REGULATION OF INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) AND IGF-BINDING PROTEINS BY TUMOR-NECROSIS-FACTOR

The purpose of the present study was to determine 1) whether exogenous administration of tumor necrosis factor-alpha (TNF-alpha) alters insu lin-like growth factor-I (IGF-I) and IGF-binding proteins (BPs) and 2) whether the enhanced endogenous production of TNF mediates the lipopo lysaccharide (LPS)-induced changes in the IGF system. The overnight in fusion of murine TNF-alpha reduced circulating concentrations of both growth hormone (GH) and IGF-I in fasted rats. Furthermore, TNF-alpha d ecreased IGF-I content in liver, gastrocnemius muscle, and pituitary. In contrast, TNF-alpha increased IGF-I content in kidney and brain. IG FBP-1 was increased in plasma, liver, and muscle in response to TNF-al pha. In a second study, rats were injected with LPS after treatment wi th a neutralizing anti-TNF antibody (Ab), and blood and tissues were c ollected 4 h later. In LPS-treated rats, plasma concentrations of GH a nd IGF-I were reduced. LPS also decreased the IGF-I content in liver a nd skeletal muscle and increased plasma, liver, and muscle concentrati ons of IGFBP-1. Pretreatment with anti-TNF Ab attenuated the LPS-induc ed reduction in IGF-I and the increased IGFBP-1 in plasma and Liver an d completely prevented the decrease in IGF-I observed in muscle. In co ntrast, the LPS-induced decrease in plasma GH and the increased IGFBP- 1 observed in muscle were unaltered by the anti-TNF Ab. These results indicate that the GH/IGF axis is sensitive to TNF-alpha and that enhan ced endogenous production of TNF mediates a major portion of the LPS-i nduced decrease in IGF-I in plasma, liver, and muscle, as well as a sm aller portion of the concomitant elevation in IGFBP-1 in plasma and li ver.