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      PECAM-1 ligation negatively regulates TLR4 signaling in macrophages.

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          Abstract

          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-alpha, IL-6, and IFN-beta production by inhibiting JNK, NF-kappaB, 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.

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          Author and article information

          Journal
          J. Immunol.
          Journal of immunology (Baltimore, Md. : 1950)
          0022-1767
          0022-1767
          Dec 01 2007
          : 179
          : 11
          Affiliations
          [1 ] Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
          Article
          179/11/7344
          10.4049/jimmunol.179.11.7344
          18025177
          96ad8909-1e09-4444-9e2e-291b3ef6b933
          History

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