Effect of IL-6 on IGF Binding Protein-3: A Study in IL-6 Transgenic Mice and in Patients with Systemic Juvenile Idiopathic Arthritis

Benedetti, Fabrizio

doi:10.1210/en.142.11.4818

Cited by 75 publications

(107 citation statements)

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“…In agreement with an in vitro observation showing no effect of IL-6 on GH-induced IGF-I mRNA expression in cultured hepatocytes [14], we found that IGF-I protein levels in liver extracts were similar in transgenic NSE/hIL-6 mice and in non-transgenic littermates [15]. Taken together, these observations exclude a direct effect of IL-6 overexpression on liver IGF-I production, and show that the decrease in circulating IGF-I levels in NSE/hIL-6 mice cannot be explained by low liver IGF-I production.…”

Section: Abnormalities Of the Insulin-like Growth Factor-i System In supporting

confidence: 92%

Role of Interleukin-6 in Growth Failure: An Animal Model

2002

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Indirect evidence suggests a link between factors produced during the inflammatory response and stunted growth. The demonstration of this link was provided by the observation that mice transgenic for the inflammatory cytokine interleukin-6 (IL-6), expressing high circulating levels of IL-6 since birth, show a marked decrease in growth rate leading to adult mice 50–70% the size of wild-type littermates. The growth defect is completely abolished by neutralization of IL-6. In these mice the production of GH is normal, while circulating levels of IGF-I are markedly decreased. Administration of IL-6 to wild-type mice results in a marked decrease in IGF-I levels. These observations show that in vivo high levels of IL-6 are associated with low levels of IGF-I. However, IL-6 does not directly affect IGF-I production both in vitro and in vivo. In contrast, markedly decreased levels of IGFBP-3 are present in the IL-6 transgenic mice and administration of IL-6 to wild-type mice results in a marked decrease in IGFBP-3 levels. In these mice the decrease in IGFBP-3 levels is associated with impaired formation of the 150 kD ternary complex, even in the presence of normally functional ALS. As a consequence, IL-6 transgenic mice show increased clearance of circulating IGF-I, suggesting that IL-6 decreases IGF-I levels by increased clearance. Proteolytic degradation of IGFBP-3 occurs in the IL-6 transgenic mice, suggesting that the decrease in IGFBP-3 could be at least in part due to proteolysis. The abnormalities of the IGF-I system observed in the IL-6 transgenic mice are similar to those found in patients with systemic juvenile idiopathic arthritis, one of the chronic inflammatory diseases characterized by stunted growth and prominent production of IL-6. The IL-6 transgenic mice represent a faithful animal model of the growth impairment associated with chronic inflammation and may therefore provide information relevant to the understanding and treatment of this complication of inflammatory diseases.

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Section: Abnormalities Of the Insulin-like Growth Factor-i System In supporting

confidence: 92%

Role of Interleukin-6 in Growth Failure: An Animal Model

2002

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“…An association between IL-6 and IGFBP-3 proteolysis was expected since IL-6 transgenic mice have increased IGFBP-3 proteolysis [18]. In addition, several states characterized by increased IGFBP-3 proteolysis, e.g., the post-operative state [21], exercise [22], critical illness [24, 25], type 2 diabetes [19], and arthritis [18] have elevated levels of IL-6 [12, 13, 20, 23, 25].…”

Section: Resultsmentioning

confidence: 99%

“…IL-6 has been shown to reduce GH sensitivity in mice [49]. In vivo experiments with mice over-expressing IL-6 have shown unchanged [18] or reduced [49] IGF-I expression in the liver. In our study, total IGF-I concentrations were not changed by an IL-6 infusion.…”

Section: Resultsmentioning

confidence: 99%

“…The factors that induce IGFBP-3 proteolysis in vivo are largely unknown, but IL-6 has been proposed to be one such factor since IL-6 transgenic mice have increased proteolytic degradation of IGFBP-3 [18]. Increased IGFBP-3 proteolysis is associated with moderately elevated IL-6 levels in type 2 diabetes [19, 20], after major surgery [11, 21] and after exercise [13, 22], or with markedly elevated IL-6 levels in arthritis [18, 23] and in critical illness [24, 25]. In addition, in vitro studies have shown that IL-6 increases the activity of proteases that degrade IGFBP-3 in vitro including matrix metalloproteinases (MMPs) [26, 27].…”

Section: Introductionmentioning

confidence: 99%

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Acute Interleukin-6 Infusion Increases IGFBP-1 but Has No Short-Term Effect on IGFBP-3 Proteolysis in Healthy Men

