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Effect of IL-6 on IGF Binding Protein-3: A Study in IL-6 Transgenic Mice and in Patients with Systemic Juvenile Idiopathic Arthritis

Pediatria Generale e Reumatologia (F.D.B., C.M., M.O., P.P., M.V., A.M.), Dipartimento di Scienze Pediatriche, Instituto di Ricerca e Cura a Cattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy; Dipartimento di Biotecnologie Cellulari ed Ematologia (T.A.), Sezione Genetica Molecolare, Policlinico Umberto I, 00198 Roma, Italy, IRBM P. Angeletti (E.F.), 00040 Pomezia (Roma), Italy; and Dipartimento di Scienze Endocrinologiche e Metaboliche (S.G., A.B.), Università di Genova, 16132 Genova, Italy

Address all correspondence and requests for reprints to: Alberto Martini, M.D., Professor of Pediatrics, Instituto di Ricerca e Cura a Cattare Scientifico San Matteo, Università degli Studi di Pavia, Piazzale Golgi 2, 27100 Pavia Italy. E-mail: amartini{at}smatteo.pv.it

Stunted growth is a common complication of childhood diseases characterized by chronic inflammation or infections. We previously demonstrated that NSE/hIL-6 transgenic mice, overexpressing the inflammatory cytokine IL-6 since early phase of life, showed a marked growth defect associated with decreased IGF-I levels, suggesting that IL-6 is one of the factors involved in stunted growth complicating chronic inflammation in childhood. Here we show that NSE/hIL-6 mice have normal liver IGF-I production, decreased levels of IGF binding protein-3 (IGFBP-3) and increased serum IGFBP-3 proteolysis. Reduced IGFBP-3 levels results in a marked decrease in the circulating 150-kDa ternary complex, even in the presence of normally functional acid labile subunit. Pharmacokinetic studies showed that NSE/hIL-6 mice have accelerated IGF-I clearance. Patients with systemic juvenile idiopathic arthritis (s-JIA), a chronic inflammatory disease characterized by prominent IL-6 production and complicated by stunted growth associated with low IGF-I levels, have markedly decreased IGFBP-3 levels, increased serum IGFBP-3 proteolysis and normal acid labile subunit levels. Our data show that chronic overproduction of IL-6 causes decreased IGFBP-3 levels, resulting in a decreased association of IGF-I in the 150-kDa complex. Decreased levels of IGF-I appear to be secondary to increased clearance.

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