Role of interleukin-6 in growth failure: an animal model.
Indirect evidence suggests a link between factors produced during the inflammatory response and stunted growth. The demonstration of this link was provided by the observation that mice transgenic for the inflammatory cytokine interleukin-6 (IL-6), expressing high circulating levels of IL-6 since birth, show a marked decrease in growth rate leading to adult mice 50-70% the size of wild-type littermates. The growth defect is completely abolished by neutralization of IL-6. In these mice the production of GH is normal, while circulating levels of IGF-I are markedly decreased. Administration of IL-6 to wild-type mice results in a marked decrease in IGF-I levels. These observations show that in vivo high levels of IL-6 are associated with low levels of IGF-I. However, IL-6 does not directly affect IGF-I production both in vitro and in vivo. In contrast, markedly decreased levels of IGFBP-3 are present in the IL-6 transgenic mice and administration of IL-6 to wild-type mice results in a marked decrease in IGFBP-3 levels. In these mice the decrease in IGFBP-3 levels is associated with impaired formation of the 150 kD ternary complex, even in the presence of normally functional ALS. As a consequence, IL-6 transgenic mice show increased clearance of circulating IGF-I, suggesting that IL-6 decreases IGF-I levels by increased clearance. Proteolytic degradation of IGFBP-3 occurs in the IL-6 transgenic mice, suggesting that the decrease in IGFBP-3 could be at least in part due to proteolysis. The abnormalities of the IGF-I system observed in the IL-6 transgenic mice are similar to those found in patients with systemic juvenile idiopathic arthritis, one of the chronic inflammatory diseases characterized by stunted growth and prominent production of IL-6. The IL-6 transgenic mice represent a faithful animal model of the growth impairment associated with chronic inflammation and may therefore provide information relevant to the understanding and treatment of this complication of inflammatory diseases.
De Benedetti
F
F
Pediatria Generale e Reumatologia, IRCCS Policlinico San Matteo, Pavia, Italia. f.debenedetti@smatteo.pv.it
Meazza
C
C
Martini
A
A
D000818:Animals; D010450:Endopeptidases / Q000097:blood; D006130:Growth Disorders / Q000209:etiology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008657:Metabolic Clearance Rate; D051379:Mice; D008822:Mice, Transgenic; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats
D018972:Insulin-Like Growth Factor Binding Protein 3; D015850:Interleukin-6; D007334:Insulin-Like Growth Factor I; D010450:Endopeptidases; D010751:Phosphopyruvate Hydratase