Endogenous IGF-I regulates IGF binding protein production in human intestinal smooth muscle cells

Human intestinal smooth muscle in culture produces insulin-like growth factor (IGF)-I and TGF binding protein (IGFBP)-3, IGFBP-4, and IGFBP-5, which modulate the effects of TGF-I. This study examined the regulation of IGFBP production by endogenous IGF-L RB-IGF-I, an agonist unaffected by IGFBPs, elicited concentration-dependent increase in growth, measured by [H-3]thymidine incorporation, and production of IGFBP-3, IGFBP-4, and IGFBP-4, measured by Western blot. Antagonists of the IGF-I receptor, IGF-I Analog or monoclonal antibody 1H7, elicited concentration-dependent inhibition of growth and decrease in IGFBP-3, IGFBP-4, and IGFBP-5 production, implying that endogenous IGF-I stimulated growth and IGFBP production. R3-IGF-I-induced increase in IGFBP-3, IGFBP-4, and IGFBP-5 production was partially inhibited by a mitogen-activated protein (MAP) kinase or a phosphatidylinositol-3-kinase (PI 3-kinase) inhibitor and abolished by the combination. We conclude that endogenous IGF-I stimulates growth and IGFBP-3, IGFBP-4, and IGFBP-5 production in human intestinal smooth muscle cells. Regulation of IGFBP production by IGF-I is mediated by activation of distinct MAP kinase and PT 3-kinase pathways, the same pathways through which IGF-I stimulates growth.