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

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-1 alpha are expressed in cultured type l cortical rat astrocytes, cort ical neurones and cerebellar granule cells. Here, we investigated the possi ble functions of CXCR4 expressed in rat type-I cortical astrocytes and demo nstrated that SDF-1 alpha stimulated the proliferation of these cells in vi tro. The proliferative activity induced by SDF-1 alpha in astrocytes was re duced by PD98059, indicating the involvement of extracellular signal-regula ted kinases (ERK1/2) in the astrocyte proliferation induced by CXCR4 stimul ation. This observation was further confirmed showing that SDF-1 alpha trea tment selectively activated ERK1/2, but not p38 or stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). Moreover, both astrocyte prolif eration and ERK1/2 phosphorylation, induced by SDF-1 alpha, were inhibited by pertussis toxin (PTX) and wortmannin treatment indicating the involvemen t of a PTX sensitive G-protein and of phosphatidyl inositol-3 kinase in the signalling of SDF-1 alpha. In addition, Pyk2 activation represent an upstr eam components for the CXCR4 signalling to ERK1/2 in astrocytes. To our kno wledge, this is the first report demonstrating a proliferative effect for S DF-1 alpha. in primary cultures of rat type-I astrocytes, and showing that the activation of ERK1/2 is responsible far this effect. These data suggest that CXCR4/SDF-1 should play an important role in physiological and pathol ogical glial proliferation, such as brain development, reactive gliosis and brain tumour formation.