system (CNS) act as important regulators for neuropathogenesis in the injured CNS via producing proinflammatory mediators, such as nitric oxide (NO), TNF-,, and IL-1,. Neurotrophin-3 (NT-3) is a well-known trophic factor for neural survival, development, and plasticity. Activated microglia are NT-3-producing cells in the injured CNS, and express its receptor-TrkC. However, little is known about the effect of NT-3 on activated microglia. In this study, pre-treatment of a mouse microglial cell line, BV2, with NT-3 for 24 h indicated that NT-3 reduced the inducible form of NO synthase (iNOS), NO, and TNF-, in BV2 stimulated with lipopolysaccharide (LPS). NT-3 exerted less effect on the reduction of these proinflammatory mediators when it was added to BV2 cultures either simultaneously with LPS or post LPS treatment. These findings indicate that NT-3 may serve as an anti-inflammatory factor to suppress microglial activation. J. Cell. Biochem. 90: 227,233, 2003. © 2003 Wiley-Liss, Inc. [source] Modulation of peroxisome proliferator-activated receptor-, activity by N -acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial culturesJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Manjeet K. Paintlia Abstract Glial cells secrete proinflammatory mediators in the brain in response to exogenous stimuli such as infection and injury. Previously, we documented that systemic maternal lipopolysaccharide (LPS)-exposure at embryonic gestation day 18 causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by N -acetyl cysteine (NAC; precursor of glutathione). The present study delineates the underlying mechanism of NAC-mediated attenuation of inhibition of OL development in LPS-stimulated mixed glial cultures. Factors released by LPS-stimulated mixed glial cultures inhibited OL development as shown by decrease in both proliferation 3bromo-deoxyuridine+/chondroitin sulfate proteoglycan,NG2+, hereafter BrdU+/NG+ and differentiation (O4+ and myelin basic protein+) of OL-progenitors. Correspondingly, an impairment of peroxisomal proliferation was shown by a decrease in the level of peroxisomal proteins in the developing OLs following exposure to LPS-conditioned media (LCM). Both NAC and WY14643, a peroxisome proliferator-activated receptor (PPAR)-, agonist attenuated these LCM-induced effects in OL-progenitors. Similar to WY14643, NAC attenuated LCM-induced inhibition of PPAR-, activity in developing OLs. Studies conducted with cytokines and diamide (a thiol-depleting agent) confirmed that cytokines are active agents in LCM which may be responsible for inhibition of OL development via peroxisomal dysfunction and induction of oxidative stress. These findings were further corroborated by similar treatment of developing OLs generated from PPAR-,(,/,) and wild-type mice or B12 oligodendroglial cells co-transfected with PPAR-, small interfering RNAs/pTK-PPREx3-Luc plasmids. Collectively, these data provide evidence that the modulation of PPAR-, activity, thus peroxisomal function by NAC attenuates LPS-induced glial factors-mediated inhibition of OL development suggesting new therapeutic interventions to prevent the devastating effects of maternal infections. [source] Inflammation: A new candidate in modulating adult neurogenesisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2008Sulagna Das Abstract Any pathological perturbation to the brain provokes a cascade of molecular and cellular events, which manifests in the form of microglial activation and release of various proinflammatory molecules. This eventually culminates in a profound neuroinflammatory reaction that characterizes the brain's response to stress, injury, or infection. The inflammatory cascade is an attempt by the system to eliminate the challenge imposed on the brain, clear the system of the dead and damaged neurons, and rescue the normal functioning of this vital organ. However, during the process of microglial activation, the proinflammatory mediators released exert certain detrimental effects, and neural stem cells and progenitor cells are likely to be affected. Here we review how the proliferation, maturation, and migration of the neural stem cells are modulated under such an inflammatory condition. The fate of the noncommitted neural stem cells and its differentiation potency are often under strict regulation, and these proinflammatory mediators seem to disrupt this critical balance and finely tune the neurogenesis pattern in the two niches of neurogenesis, the subventricular zone and the subgranular zone of the hippocampus. Moreover, the migration ability of these stem cells, which is important for localization to the proper site, is also affected in a major way by the chemokines released following inflammation. © 2007 Wiley-Liss, Inc. [source] Anti-inflammatory effects of continuous passive motion on meniscal fibrocartilageJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2005Mario Ferretti Abstract Motion-based therapies have been applied to promote healing of arthritic joints. The goal of the current study was to determine the early molecular events that are responsible for the beneficial actions of motion-based therapies on meniscal fibrocartilage. Rabbit knees with Antigen-Induced-Arthritis (AIA) were exposed to continuous passive motion (CPM) for 24 or 48 h and compared to immobilized knees. The menisci were harvested and glycosaminoglycans (GAG), interleukin-1, (IL-1,), matrix metalloproteinase-1 (MMP-1), cyclooxygenase-2 (COX-2), and interleukin-10 (IL-10) were determined by histochemical analysis. Within 24 h, immobilized knees exhibited marked GAG degradation. The expression of proinflammatory mediators MMP-1, COX-2, and IL-1, was notably increased within 24 h and continued to increase during the next 24 h in immobilized knees. Knees subjected to CPM revealed a rapid and sustained decrease in GAG degradation and the expression of all proinflammatory mediators during the entire period of CPM treatment. More importantly, CPM induced synthesis of the anti-inflammatory cytokine IL-10. The results demonstrate that mechanical signals generated by CPM exert potent anti-inflammatory signals on meniscal fibrochondrocytes. Furthermore, these studies explain the molecular basis of the beneficial effects of CPM observed on articular cartilage and suggest that CPM suppresses the inflammatory process of arthritis more efficiently than immobilization. © 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Localized antimicrobial peptide expression in human gingivaJOURNAL OF PERIODONTAL RESEARCH, Issue 5 2001Beverly A. Dale The stratified epithelia of the oral cavity are continually exposed to bacterial challenge that is initially resisted by innate epithelial factors and by the recruitment of neutrophils. Antimicrobial peptides from phagocytes and epithelia contribute to this antimicrobial barrier. Using antibodies and in situ hybridization, we explored antimicrobial peptide expression in the varied epithelia of the periodontium and in cultured gingival epithelial cells. In gingival tissue, mRNA for the ,-defensins, human beta-defensin 1 (hBD-1) and human beta-defensin 2 (hBD-2) was predominately localized in suprabasal stratified epithelium and the peptides were detected in upper epithelial layers consistent with the formation of the stratified epithelial barrier. In cultured epithelial cells, both hBD-1 and -2 peptides were detected only in differentiating, involucrin-positive epithelial cells, although hBD-2 required stimulation by proinflammatory mediators or bacterial products for expression. ,-defensins were not detected in junctional epithelium (JE) that serves as the attachment to the tooth surface. In contrast, ,-defensins and cathelicidin family member LL-37 were detected in polymorphonuclear neutrophils (PMNs) that migrate through the JE, a localization that persists during inflammation, when the JE and surrounding tissue are highly infiltrated with PMNs. Thus, the undifferentiated JE contains exogenously expressed ,-defensins and LL-37, and the stratified epithelium contains endogenously expressed ,-defensins. These findings show that defensins and other antimicrobial peptides are localized in specific sites in the gingiva, are synthesized in different cell types, and are likely to serve different roles in various regions of the periodontium. [source] Melatonin protects against endosulfan-induced oxidative tissue damage in ratsJOURNAL OF PINEAL RESEARCH, Issue 4 2008Gülden Z. Omurtag Abstract:, Endosulfan is a chlorinated cyclodiene insecticide which induces oxidative stress. In this study, we investigated the possible protective effect of melatonin, an antioxidant agent, against endosulfan (Endo)-induced toxicity in rats. Wistar albino rats (n = 8) were administered endosulfan (22 mg/kg/day orally) followed by either saline (Endo group) or melatonin (10 mg/kg/day, Endo + Mel group) for 5 days. In other rats, saline (control group) or melatonin (10 mg/kg/day, Mel group) was injected for 5 days, following corn oil administration (vehicle of endosulfan). Measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were performed in liver and kidney. Furthermore, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine levels, lactate dehydrogenase (LDH) activity were measured in the serum samples, while tumor necrosis factor-, (TNF-,), interleukin-, (IL-,) and total antioxidant capacity (AOC) were assayed in plasma samples. Endosulfan administration caused a significant decrease in tissue GSH and plasma AOC, which was accompanied with significant rises in tissue MDA and collagen levels and MPO activity. Moreover, the proinflammatory mediators (TNF-, and IL-,), LDH activity, AST, ALT, creatinine and BUN levels were