Certain autoimmune diseases, such RA and SLE, arise from an inapp

Certain autoimmune diseases, such RA and SLE, arise from an inappropriate immune response of the body against self antigens. SLE, for instance, is charac terized by the loss of Volasertib cancer tolerance to self nuclear antigens, the deposition of immune complexes in tissues, and multiorgan involvement. Studies have shown that nuclear acid sensing pathways implicated in the subversion of the innate immune response to discriminate between self antigen and foreign Inhibitors,Modulators,Libraries antigens are those mediated by the TLRs in the context Inhibitors,Modulators,Libraries of SLE pathogenesis. BTK, which is a downstream kinase of SYK, has been implicated in TLR signaling recently, whereas the role of SYK in TLR signaling is not well appreciated. It has been reported that the TLR9 agonist CpG could induce TLR 9 Inhibitors,Modulators,Libraries independent SYK phosphorylation and activation through actin cytoskel eton reorganization, leading to activation of Src family kinases.

Recruitment of SYK to TLR9 and phosphoryl ation of TLR9 are required for CpG induced cytokine pro duction. Inhibitors,Modulators,Libraries We therefore used RO9021 to study the role of SYK in TLR9 signaling. Interestingly, the kinase function of SYK is essential for TLR9 mediated responses in human B cells. Inhibition of SYK kinase function Inhibitors,Modulators,Libraries resulted in a decreased level of plasmablasts, IgM, IgG and IL 6 upon B cell differentiation in the presence of TLR9 ligand. In addition, RO9021 also potently inhibited IFN production by human pDCs upon TLR9 activation. Importantly, the effects on TLR9 responses are specific because RO9021 did not inhibit TLR4 dependent TNF production by human monocytes or acti vation of the JAK STAT pathway stimulated with either IL 2 or IFN.

Our study showed for the first time that kinase activity of SYK is critical for TLR9 signaling pathway in B cells and pDCs. The role of SYK in TLR signaling in B cells and pDCs could kinase inhibitor Cisplatin have significant implication for SYK inhibitors as therapeutic agents for SLE since the development and pro gression of the disease are believed to be driven by the in appropriate activation of TLR7, TLR8 and TLR9. Other studies have indicated that autoimmunity in RA and psoria sis also is mediated through one or more of these TLRs. In this regard, it is noteworthy that TLR antagonists such as IRS 954 and IMO 8400 are currently undergoing clinical trials in SLE. Consistent with its inhibitory activities in various innate and adaptive immune responses, oral administration of RO9021 inhibited arthritis progression in the mCIA model. Importantly, there was correlation bet ween pharmacokinetics analysis of compound exposure and pharmacodynamics analysis based on anti IgD induced CD69 expression on B cells, indicating on target mode of action.

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