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

Stunted growth is a major complication of chronic inflammation and rec urrent 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 circul ating IL-6 since early after birth presented a reduced growth rate tha t led to mice 50-70% the size of nontransgenic littermates. Administra tion of a monoclonal antibody to the murine IL-6 receptor partially re verted the growth defect. In NSE/hIL-6 transgenic mice, circulating IG F-I levels were significantly lower than those of nontransgenic litter mates; on the contrary, the distribution of growth hormone pituitary c ells, as well as circulating growth hormone levels, were normal. Treat ment of nontransgenic mice of the same strain with IL-6 resulted in a significant decrease in IGF-I levels. Moreover, in patients with syste mic juvenile rheumatoid arthritis, circulating IL-6 levels were negati vely correlated with IGF-I levels. Our findings suggest that IL-6-medi ated decrease in IGF-I production represents a major mechanism by whic h chronic inflammation affects growth.