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Increased Cytokine Production (increased + cytokine_production)
Selected AbstractsThe zinc finger protein Gfi1 acts upstream of TNF to attenuate endotoxin-mediated inflammatory responses in the lungEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2006Jianmin Jin Abstract Gfi1 is a 55-kD nuclear zinc finger protein that is differentially expressed in lymphoid and myeloid cells. Gfi1,/, mice show a very strong systemic response to the endotoxin LPS and die rapidly within 36,h with symptoms of septic shock. Here we report that the pathohysiological processes for this exaggerated inflammatory response take place in the lung. After LPS treatment, lungs of Gfi1,/, mice showed a rapid accumulation of mononuclear cells and a significant overproduction of inflammatory cytokines such as TNF, IL-1, and IL-6. Increased cytokine production was also observed in blood-free perfused lungs from Gfi1,/, mice exposed to either LPS or overventilation. Alveolar macrophages but not airway epithelial cells from Gfi1,/, mice were found to be responsible for the enhanced cytokine production. Strikingly, when the TNF gene was deleted, Gfi1,/, animals were completely rescued from LPS hypersensitivity and had significantly lower IL-1, and IL-6 levels. We conclude that the unrestrained endotoxin response of Gfi1,/, mice occurs mainly in the lung and that Gfi1 represents a novel factor limiting the inflammatory immune response of this organ, and propose that Gfi1 exerts its regulatory function in alveolar macrophages downstream of the LPS receptor (TLR4) and upstream of TNF. [source] PI3K limits TNF- , production in CD16-activated monocytesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2009Phillip R. Kramer Abstract IgG complexes bind to Fc receptor family members Fc,RI (CD64), Fc,RII (CD32) and Fc,RIII (CD16), activating cell MAPK and PI3K resulting in increased cytokine production from particular leukocytes. The signaling molecules involved in cytokine production after cross-linking CD16 have not been determined in monocytes. To address this question, TNF-,, IL-1, and IL-6 were measured in activated monocytes after inhibiting MEK1/2, PI3K and glycogen synthase kinase-, (GSK-3,). The roles of GSK-3, and NF-,B were then determined using reporter assays and siRNA treatment. The data suggested that an MAPK pathway stimulated TNF-, release but that active PI3K limited TNF-,, IL-1, and IL-6 cytokine production after cross-linking CD16. PI3K was also shown to limit nuclear translocation of NF-,B. The limiting effect of PI3K on TNF-, production from activated monocytes depended on the decrease of GSK-3, activity, which significantly reduced the transactivation of NF-,B. Moreover, the TNF-, production induced by CD16 cross-linking was reduced in monocytes after treatment with siRNA against NF-,B, implying that this transcription factor functioned in TNF-, production. The results suggest that CD16 cross-linking activated PI3K and that active PI3K limited TNF-, production by inhibiting GSK-3, activity, that blocked the action of NF-,B. [source] Circulating Toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis CAPMIS, Issue 4 2010JIU-PING WANG Wang J-P, Zhang Y, Wei X, Li J, Nan X-P, Yu H-T, Li Y, Wang P-Z, Bai X-F. Circulating Toll-like receptor (TLR) 2, TLR4, and regulatory T cells in patients with chronic hepatitis C. APMIS 2010; 118: 261,70. The mechanism of hepatitis C virus (HCV) involvement in innate immune responses and immune modulation has not been well characterized. In the present work, we studied Toll-like receptor (TLR) 2 and TLR4, which were recently recognized as the important components of innate immunity, as well as CD4+ CD25+ CD127low/, regulatory T cells (Tregs), which actively suppress pathological and physiological immune response during HCV infection. The study involved 31 chronic hepatitis C patients and 20 healthy controls. TLR2 and TLR4 expression in peripheral blood monocytes and the number of Tregs were examined by flow cytometric analysis. Overexpression of TLR2 and TLR4 was found in chronic hepatitis C patients as compared with controls. Furthermore, increased cytokine production, including that of ,-interferon, tumor necrosis factor-,, interleukin (IL)-6, and IL-8, was observed in peripheral blood mononuclear cells from chronic hepatitis C patients after challenge with TLR2 and TLR4 agonists. The number of Tregs was significantly higher in chronic hepatitis C patients and the increased Tregs