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Published online before print February 24, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0403128

Received for publication April 1, 2003.
Revised December 15, 2003.
Accepted for publication January 29, 2004.

Article

Fc receptor signaling in primary human microglia: differential roles of PI-3K and Ras/ERK MAPK pathways in phagocytosis and chemokine induction

Xianyuan Song ^*, Sakae Tanaka , Dianne Cox , and Sunhee C. Lee ^*@

Departments of *Pathology and Anatomy, Albert Einstein College of Medicine, Bronx, New York; and Department of Orthopedic Surgery, University of Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: slee{at}aecom.yu.edu.

	Abstract

Cryptococcus neoformans monoclonal antibody immune complex (IC) induces -chemokines and phagocytosis in primary human microglia via activation of Fc receptor for immunoglobulin G (FcR). In this report, we investigated microglial FcR signal-transduction pathways by using adenoviral-mediated gene transfer and specific inhibitors of cell-signaling pathways. We found that Src inhibitor PP2 and Syk inhibitor piceatannol inhibited phagocytosis, macrophage-inflammatory protein-1 (MIP-1) release, as well as phosphorylation of extracellular-regulated kinase (ERK) and Akt, consistent with Src/Syk involvement early in FcR signaling. Constitutively active mitogen-activated protein kinase kinase (MEK) induced MIP-1, and Ras dominant-negative (DN) inhibited IC-induced ERK phosphorylation and MIP-1 production. These results suggest that the Ras/MEK/ERK pathway is necessary and sufficient in IC-induced MIP-1 expression. Neither Ras DN nor the MEK inhibitor U0126 inhibited phagocytosis. In contrast, phosphatidylinositol-3 kinase (PI-3K) inhibitors Wortmannin and LY294002 inhibited phagocytosis without affecting ERK phosphorylation or MIP-1 production. Conversely, Ras DN or U0126 did not affect Akt phosphorylation. Together, these results demonstrate distinct roles played by the PI-3K and Ras/MEK/ERK pathways in phagocytosis and MIP-1 induction, respectively. Our results demonstrating activation of functionally distinct pathways following microglial FcR engagement may have implications for human central nervous system diseases.

Key Words: macrophage-inflammatory protein-1 • immune complex • MEK

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