significantly elevated in the endosulfan-treated rats. On the other hand, melatonin treatment reversed all these biochemical alterations induced by endosulfan. Our results suggest that oxidative mechanisms play an important role in endosulfan-induced tissue damage and melatonin, by inhibiting neutrophil infiltration, balancing oxidant,antioxidant status and regulating the generation of inflammatory mediators, ameliorates oxidative organ injury as a result of endosulfan toxicity. [source] The Physiology of Endothelial Xanthine Oxidase: From Urate Catabolism to Reperfusion Injury to Inflammatory Signal TransductionMICROCIRCULATION, Issue 3 2002AVEDIS MENESHIAN ABSTRACT Xanthine oxidoreductase (XOR) is a ubiquitous metalloflavoprotein that appears in two interconvertible yet functionally distinct forms: xanthine dehydrogenase (XD), which is constitutively expressed in vivo; and xanthine oxidase (XO), which is generated by the posttranslational modification of XD, either through the reversible, incremental thiol oxidation of sulfhydryl residues on XD or the irreversible proteolytic cleavage of a segment of XD, which occurs at low oxygen tension and in the presence of several proinflammatory mediators. Functionally, both XD and XO catalyze the oxidation of purines to urate. However, whereas XD requires NAD+ as an electron acceptor for these redox reactions, thereby generating the stable product NADH, XO is unable to use NAD+ as an electron acceptor, requiring instead the reduction of molecular oxygen for this purine oxidation and generating the highly reactive superoxide free radical. Nearly 100 years of study has documented the physiologic role of XD in urate catabolism. However, the rapid, posttranslational conversion of XD to the oxidantgenerating form XO provides a possible physiologic mechanism for rapid, posttranslational, oxidant-mediated signaling. XO-generated reactive oxygen species (ROS) have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury and multisystem organ failure. More recently, the concept of physiologic signal transduction mediated by ROS has been proposed, and the possibility of XD to XO conversion, with subsequent ROS generation, serving as the trigger of the microvascular inflammatory response in vivo has been hypothesized. This review presents the evidence and basis for this hypothesis. [source] Increased prostaglandin E2 levels in the airway of patients with eosinophilic bronchitisALLERGY, Issue 1 2008B. Sastre Background:, Eosinophilic bronchitis is a common cause of chronic cough, which like asthma is characterized by sputum eosinophilia, but unlike asthma there is no variable airflow obstruction or airway hyperresponsiveness. We tested the hypothesis that the different airway function in patients with eosinophilic bronchitis and asthma could be caused by an imbalance in the production of bronchoconstrictor (LTC4) and bronchoprotective (prostaglandin E2; PGE2) lipid mediators. Methods:, We measured cytokines levels, proinflammatory mediators and eicosanoids concentration in sputum from 13 subjects with nonasthmatic eosinophilic bronchitis, 13 subjects with asthma, and 11 healthy control subjects. Cytokines mRNA levels were measured by real time PCR, proinflammatory mediators, PGE2, and LTC4 were measured by enzyme immunoassays. Results:, The median sputum eosinophil count was not statistically different in patients with asthma (7.95%) and eosinophilic bronchitis (15.29%). The levels of mRNA specific to interleukin-5 (IL-5), IL-4, IL-10, IL-13, interferon , (IFN-,), IL-2, vascular endothelial growth factor and transforming growth factor , were similar in both conditions. In addition, no differences were found between asthma and eosinophilic bronchitis in proinflammatory cytokines, such as IL-8, IFN-, and tumor necrosis factor , (TNF-,) levels. Sputum cysteinyl-leukotrienes concentration was raised both in eosinophilic bronchitis and asthma patients. We found that induced sputum PGE2 concentrations were significantly increased in subjects with eosinophilic bronchitis (838.3 ± 612 pg/ml) when compared with asthmatic (7.54 ± 2.14 pg/ml) and healthy subjects (4 ± 1.3 pg/ml). Conclusion:, This data suggest that the difference in airway function observed in subjects with eosinophilic bronchitis and asthma could be due to differences in PGE2 production in the airways. [source] Omega-3 fatty acid regulates inflammatory cytokine/mediator messenger RNA expression in Porphyromonas gingivalis -induced experimental periodontal diseaseMOLECULAR ORAL MICROBIOLOGY, Issue 4 2007L. Kesavalu Introduction:,Porphyromonas gingivalis is strongly implicated in the etiology of adult periodontitis by inducing inflammatory cytokines, resulting in gingival and periodontal tissue inflammation and alveolar bone resorption. This study tested the hypothesis that supplementing the diet with