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 decreased IGF-I levels, suggesting that IL-6 is one of the factors involved in stunted growth complicating chronic inflammation in childhood. Here we show that NSE/hIL-6 mice have normal liver IGF-I production, decreased levels of IGF binding protein-3 (IGFBP-3) and increased serum IGFBP-3 proteolysis. Reduced IGFBP-3 levels results in a marked decrease in the circulating 150-kDa ternary complex, even in the presence of normally functional acid labile subunit. Pharmacokinetic studies showed that NSE/hIL-6 mice have accelerated IGF-I clearance. Patients with systemic juvenile idiopathic arthritis (s-JIA), a chronic inflammatory disease characterized by prominent IL-6 production and complicated by stunted growth associated with low IGF-I levels, have markedly decreased IGFBP-3 levels, increased serum IGFBP-3 proteolysis and normal acid labile subunit levels. Our data show that chronic overproduction of IL-6 causes decreased IGFBP-3 levels, resulting in a decreased association of IGF-I in the 150-kDa complex. Decreased levels of IGF-I appear to be secondary to increased clearance.
De Benedetti
F
F
Pediatria Generale e Reumatologia, Dipartimento di Scienze Pediatriche, Instituto di Ricerca e Cura a Cattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy.
Meazza
C
C
Oliveri
M
M
Pignatti
P
P
Vivarelli
M
M
Alonzi
T
T
Fattori
E
E
Garrone
S
S
Barreca
A
A
Martini
A
A
D000293:Adolescent; D000818:Animals; D001171:Arthritis, Juvenile / Q000097:blood*; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics; D010447:Peptide Hydrolases / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D012016:Reference Values
D002352:Carrier Proteins; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D015850:Interleukin-6; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I; D010447:Peptide Hydrolases; D010751:Phosphopyruvate Hydratase