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PECAM-1 Ligation Negatively Regulates TLR4 Signaling in Macrophages¹

Yuxiang Rui^2,*,, Xingguang Liu^2,, Nan Li, Yingming Jiang, Guoyou Chen, Xuetao Cao^3,*, and Jianli Wang^3,*

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

Uncontrolled TLR4 signaling may induce excessive production of proinflammatory cytokines and lead to harmful inflammation; therefore, negative regulation of TLR4 signaling attracts much attention now. PECAM-1, a member of Ig-ITIM family, can mediate inhibitory signals in T cells and B cells. However, the role and the mechanisms of PECAM-1 in the regulation of TLR4-mediated LPS response in macrophages remain unclear. In this study, we demonstrate that PECAM-1 ligation with CD38-Fc fusion protein negatively regulates LPS-induced proinflammatory cytokine TNF-, IL-6, and IFN-β production by inhibiting JNK, NF-B, and IFN regulatory factor 3 activation in macrophages. In addition, PECAM-1 ligation-recruited Src homology region 2 domain-containing phosphatase 1 (SHP-1) and Src homology region 2 domain-containing phosphatase 2 (SHP-2) may be involved in the inhibitory effect of PECAM-1 on TLR4 signaling. Consistently, silencing of PECAM-1 enhances the macrophage response to LPS stimulation. Taken together with the data that PECAM-1 is constitutively expressed in macrophages and its expression is up-regulated by LPS stimulation, PECAM-1 might function as a feedback negative regulator of LPS inflammatory response in macrophages. This study may provide a potential target for intervention of inflammatory 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 National Natural Science Foundation of China Grants 30671909, 30490240, and 30121002, National Key Basic Research Program of China Grants 2007CB512403 and 2003CB515503, and Shanghai Committee of Science and Technology Grant 05DZ22106.

² Y.R. and X.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jianli Wang, Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China, or Xuetao Cao, Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. E-mail addresses: jlwang{at}zju.edu.cn or caoxt{at}public3.sta.net.cn

⁴ Abbreviations used in this paper: IRF3, IFN regulatory factor 3; SHP-1, Src homology 2 domain-containing tyrosine phosphatase 1; SHP-2, Src homology 2 domain-containing protein tyrosine phosphatase 2; DSS, disuccinimidyl suberate; siRNA, small interfering RNA.