Inflammation is a modulator of the insulin-like growth factor (IGF)/IGF-binding protein system inducing reduced bioactivity of IGFs in cystic fibrosis

Abstract

Objective: In inflammatory bowel diseases, increased serum interleukin (IL)-6 levels are associated with high serum insulin-like growth factor-binding protein 2 (IGFBP-2) levels, and cytokines modify the insulin-like growth factor (IGF)/IGFBP system in models in vitro. In cystic fibrosis (CF) the IGF/IGFBP system has not been extensively studied, and relationships with proinflammatory cytokines have not been explored. The aim of this study was to investigate the IGF/IGFBP system and verify changes dependent on IL-1b, IL-6, tumour necrosis factor a (TNFa), and insulin. Methods: Eighteen subjects with CF (mean age 26.6^1.1 years) and 18 controls, comparable for age, sex, and body mass index, were enrolled. Serum IGF-I, IGF-II, IGFBP-2, IGFBP-3, IL-1b, IL-6, TNFa, insulin and C-peptide were measured. Different molecular forms of IGFBP-2 and IGFBP-3 were investigated by Western immunoblotting. The patients were analysed as a whole and as two subgroups depending on established clinical criteria (Swachman -Kulczycki score). Results: Patients had higher serum concentrations of IL-1b, IL-6, TNFa and IGFBP-2 than controls. Serum concentrations of IGF-I and IGF-II were significantly lower and insulin and C-peptide levels significantly increased in CF compared with healthy controls whereas IGFBP-3 serum concentrations were similar, with comparable IGF-I/IGFBP-3 and decreased IGF-I/IGFBP-2 and IGF-II/IGFBP-2 molar ratios. From correlation analysis we detected a significant positive correlation between IGFBP-2 and IL-6 and a negative correlation between IGFBP-2 and IGFBP-3. Conclusions: Our findings suggest that inflammation is an important modulator of the IGF/IGFBP system with an overall reduction in IGF bioactivity in CF.European Journal of Endocrinology 154 47-52

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

“…We showed that in inflammatory bowel diseases in relapse, serum IL-6 and IGFBP-2 were increased and positively correlated (17). We also observed similar relationships in patients with cystic fibrosis, suggesting reduced IGF bioactivity (18). In caco-2 cells, we showed that both IL-1 and IL-6 reduced IGFBPs-2 and -4 concentrations (19).…”

“…We detected similar relationships in the corresponding serum proteins in inflammatory bowel diseases and cystic fibrosis patients. These findings suggested that IGFBP-2 reacted as an acute phase protein (17,18). Possibly, IL-6 regulates IGFBP-2 gene expression or there is a common factor upregulating both genes.…”

Obesity, growth hormone and weight loss

“…The mechanism subserving this link is presently not known. Recent data suggest that inflammatory mediators may play a role in inducing reduced IGF-I bioactivity (90) and in recent years adipose tissue has emerged as an important source of pro-inflammatory mediators (51). The question of whether these mediators play a role in the IGF-I/IGF-binding protein system in obesity requires future study.…”

Tratamento com hormônio de crescimento em crianças com doenças crônicas

“…Alguns autores sugerem condição de resistência ao GH nos pacientes com FC (30). O aumento das citoquinas pró-inflamatórias na doença levaria à diminuição na produção hepática de IGF-1, além de diminuir a bioatividade do IGF-1 circulante (31,32). Hardin e cols.…”