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 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.
De Benedetti
F
F
Clinica Pediatrica, Università degli Studi di Pavia, IRCCS Policlinico San Matteo, Italy.
Alonzi
T
T
Moretta
A
A
Lazzaro
D
D
Costa
P
P
Poli
V
V
Martini
A
A
Ciliberto
G
G
Fattori
E
E
D000293:Adolescent; D000818:Animals; D001171:Arthritis, Juvenile / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D001786:Blood Glucose / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D004195:Disease Models, Animal; D004435:Eating; D006130:Growth Disorders / Q000209:etiology* / Q000235:genetics*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000096:biosynthesis; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D010902:Pituitary Gland / Q000737:chemistry
D001786:Blood Glucose; D015850:Interleukin-6; D007334:Insulin-Like Growth Factor I; D010751:Phosphopyruvate Hydratase