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Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294
Costimulation between T cells and APCs is required for adaptive immune responses. CD40, an important costimulatory molecule, is expressed on a variety of cell types, including macrophages and microglia. The aberrant expression of CD40 is implicated in diseases including multiple sclerosis, rheumatoid arthritis, and Alzheimer’s disease, and inhibition of CD40 signaling has beneficial effects in a number of animal models of autoimmune diseases. In this study, we discovered that IL-10, a cytokine with anti-inflammatory properties, inhibits LPS-induced CD40 gene expression. We previously demonstrated that LPS induction of CD40 in macrophages/microglia involves both NF-
B activation and LPS-induced production of IFN-
, which subsequently activates STAT-1
. IL-10 inhibits LPS-induced IFN- gene expression and subsequent STAT-1 activation, but does not affect NF-B activation. Our results also demonstrate that IL-10 inhibits LPS-induced recruitment of STAT-1, RNA polymerase II, and the coactivators CREB binding protein and p300 to the CD40 promoter, as well as inhibiting permissive histone H3 acetylation (AcH3). IL-10 and LPS synergize to induce suppressor of cytokine signaling (SOCS)-3 gene expression in macrophages and microglia. Ectopic expression of SOCS-3 attenuates LPS-induced STAT activation, and inhibits LPS-induced CD40 gene expression, comparable to that seen by IL-10. These results indicate that SOCS-3 plays an important role in the negative regulation of LPS-induced CD40 gene expression by IL-10.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Hongwei Qin, Department of Cell Biology, 1918 University Boulevard, MCLM 392, University of Alabama at Birmingham, Birmingham, AL 35294-0005. E-mail address: hqin{at}uab.edu
2 Abbreviations used in this paper: IKK, IB kinase; TIR, Toll-IL-1R; TRIF, TIR domain-containing adaptor-inducing IFN-; IRF, IFN regulatory factor-3; GAS, IFN-
activation site; Pol II, polymerase II; AcH3, histone H3 acetylation; SOCS, suppressor of cytokine signaling; SH, Src homology; ChIP, chromatin immunoprecipitation; CBP, CREB binding protein; MFI, mean fluorescence intensity; RPA, RNase protection assay; EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; UN, untreated.
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