were associated with HCV genotype 1b. In vitro studies demonstrated that circulating Tregs suppress T-cell responses in chronic hepatitis C patients. Significant correlations were found between the viral load and Treg number and between TLR2 and TLR4 level in chronic hepatitis C patients. Taken together with other published data, these results suggest that TLR2, TLR4, and Tregs correlate closely with chronic HCV infection. [source] SIGIRR/TIR-8 is an inhibitor of toll-like receptor signaling in primary human cells and regulates inflammation in models of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 8 2010Stefan K. Drexler Objective Single-immunoglobulin interleukin-1 receptor,related (SIGIRR), which is also known as Toll/interleukin-1 receptor 8 (TIR-8), is a member of the TIR domain,containing family of receptors and was first characterized as an inhibitor of interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) signaling. In the Dextran sulfate sodium,induced colitis model, SIGIRR,/, mice were shown to have increased inflammation and to be more susceptible to endotoxin challenge. Increasing evidence implicates TLR and IL-1R signaling in the pathology of rheumatoid arthritis (RA). Therefore, the purpose of this study was to investigate the involvement of SIGIRR in regulating inflammation in disease-relevant models. Methods Primary human monocyte-derived macrophages and dendritic cells (DCs) were used to overexpress SIGIRR as well as to knock down endogenously expressed SIGIRR using small interfering RNAs. SIGIRR was also overexpressed in synovial cells derived from RA patients. To investigate the role of SIGIRR in vivo, zymosan-induced arthritis (ZIA) and collagen antibody,induced arthritis (CAIA) were induced in SIGIRR-knockout mice. Results SIGIRR overexpression inhibited TLR-induced cytokine production in macrophages and DCs, while SIGIRR knockdown resulted in increased cytokine production following TLR stimulation. Moreover, SIGIRR overexpression inhibited the spontaneous release of cytokines by human RA synovial cells. The role of SIGIRR as an inhibitor of inflammation was confirmed in vivo, since SIGIRR,/, mice developed a more severe disease in both the ZIA and CAIA models. Conclusion Our study is the first to show the expression pattern and function of SIGIRR in primary human cells. Furthermore, this investigation defines the role of SIGIRR in disease-relevant cell types and demonstrates that SIGIRR is a potential therapeutic target for RA. [source] Neutrophils and monocytes as potentially important sources of proinflammatory cytokines in diabetesCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2006E. Hatanaka Summary Neutrophils and monocytes play a central role in host defence. The invading leucocytes are capable of synthesizing and releasing a variety of proinflammatory mediators including cytokines. Given the importance of cytokines in the progression of chronic and acute inflammatory processes, we aimed to ascertain whether the release of interleukin (IL)-8, IL-1,, tumour necrosis factor (TNF)-, and IL-1ra of neutrophils and monocytes was modified in diabetes. To this end, we measured the release of cytokines in suspensions of cell culture in basal and lipopolysaccharide (LPS)-stimulated conditions. In basal conditions, neutrophils of diabetics release 1·6, 3·2, 1·9 and 1·9-fold higher amounts of IL-8, IL-1,, TNF-, and IL-1ra, respectively, than do healthy controls. Under our experimental conditions, this effect was more evident for neutrophils than for monocytes. Incremental cytokine production was also found to occur when neutrophils were stimulated with LPS. IL-8, IL-1, and TNF-, increased, respectively, by 4·0, 1·7 and 2·8-fold. Although the effect was more marked for neutrophils, monocytes showed a tendency for increased cytokine production. The discovery of this increase in cytokines released by the neutrophils of diabetics contributes towards a clearer understanding of other deficiencies described for neutrophils in diabetes, such as the migration of neutrophils to inflammatory sites, phagocytes, release of lytic proteases, production of reactive oxygen species and apoptosis. The excessive production of cytokines may lead to inappropriate activation and tissue injury and even to increased susceptibility to invasive microorganisms. Thus, the increased responsiveness of neutrophils of diabetics demonstrated in this study may be considered part of the scenario of diabetes physiopathology. [source] | ||||||||||