Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation.

TLDR

Stunted growth is a major complication of chronic inflammation and recurrent infections in children, as exemplified by systemic juvenile rheumatoid arthritis, which is characterized by markedly elevated IL‑6 levels and growth impairment. In NSE/hIL‑6 transgenic mice, chronic IL‑6 overexpression reduces growth to 50‑70 % of littermates, lowers circulating IGF‑I while leaving growth hormone normal, and this defect is partially reversed by anti‑IL‑6R antibody, while similar IL‑6–induced IGF‑I suppression is observed in nontransgenic mice and correlates negatively with IGF‑I in systemic juvenile rheumatoid arthritis patients, indicating that IL‑6‑mediated IGF‑I reduction is a key mechanism of inflammation‑associated growth failure.

Abstract

Stunted growth is a major complication of chronic inflammation and recurrent infections in children. Systemic juvenile rheumatoid arthritis is a chronic inflammatory disorder characterized by markedly elevated circulating levels of IL-6 and stunted growth. In this study we found that NSE/hIL-6 transgenic mouse lines expressing high levels of circulating IL-6 since early after birth presented a reduced growth rate that led to mice 50-70% the size of nontransgenic littermates. Administration of a monoclonal antibody to the murine IL-6 receptor partially reverted the growth defect. In NSE/hIL-6 transgenic mice, circulating IGF-I levels were significantly lower than those of nontransgenic littermates; on the contrary, the distribution of growth hormone pituitary cells, as well as circulating growth hormone levels, were normal. Treatment of nontransgenic mice of the same strain with IL-6 resulted in a significant decrease in IGF-I levels. Moreover, in patients with systemic juvenile rheumatoid arthritis, circulating IL-6 levels were negatively correlated with IGF-I levels. Our findings suggest that IL-6-mediated decrease in IGF-I production represents a major mechanism by which chronic inflammation affects growth.