TY - JOUR
T1 - Fcγ receptor signaling in primary human microglia
T2 - Differential roles of PI-3K and Ras/ERK MAPK pathways in phagocytosis and chemokine induction
AU - Song, Xianyuan
AU - Tanaka, Sakae
AU - Cox, Dianne
AU - Lee, Sunhee C.
PY - 2004/6
Y1 - 2004/6
N2 - Cryptococcus neoformans monoclonal antibody immune complex (IC) induces β-chemokines and phagocytosis in primary human microglia via activation of Fe receptor for immunoglobulin G (FcγR). In this report, we investigated microglial FcγR 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-1α (MIP-1α) release, as well as phosphorylation of extracellular-regulated kinase (ERK) and Akt, consistent with Src/Syk involvement early in FcγR signaling. Constitutively active mitogen-activated protein kinase kinase (MEK) induced MIP-1α, and Ras dominant-negative (DN) inhibited IC-induced ERK phosphorylation and MIP-1α production. These results suggest that the Ras/MEK/ERK pathway is necessary and sufficient in IC-induced MIP-1α 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-1α 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-1α induction, respectively. Our results demonstrating activation of functionally distinct pathways following microglial FcγR engagement may have implications for human central nervous system diseases.
AB - Cryptococcus neoformans monoclonal antibody immune complex (IC) induces β-chemokines and phagocytosis in primary human microglia via activation of Fe receptor for immunoglobulin G (FcγR). In this report, we investigated microglial FcγR 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-1α (MIP-1α) release, as well as phosphorylation of extracellular-regulated kinase (ERK) and Akt, consistent with Src/Syk involvement early in FcγR signaling. Constitutively active mitogen-activated protein kinase kinase (MEK) induced MIP-1α, and Ras dominant-negative (DN) inhibited IC-induced ERK phosphorylation and MIP-1α production. These results suggest that the Ras/MEK/ERK pathway is necessary and sufficient in IC-induced MIP-1α 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-1α 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-1α induction, respectively. Our results demonstrating activation of functionally distinct pathways following microglial FcγR engagement may have implications for human central nervous system diseases.
KW - Immune complex
KW - MEK
KW - Macrophage-inflammatory protein-1α
KW - Src kinase
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U2 - 10.1189/jlb.0403128
DO - 10.1189/jlb.0403128
M3 - Article
C2 - 14982949
AN - SCOPUS:2642518949
SN - 0741-5400
VL - 75
SP - 1147
EP - 1155
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 6
ER -