Stromal cell‐derived factor‐1α induces astrocyte proliferation through the activation of extracellular signal‐regulated kinases 1/2 pathway

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Abstract
Stromal cell‐derived factor‐1 (SDF‐1), the ligand of the CXCR4 receptor, is a chemokine involved in chemotaxis and brain development that also acts as co‐receptor for HIV‐1 infection. We previously demonstrated that CXCR4 and SDF‐1α are expressed in cultured type‐I cortical rat astrocytes, cortical neurones and cerebellar granule cells. Here, we investigated the possible functions of CXCR4 expressed in rat type‐I cortical astrocytes and demonstrated that SDF‐1α stimulated the proliferation of these cells in vitro. The proliferative activity induced by SDF‐1α in astrocytes was reduced by PD98059, indicating the involvement of extracellular signal‐regulated kinases (ERK1/2) in the astrocyte proliferation induced by CXCR4 stimulation. This observation was further confirmed showing that SDF‐1α treatment selectively activated ERK1/2, but not p38 or stress‐activated protein kinase/c‐Jun N‐terminal kinase (SAPK/JNK). Moreover, both astrocyte proliferation and ERK1/2 phosphorylation, induced by SDF‐1α, were inhibited by pertussis toxin (PTX) and wortmannin treatment indicating the involvement of a PTX sensitive G‐protein and of phosphatidyl inositol‐3 kinase in the signalling of SDF‐1α. In addition, Pyk2 activation represent an upstream components for the CXCR4 signalling to ERK1/2 in astrocytes. To our knowledge, this is the first report demonstrating a proliferative effect for SDF‐1α in primary cultures of rat type‐I astrocytes, and showing that the activation of ERK1/2 is responsible for this effect. These data suggest that CXCR4/SDF‐1 should play an important role in physiological and pathological glial proliferation, such as brain development, reactive gliosis and brain tumour formation.