omega-3 fatty acid (,-3 FA; i.e. fish oil) would exert anti-inflammatory effects in the gingival tissues of P. gingivalis -infected rats. Methods:, Rats were fed either fish oil or corn oil diets ad libitum for 22 weeks and infected with P. gingivalis strain 381 or strain A7A1-28. After sacrifice, rat gingival tissues were excised and the RNA was isolated and analyzed for proinflammatory mediators [interleukin-1, (IL-1,), tumor necrosis factor-, (TNF-,), IL-6], T helper type 1 and type 2 cytokines [interferon-, (IFN-,), IL-4, IL-10), antioxidant enzymes [catalase (CAT), superoxide dismutase (SOD)], and genes critical for eicosanoid mediator production [cyclo-oxygenase-2 (COX-2), 5-lipoxygenase (5-LO)] by reverse transcription-polymerase chain reaction using rat-specific primers. Results:, Rats on the ,-3 FA diet exhibited decreased proinflammatory cytokine gene expression (IL-1,, TNF-,) and enhanced IFN-,, CAT and SOD messenger RNA expression compared to rats fed a corn oil diet, supporting a diet-induced modulation of host inflammatory reactions. Analyses of alveolar bone resorption in the rats related to gene expression profiles demonstrated significant positive correlations with IL-1,, IL-6 and COX-2 and negative correlations with CAT and SOD. Conclusion:, These findings suggest that diets enriched for ,-3 FA modulate the local gingival inflammatory milieu of the host following oral P. gingivalis infection, which impacts on alveolar bone resorption in rats. [source] Blockade of the interleukin-7 receptor inhibits collagen-induced arthritis and is associated with reduction of T cell activity and proinflammatory mediatorsARTHRITIS & RHEUMATISM, Issue 9 2010Sarita A. Y. Hartgring Objective To study the effects of interleukin-7 receptor ,-chain (IL-7R,) blockade on collagen-induced arthritis (CIA) and to investigate the effects on T cell numbers, T cell activity, and levels of proinflammatory mediators. Methods We studied the effect of anti,IL-7R, antibody treatment on inflammation and joint destruction in CIA in mice. Numbers of thymocytes, splenocytes, T cell subsets, B cells, macrophages, and dendritic cells were assessed. Cytokines indicative of Th1, Th2, and Th17 activity and several proinflammatory mediators were assessed by multianalyte profiling in paw lysates. In addition, T cell,associated cytokines were measured in supernatants of lymph node cell cultures. Results Anti,IL-7R, treatment significantly reduced clinical arthritis severity in association with reduced radiographic joint damage. Both thymic and splenic cellularity were reduced after treatment with anti,IL-7R,. IL-7R, blockade specifically reduced the total number of cells as well as numbers of naive, memory, CD4+, and CD8+ T cells from the spleen and significantly reduced T cell,associated cytokines (interferon-,, IL-5, and IL-17). IL-7R, blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor ,, IL-1,, IL-6, matrix metalloproteinase 9, and RANKL. IL-7R, blockade did not significantly affect B cells, macrophages, and dendritic cells. B cell activity, indicated by serum anticollagen IgG antibodies, was not significantly altered. Conclusion Blockade of IL-7R, potently inhibited joint inflammation and destruction in association with specific reductions of T cell numbers, T cell,associated cytokines, and numerous mediators that induce inflammation and tissue destruction. This study demonstrates an important role of IL-7R,driven immunity in experimental arthritis and indicates the therapeutic potential of IL-7R, blockade in human arthritic conditions. [source] Attenuation of pain and inflammation in adjuvant-induced arthritis by the proteasome inhibitor MG132ARTHRITIS & RHEUMATISM, Issue 7 2010Aisha S. Ahmed Objective In rheumatoid arthritis (RA), pain and joint destruction are initiated and propagated by the production of proinflammatory mediators. Synthesis of these mediators is regulated by the transcription factor NF-,B, which is controlled by the ubiquitin proteasome system (UPS). The present study explored the effects of the proteasome inhibitor MG132 on inflammation, pain, joint destruction, and expression of sensory neuropeptides as markers of neuronal response in a rat model of arthritis. Methods Arthritis was induced in rats by injection of heat-killed Mycobacterium butyricum. Arthritis severity was scored, and nociception was evaluated by mechanical pressure applied to the hind paw. Joint destruction was assessed by radiologic and histologic analyses. NF-,B DNA-binding activity was analyzed by electromobility shift assay, and changes in the expression of the p50 NF-,B subunit and the proinflammatory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) were detected by immunohistochemistry. Results Arthritic rats treated with MG132 demonstrated a marked reduction in inflammation, pain, and joint destruction. The