Signal transduction by the chemokine receptor CXCR3 - Activation of Ras/ERK, Src, and phosphatidylinositol 3-kinase/Akt controls cell migration and proliferation in human vascular pericytes

Hepatic stellate cells (HSC) and glomerular mesangial cells (MC) are tissue -specific pericytes involved in tissue repair, a process that is regulated by members of the chemokine family. In this study, we explored the signal t ransduction pathways activated by the chemokine receptor CXCR3 in vascular pericytes, In HSC, interaction of CXCR3 with its ligands resulted in increa sed chemotaxis and activation of the Ras/ERK cascade. Activation of CXCR3 a lso stimulated Src phosphorylation and kinase activity and increased the ac tivity of phosphatidylinositol 3-kinase and its downstream pathway, Akt. Th e increase in ERK activity was inhibited by genistein and PP1, but not by w ortmannin, indicating that Src activation is necessary for the activation o f the Ras/ERK pathway by CXCR3. Inhibition of ERI( activation resulted in a decreased chemotactic and mitogenic effect of CXCR3 ligands. In MC, which respond to CXCR3 ligands with increased DNA synthesis, CXCR3 activation res ulted in a biphasic stimulation of ERK activation, a pattern similar to the one observed in HSC exposed to platelet-derived growth factor, indicating that this type of response is related to the stimulation of cell proliferat ion. These data characterize CXCR3 signaling in pericytes and clarify the r elevance of downstream pathways in the modulation of different biologic res ponses.