Direct stimulatory effect of insulin-like growth factor-I on monocyte and macrophage tumor necrosis factor-α production

Abstract

GH has been demonstrated to play a physiological role in the priming of macrophages for tumor necrosis factor-α (TNFα) synthesis. Although evidence has been presented that GH exerts this effect by an indirect mechanism, the mediators of GH stimulation of TNFα synthesis have not been identified. Because insulin-like growth factor-I (IGF-I) is a major mediator of many GH effects, in the present study we investigated the direct in vitro effect of this growth factor on macrophage TNFα production. Treatment of murine macrophages with physiological concentrations of IGF-I (0.13-130 nM) enhanced both basal and lipopolysaccharide-stimulated macrophage TNFα release and messenger RNA levels. Induction of basal TNFα production was also observed after treatment of the cells with supraphysiological concentrations of insulin (130-1300 nM). Exposure of human monocytes to IGF-I led to a similar increase of basal TNFα production and messenger RNA expression. Preexposure of macrophages with specific antibodies against IGF-I and IGF-I receptor before IGF-I addition resulted in a complete abrogation of the stimulatory effect of IGF-I on TNFα production, indicating that specific binding of IGF- I to its receptor is required for macrophage TNFα induction by IGF-I. In contrast to the stimulatory effect of IGF-I, neither GH (0.1-10 μg/ml) nor IGF-II (0.13-130 nM) enhanced macrophage TNFα release in vitro. To assess the role of the tyrosine kinase system in mediating IGF-I-induced basal TNFα production, macrophages were preincubated with the specific tyrosine kinase inhibitors, genistein and tyrphostin A9, before IGF-I exposure. Addition of these compounds resulted in a dose dependent inhibition of the stimulatory effect of IGF-I on macrophage TNFα release, indicating that protein tyrosine kinase activation is required for TNFα stimulation by IGF-I. Taken together, these results demonstrate that IGF-I is a monocyte/macrophage activating factor that enhances TNFα production, and that such effect is mediated via the IGF-I receptor and involves tyrosine kinase activation.