elevated DNA-binding activity of the NF-,B/p50 homodimer and p50, as well as the neuronal expression of SP and CGRP, observed in the ankle joints of arthritic rats were normalized after treatment with MG132. Conclusion In arthritic rats, inhibition of proteasome reduced the severity of arthritis and reversed the pain behavior associated with joint inflammation. These effects may be mediated through the inhibition of NF-,B activation and may possibly involve the peripheral nervous system. New generations of nontoxic proteasome inhibitors may represent a novel pharmacotherapy for RA. [source] Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis,ARTHRITIS & RHEUMATISM, Issue 4 2009Bernard Vandooren Objective Peripheral spondylarthritis (SpA) is characterized by macrophages that express CD163, a marker of alternative activation (M2). The purpose of this study was to assess whether this differential infiltration with macrophage subsets was associated with a different local inflammatory milieu in SpA as compared with rheumatoid arthritis (RA). Methods The effect of SpA and RA synovial fluid (SF) on macrophage polarization was tested in vitro on normal peripheral blood monocytes. SF levels of classically activated macrophage (M1),derived and alternatively activated macrophage (M2),derived mediators were analyzed by enzyme-linked immunosorbent assay and multiparameter Luminex bead assay in 47 patients with non-psoriatic SpA, 55 with RA, and 15 with psoriatic arthritis (PsA). Paired synovial biopsy samples were analyzed histologically. Results SF from SpA patients promoted preferential expression of the M2 markers CD163 and CD200R in vitro, even if SF levels of the prototypical M2-polarizing factors (interleukin-4 [IL-4], IL-13, and IL-10) were not increased as compared with those in RA SF. Despite a similar degree of overall joint inflammation in SpA and RA, SpA synovitis displayed strongly reduced SF levels of M1-derived, but not M2-derived, mediators, such as tumor necrosis factor , (TNF,), IL-1,, IL-12p70, and interferon-,,inducible protein 10. SF levels of M1-derived mediators correlated well with peripheral joint inflammation in RA, but neither these mediators nor IL-1, and IL-17 did so in SpA. Of interest, the SF cytokine profile in PsA, a more destructive subtype of SpA, was similar to that in non-psoriatic SpA. Conclusion The local inflammatory milieu is clearly different in SpA as compared with RA peripheral arthritis. Synovitis in SpA, including that in PsA, is characterized by a selective decrease in M1-derived proinflammatory mediators, such as TNF, and IL-1,. [source] Proinflammatory mediator,induced reversal of CD4+,CD25+ regulatory T cell,mediated suppression in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 3 2007Jocea M. R. van Amelsfort Objective We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg,mediated suppression. Methods Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25, and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor , (TNF,), or IL-7. Results Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25, and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg,mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNF,, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg,mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression. Conclusion Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA. [source] Superallergens: a novel mechanism of IgE-mediated activation of human basophils and mast cellsCLINICAL & EXPERIMENTAL ALLERGY REVIEWS, Issue 2004G. Marone Summary Here we report that specific proteins induced in vivo by viruses (e.g. protein Fv), viral proteins (e.g. gp120) or bacterial proteins (e.g. protein L and protein A) can activate human mast cells and basophils (Fc,RI+ cells) to release proinflammatory mediators and cytokines, thereby functioning as immunoglobulin superallergens. Protein Fv acts as an endogenous immunoglobulin superallergen by interacting with IgE VH3+. Similarly, gp120 of HIV-1 is a viral superallergen activating Fc,RI+ cells through interaction with IgE VH3+. Protein A of Staphylococcus aureus functions by interacting with IgE VH3+. Finally, Peptostreptococcus magnus, protein L and a fragment denoted B1,B4 induce mediator release from Fc,RI+ cells through interaction with , light chains of IgE bound on human Fc,RI+ cells. Thus, we have identified a novel mechanism by which endogenous, bacterial and viral proteins specifically activate Fc,RI+ cells, thereby acting as immunoglobulin superallergens. The in vivo implications of IgE-mediated activation of human Fc,RI+ cells by these immunoglobulin superallergens have yet to be defined. However, it is not inconceivable that endogenous, bacterial and viral superallergens play a pathophysiological role in certain forms of allergic reactions. [source] | |||||||||||||||||||||||||