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Immune Complex/Ig Negatively Regulate TLR4-Triggered Inflammatory Response in Macrophages through FcRIIb-Dependent PGE₂ Production¹

Yan Zhang^2,*,, Shuxun Liu^2,*, Juan Liu^*, Ting Zhang, Qian Shen^*, Yizhi Yu^* and Xuetao Cao^3,*,

^* Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, Peoples Republic of China

Excessive activation of TLR may induce endotoxin shock and inflammatory diseases, so the negative regulation of TLR-triggered inflammatory 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- and IL-6 from macrophages by preferentially inducing PGE₂. Pretreatment of mice with IC can protect wild-type mice, but not FcRIIb^–/– mice, from lethal endotoxin shock, and significantly reduce the levels of serum TNF- and IL-6 in wild-type mice but not in FcR IIb^–/– mice. Furthermore, blockade of PGE₂ by celecoxib restores LPS-induced production of TNF- and IL-6 in the presence of IC both in vitro and in vivo. Accordingly, blockade of PGE₂ 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 FcRIIb-dependent PGE₂. In addition, our results suggest that down-regualtion of NF-B 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.

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 This work was supported by Grants 30471632, 30771985, 30721091, and 30490240 from the National Natural Science Foundation of China, by Grants 2004CB518807 and 2007CB512403 from the National Key Research Program of China, and by Grant 2007AA021104 from the National High Biotechnology Development Program of China.

² Y.Z. and S.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Xuetao Cao, Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, P.R. China. E-mail address: caoxt{at}public3.sta.net.cn

⁴ Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; BMDM, bone marrow-derived macrophage; IC, immune complex; IVIg, i.v. Ig; PKA, protein kinase A; COX, cyclooxygenase; WT, wild type.

⁵ The online version of this article contains supplemental material.