Pihl

Carlsson-Skwirut²,

Berg³

et al. 2006

Horm Res Paediatr

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Human conditions of elevated interleukin-6 (IL-6) and transgenic mice overexpressing IL-6 have increased proteolytic degradation of insulin-like growth factor binding protein (IGFBP)-3. In addition, IL-6 alters the hepatic expression of insulin-like growth factor-I (IGF-I) and the IGFBPs in vitro. The aim of the present study was to investigate whether moderately elevated IL-6 levels have short-term effects on circulating IGF-I, IGFBP-1 and IGFBP-3 proteolysis in vivo. Healthy men received a 3-h IL-6 (n = 6) or saline (n = 6) infusion and blood samples were collected prior to and up to 8 h after the start of infusion. Free IGF-I, total IGF-I, IGFBP-1, insulin and cortisol were measured using immunoassays. Serum IGFBP-3 proteolysis was analyzed by Western immunoblot and by in vitro degradation of ¹²⁵I-IGFBP-3. We found that IL-6 concentrations reaching approximately 100 pg/ml significantly increased IGFBP-1 after the end of infusion in the absence of changes in insulin. In addition, plasma levels of cortisol were increased in response to IL-6 during and after infusion compared to saline. There was no effect of IL-6 on IGFBP-3 proteolysis, total IGF-I or free dissociable IGF-I. These data suggest that moderately elevated levels of IL-6 such as in the post-operative state or after exercise may contribute to increased levels of IGFBP-1. Although this study does not exclude that high levels and/or prolonged exposure to IL-6 may induce IGFBP-3 proteolysis in sepsis or chronic inflammatory disease, it suggests that IL-6 released from exercising skeletal muscle is not directly involved in proteolysis of circulating IGFBP-3.

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“…In a transgenic mouse model, De Benedetti et al [17, 18] have suggested that IL-6 may be part of the mechanism by which chronic inflammation inhibits growth. Thus, overexpression of IL-6 was followed by reduced plasma IGF-I and longitudinal growth, without influence on liver IGF-I production.…”

Section: Introductionmentioning

confidence: 99%

The Insulin-Like Growth Factor System and Markers of Inflammation in Adult Patients with Inflammatory Bowel Disease

Eivindson¹,

Nielsen

Grønbæk³

et al. 2005

Horm Res Paediatr

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Background and Objectives:Catabolism and growth impairment are well-known complications of inflammatory bowel disease (IBD). Recent studies have demonstrated significant changes in the IGF system in IBD patients. The aim of the present study was to investigate correlations between the IGF system and markers of inflammation in IBD. Methods:A cross-sectional study comprising 99 IBD patients (Crohn’s disease (CD, n = 50) and ulcerative colitis (UC, n = 49)). Correlations between markers of inflammation and IGF-I, IGF-II and IGFBP-3 were examined in CD and UC patients in remission and relapse. The patients were clinically scored using Crohn’s Disease Activity Index (CDAI) for CD patients and Activity Index (AI) for UC patients. Results: In the UC group we found correlations between IGF-I and CRP (r_s = Spearman’s rho) (r_s = –0.40, p < 0.01) and albumin (r_s = 0.46, p < 0.001), IGFBP-3 and albumin (r_s = 0.36, p < 0.01) and AI score (r_s = –0.31, p < 0.05). IGF-II correlated with CRP (r_s = –0.42, p < 0.01), IL-6 (r_s = –0.65, p < 0.001), albumin (r_s = 0.41, p < 0.01), AI score (r_s = –0.30, p < 0.05) and orosomucoid (r_s = –0.47, p < 0.001). In the CD group we found correlations between IGF-I and CRP (r_s = –0.40, p < 0.05), and albumin (r_s = –0.46, p < 0.01), IGFBP-3 and albumin (r = 0.36, p < 0.01). IGF-II correlated with IL-6 (r_s = –0.65, p < 0.001), albumin (r_s = 0.41, p < 0.01), CDAI score (r_s = –0.30, p < 0.05) and orosomucoid (r_s = –0.47, p < 0.001). Conclusions: IGF-I, IGF-II and IGFBP-3 are correlated to albumin and IGF-I and IGF-II are correlated to CRP in IBD patients. Further, IGF-II is correlated to IL-6 in IBD patients. This may suggest a correlation between inflammation and the IGF system with involvement in muscle and bone catabolism in IBD.

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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 Idiopathic Arthritis

Cited by 75 publications

References 0 publications

Role of Interleukin-6 in Growth Failure: An Animal Model

Role of Interleukin-6 in Growth Failure: An Animal Model

Acute Interleukin-6 Infusion Increases IGFBP-1 but Has No Short-Term Effect on IGFBP-3 Proteolysis in Healthy Men

The Insulin-Like Growth Factor System and Markers of Inflammation in Adult Patients with Inflammatory Bowel Disease

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