Interferon-gamma-mediated activation of STAT1 alpha regulates growth factor-induced mitogenesis

Immunomodulatory cytokines and growth factors act in a complex network to regulate diverse biologic processes. Pretreatment of two types of human vascular pericytes, liver fat-storing cells or glomerular mesangial cells, with IFN-gamma dramatically enhanced DNA synthesis in response to PDGF or EGF. IFN-gamma by itself had very little effect on DNA synthesis, At least 24-h exposure of the cells to IFN-gamma is required for enhancement of growth factor-induced mitogenesis. IFN-gamma pretreatment did not influence PDGF or EGF receptor autophosphorylation, activation of phospholipase C gamma 1, and phosphatidylinositol 3-kinase, or mitogen-activated protein kinase activity, However, IFN-gamma pretreatment markedly potentiated the DNA binding activity of STAT1 alpha in response to PDGF or EGF, Incubation of cells with antisense oligonucleotides targeting STAT1 alpha mRNA resulted in inhibition of DNA synthesis induced by the combination of IFN-gamma and PDGF or EGF. These data indicate that interaction between IFN-gamma and growth factors at the level of STAT1 alpha results in increased DNA synthesis, and establish a role for STAT1 alpha in this important biologic function of growth factors.