Journal of Biological Chemistry
Volume 275, Issue 47, 24 November 2000, Pages 37224-37231
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MECHANISMS OF SIGNAL TRANSDUCTION
CD45 Inhibits CD40L-induced Microglial Activation via Negative Regulation of the Src/p44/42 MAPK Pathway*

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It has been reported that ligation of CD40 with CD40 ligand (CD40L) results in microglial activation as evidenced by p44/42 mitogen-activated protein kinase (MAPK) dependent tumor necrosis factor α (TNF-α) production. Previous studies have shown that CD45, a functional transmembrane protein-tyrosine phosphatase, is constitutively expressed at moderate levels on microglial cells and this expression is greatly elevated on activated microglia. To investigate the possibility that CD45 might modulate CD40L-induced microglial activation, we treated primary cultured microglial cells with CD40L and anti-CD45 antibody. Data show that cross-linking of CD45 markedly inhibits CD40L-induced activity of the Src family kinases Lck and Lyn. Further, co-treatment of microglia with CD40L and anti-CD45 antibody results in significant inhibition of microglial TNF-α production through inhibition of p44/42 MAPK activity, a downstream signaling event resulting from Src activation. Accordingly, primary cultured microglial cells from mice deficient in CD45 demonstrate hyper-responsiveness to ligation of CD40, as evidenced by increased p44/42 MAPK activation and TNF-α production. Taken together, these results show that CD45 plays a novel role in suppressing CD40L-induced microglial activation via negative regulation of the Src/p44/42 MAPK cascade.

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Published, JBC Papers in Press, September 7, 2000, DOI 10.1074/jbc.M002006200

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This work was supported in part by a generous gift from Robert and Diane Roskamp.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.