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; Meazza, Cristina; Oliveri, Mara; Pignatti, Patrizia; Vivarelli, Marina; Alonzi, Tonino; Fattori, Elena; Garrone, Simona; Barreca, Antonina; Martini, Alberto

doi:10.1210/endo.142.11.8511

Cited by 127 publications

(45 citation statements)

References 50 publications

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“…The IL6-overexpressing mice exhibit a defective growth phenotype with a size reduction of 50-70% compared with normal non-transgenic littermates. The growth retardation in these mice was associated with decreased levels of IGF1 and IGF1-binding protein 3 (IGFBP3), yet with normal distribution of GH pituitary cells and GH production (De Benedetti et al 1997, De Benedetti et al 2001. This finding is consistent with the situation in patients with JIA where high circulating levels of IL6 are negatively correlated with IGF1 and IGFBP3 levels (Gaspari et al 2011).…”

Section: Impact Of Inflammation On Bone Growthsupporting

confidence: 61%

RECENT RESEARCH ON THE GROWTH PLATE: Impact of inflammatory cytokines on longitudinal bone growth

Sederquist¹,

Fernandez-Vojvodich²,

Zaman³

et al. 2014

Journal of Molecular Endocrinology

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Children with inflammatory diseases usually display abnormal growth patterns as well as delayed puberty. This is a result of several factors related to the disease itself, such as malnutrition, hypercortisolism, and elevated levels of pro-inflammatory cytokines. These factors in combination with glucocorticoid treatment contribute to growth retardation during chronic inflammation by systemically affecting the major regulator of growth, the GH/IGF1 axis. However, recent studies have also shown evidence of a direct effect of these factors at the growth plate level. In conditions of chronic inflammation, pro-inflammatory cytokines are upregulated and released into the circulation. The most abundant of these, tumor necrosis factor a, interleukin 1b (IL1b), and IL6, are all known to directly act on growth plate cartilage to induce apoptosis and thereby suppress bone growth. Both clinical and experimental studies have shown that growth retardation can partly be rescued when these cytokines are blocked. Therefore, therapy modulating the local actions of these cytokines may be effective for preventing growth failure in patients with chronic inflammatory disorders. In this review, we report the current knowledge of inflammatory cytokines and their role in regulating bone growth.

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Section: Impact Of Inflammation On Bone Growthsupporting

confidence: 61%

RECENT RESEARCH ON THE GROWTH PLATE: Impact of inflammatory cytokines on longitudinal bone growth

Sederquist¹,

Fernandez-Vojvodich²,

Zaman³

et al. 2014

Journal of Molecular Endocrinology

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“…However, in 1999 (16) a study in adult patients with CF reported normal spontaneous GH secretion and release after stimulation with arginine. The report a few years later of low serum IGF-I, increased IGFBP-3 proteolysis and poor growth in transgenic mice overexpressing interleukin (IL)-6 supports the hypothesis that inflammatory mediators per se could modulate the IGF/IGFBP system (17,18).…”

Section: Introductionmentioning

confidence: 74%

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

et al. 2006

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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

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“…These observations demonstrate that chronic overproduction of IL-6 can cause a growth defect, and that this growth defect is associated with abnormalities of the IGF-1 system similar to those found in patients. In further support of the relationship between IL-6 and the IGF-1 system, in patients with systemic JIA, circulating levels of IL-6 are inversely correlated with levels of IGF-1 and IGFBP-3 (46,49).…”

Section: Role Of Il-6 In Systemic Jiamentioning

confidence: 81%

“…IL-6-transgenic mice with high circulating levels of IL-6 since birth show a decreased rate of growth, attaining 50-60% of the size of their wild-type littermates as adults (46). Similar to patients with systemic JIA (47,48), IL-6-transgenic mice have normal growth hormone production but low levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) (46,49). These observations demonstrate that chronic overproduction of IL-6 can cause a growth defect, and that this growth defect is associated with abnormalities of the IGF-1 system similar to those found in patients.…”

Section: Role Of Il-6 In Systemic Jiamentioning

confidence: 99%

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

Benedetti¹,

Martini²

2005

Arthritis & Rheumatism

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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 127 publications

References 50 publications

RECENT RESEARCH ON THE GROWTH PLATE: Impact of inflammatory cytokines on longitudinal bone growth

RECENT RESEARCH ON THE GROWTH PLATE: Impact of inflammatory cytokines on longitudinal bone growth

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

Targeting the interleukin‐6 receptor: A new treatment for systemic juvenile idiopathic arthritis?

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