Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor

Abstract

The purpose of the present study was to determine 1) whether exogenous administration of tumor necrosis factor-alpha (TNF-alpha) alters insulin-like growth factor-I (IGF-I) and IGF-binding proteins (BPs) and 2) whether the enhanced endogenous production of TNF mediates the lipopolysaccharide (LPS)-induced changes in the IGF system. The overnight infusion of murine TNF-alpha reduced circulating concentrations of both growth hormone (GH) and IGF-I in fasted rats. Furthermore, TNF-alpha decreased IGF-I content in liver, gastrocnemius muscle, and pituitary. In contrast, TNF-alpha increased IGF-I content in kidney and brain. IGFBP-1 was increased in plasma, liver, and muscle in response to TNF-alpha. In a second study, rats were injected with LPS after treatment with a neutralizing anti-TNF antibody (Ab), and blood and tissues were collected 4 h later. In LPS-treated rats, plasma concentrations of GH and IGF-I were reduced. LPS also decreased the IGF-I content in liver and skeletal muscle and increased plasma, liver, and muscle concentrations of IGFBP-1. Pretreatment with anti-TNF Ab attenuated the LPS-induced reduction in IGF-I and the increased IGFBP-1 in plasma and liver and completely prevented the decrease in IGF-I observed in muscle. In contrast, the LPS-induced decrease in plasma GH and the increased IGFBP-1 observed in muscle were unaltered by the anti-TNF Ab.(ABSTRACT TRUNCATED AT 250 WORDS)

TNF-α impairs heart and skeletal muscle protein synthesis by altering translation initiation

“…After surgery, all rats were housed in individual cages with no food but with water ad libitum. We have previously reported that this experimental protocol elevates the blood TNF-␣ concentration to ϳ500 pg/ml (12). Comparable TNF-␣ values are observed in a number of inflammatory conditions, including sepsis, neoplastic disease, burn injury, and hepatic ischemia-reperfusion injury (6,7,9,11), but levels are markedly lower than those seen in rats injected with nonlethal doses of endotoxin (18).…”

“…Comparable TNF-␣ values are observed in a number of inflammatory conditions, including sepsis, neoplastic disease, burn injury, and hepatic ischemia-reperfusion injury (6,7,9,11), but levels are markedly lower than those seen in rats injected with nonlethal doses of endotoxin (18). In addition, this dose of TNF-␣ also produces peripheral insulin resistance (29) and decreases the IGF-I content in blood and muscle (12).…”

“…Rats were anesthetized with an intramuscular injection of ketamine and xylazine (90 and 9 mg/kg, respectively), and sterile surgery was performed to implant catheters in the carotid artery and jugular vein, as previously described (12,29). Briefly, the venous catheter was passed through a tightly coiled stainless steel spring and was fixed to a freely rotating swivel (Instech, Plymouth, PA); the arterial catheter was coiled and secured with tape on the dorsal surface of the rat.…”

“…Colonic temperature was determined immediately after determination of MABP and HR, as previously described (29). The plasma concentrations of insulin, IGF-I, and corticosterone were determined by RIA (12,29). Leptin concentrations were also determined by RIA (Linco Research, St. Charles, MO).…”

“…The limited ability of TNF-␣ to impair muscle protein balance at these later time points is consistent with the rapid clearance of TNF-␣ from the systemic circulation (5). However, in previous studies a primed, constant intravenous infusion of this cytokine for 24 h has been demonstrated to produce a severe insulin resistance in skeletal muscle (29) and to markedly decrease the concentration of the anabolic hormone insulin-like growth factor (IGF) I in both the circulation and muscle (12). These data suggest that a more prolonged exposure of tissues to TNF-␣ may be a prerequisite for producing detectable cytokine-induced changes in muscle protein synthesis in vivo.…”