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.

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. ( J. Clin. Invest. 1997. 99:643-650.) Key words: interleukin 6 • insulinlike growth factor-I • growth disorders • juvenile rheumatoid arthritis

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

“…These observations demonstrate that chronic overproduction of IL-6 can cause a growth defect, and that this growth defect is associated with abnormalities of the IGF-1 system similar to those found in patients. In further support of the relationship between IL-6 and the IGF-1 system, in patients with systemic JIA, circulating levels of IL-6 are inversely correlated with levels of IGF-1 and IGFBP-3 (46,49).…”

“…IL-6-transgenic mice with high circulating levels of IL-6 since birth show a decreased rate of growth, attaining 50-60% of the size of their wild-type littermates as adults (46). Similar to patients with systemic JIA (47,48), IL-6-transgenic mice have normal growth hormone production but low levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) (46,49). These observations demonstrate that chronic overproduction of IL-6 can cause a growth defect, and that this growth defect is associated with abnormalities of the IGF-1 system similar to those found in patients.…”

IGF-I, IGF-I-binding proteins and GH-binding protein in malnourished elderly patients with inflammation receiving refeeding therapy

“…However, inflammation per se may also modulate plasma IGF-I levels. First, the proinflammatory cytokines IL-1b, IL-6 and TNF-a inhibit expression of the IGF-I gene (44,45), and low circulating IGF-I concentration may be caused by a direct effect of cytokines in the liver. This effect may involve suppression of cytokine signaling inhibition of GH signaling by proinflammatory cytokines (46,47).…”

Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls

“…In transgenic mice, overexpressing IL-6 severely impaired growth associated with very low serum IGF-I concentrations was shown (16). We showed that in inflammatory bowel diseases in relapse, serum IL-6 and IGFBP-2 were increased and positively correlated (17).…”