Interferon-γ-mediated activation of STAT1α regulates growth factor- induced mitogenesis

Abstract

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-γ dramatically enhanced DNA synthesis in response to PDGF or EGF. IFN-γ by itself had very little effect on DNA synthesis. At least 24-h exposure of the cells to IFN-γ is required for enhancement of growth factor- induced mitogenesis. IFN-γ pretreatment did not influence PDGF or EGF receptor autophosphorylation, activation of phospholipase Cγ1, and phosphatidylinositol 3-kinase, or mitogen-activated protein kinase activity. However, IFN-γ pretreatment markedly potentiated the DNA binding activity of STAT1α in response to PDGF or EGF. Incubation of cells with antisense oligonucleotides targeting STAT1α mRNA resulted in inhibition of DNA synthesis induced by the combination of IFN-γ and PDGF or EGF. These data indicate that interaction between IFN-γ and growth factors at the level of STAT1α results in increased DNA synthesis, and establish a role for STAT1α in this important biologic function of growth factors.