Immune complex/Ig negatively regulate TLR4-triggered inflammatory response in macrophages through Fc gamma RIIb-dependent PGE2 production.

Yan Zhang, Shuxun Liu, Juan Liu, Ting Zhang, Qian Shen, Yizhi Yu, Xuetao Cao

Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, Peoples Republic of China.

Journal of immunology (Baltimore, Md. : 1950) 2009 Jan 1

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Excessive activation of TLR may induce endotoxin shock and inflammatory diseases, so the negative regulation of TLR-triggered infl ammatory response attracts much attention. Nonpathogenic immune complex (IC) and Ig (IC/Ig) have been shown to play important roles in the regulation of immune responses and to be therapeutic in some kinds of autoimmune diseases. However, the role of IC/Ig in the regulation of TLR-triggered inflammatory responses and the underlying mechanisms remain to be fully understood. In this study we demonstrate that IC/Ig can significantly inhibit LPS-induced secretion of TNF-alpha and IL-6 from macrophages by preferentially inducing PGE(2). Pretreatment of mice with IC can protect wild-type mice, but not Fc gammaRIIb(-/-) mice, from lethal endotoxin shock, and significantly reduce the levels of serum TNF-alpha and IL-6 in wild-type mice but not in Fc gammaR IIb(-/-) mice. Furthermore, blockade of PGE(2) by celecoxib restores LPS-induced production of TNF-alpha and IL-6 in the presence of IC both in vitro and in vivo. Accordingly, blockade of PGE(2) production in vivo results in the increased sensitivity of IC-pretreated mice to lethal endotoxin shock. Therefore, IC/Ig can negatively regulate TLR4-triggered inflammatory response in macrophages through Fc gammaRIIb-dependent PGE(2). In addition, our results suggest that down-regulation of NF-kappaB activation and TLR4 expression but activation of protein kinase A pathway in macrophages by IC/Ig contribute to the negative regulatory process. Thus we provide new manner for the immune regulation and mechanistic explanation for nonpathogenic IC/Ig in the treatment of inflammatory or autoimmune diseases.

Citation

Yan Zhang, Shuxun Liu, Juan Liu, Ting Zhang, Qian Shen, Yizhi Yu, Xuetao Cao. Immune complex/Ig negatively regulate TLR4-triggered inflammatory response in macrophages through Fc gamma RIIb-dependent PGE2 production. Journal of immunology (Baltimore, Md. : 1950). 2009 Jan 1;182(1):554-62