Effect of IL-6 on IGF binding protein-3: A study in IL-6 transgenic mice and in patients with systemic juvenile idiopathic arthritis

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 decreas ed IGF-l levels, suggesting that IL-6 is one of the factors involved in stu nted growth complicating chronic inflammation in childhood. Here we show th at NSE/hIL-6 mice have normal liver IGF-I production, decreased levels of I GF binding protein-3 (IGFBP-3) and increased serum IGFBP-3 proteolysis. Red uced IGFBP-3 levels results in a marked decrease in the circulating 150-kDa ternary complex, even in the presence of normally functional acid labile s ubunit. Pharmacokinetic studies showed that NSE/hIL-6 mice have accelerated IGF-I clearance. Patients with systemic juvenile idiopathic arthritis (s-J IA), a chronic inflammatory disease characterized by prominent IL-6 product ion and complicated by stunted growth associated with low IGF-I levels, hav e markedly decreased IGFBP-3 levels, increased serum IGFBP-3 proteolysis an d normal acid labile subunit levels. Our data show that chronic over produc tion of IL-6 causes decreased IGFBP-3 levels, resulting in a decreased asso ciation of IGF-I in the 150- kDa complex. Decreased levels of IGF-I appear to be secondary to increased clearance.