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Effect of IL-6 on IGF binding protein-3: a study in IL-6 transgenic mice and in patients with systemic juvenile
F De Benedetti1, C Meazza, M Oliveri
1Pediatria Generale e Reumatologia, Dipartimento di Scienze Pediatriche, Instituto di Ricerca e Cura a Cattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy.
Insights
Chronic inflammation-induced stunted growth in children is linked to elevated Interleukin-6 (IL-6). This study reveals IL-6 reduces IGF binding protein-3 (IGFBP-3), accelerating Insulin-like Growth Factor-I (IGF-I) clearance and impairing growth.
Area of Science:
- Pediatric Endocrinology
- Inflammatory Diseases
- Growth Disorders
Background:
- Stunted growth is a common complication of chronic childhood inflammatory diseases.
- Elevated Interleukin-6 (IL-6) is implicated in growth defects and reduced Insulin-like Growth Factor-I (IGF-I) levels.
Purpose of the Study:
- To investigate the mechanisms by which chronic IL-6 overproduction causes stunted growth.
- To examine the role of IGF binding protein-3 (IGFBP-3) and IGF-I clearance in IL-6-mediated growth impairment.
Main Methods:
- Utilized NSE/hIL-6 transgenic mice overexpressing IL-6.
- Analyzed IGF-I production, IGFBP-3 levels, IGFBP-3 proteolysis, and IGF-I pharmacokinetics.
- Compared findings with patients suffering from systemic juvenile idiopathic arthritis (s-JIA).
Main Results:
- NSE/hIL-6 mice exhibited normal liver IGF-I production but decreased IGFBP-3 and increased IGFBP-3 proteolysis.
- Reduced IGFBP-3 led to diminished circulating IGF-I ternary complex and accelerated IGF-I clearance.
- s-JIA patients showed similar patterns of decreased IGFBP-3 and increased proteolysis.
Conclusions:
- Chronic IL-6 overproduction directly causes decreased IGFBP-3 levels.
- This reduction impairs IGF-I complex formation and leads to increased IGF-I clearance, contributing to stunted growth.
- Findings highlight IL-6's critical role in growth regulation during chronic inflammation.
Abstract:
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.
