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

      , ,
      Hormone Research in Paediatrics
      S. Karger AG

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          Abstract

          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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          Responsiveness of IGF-I and IGFBP-3 to therapeutic intervention in children and adolescents with Crohn's disease.

          Abnormal linear growth is common in childhood and adolescent Crohn's disease. We have studied the concentrations of the inflammatory marker CRP and of serum IGF-I and IGFBP-3 in patients with active Crohn's disease and have assessed the changes in these parameters during therapeutic intervention with enteral nutrition or intestinal resection. Children and adolescents attending the inflammatory bowel disease clinic at our hospital underwent treatment either with enteral nutrition (Study A) or intestinal resection (Study B). These are two separate studies and the results cannot be compared. Serum concentrations of CRP, IGF-I and IGFBP-3 were determined at 0, 2, 8 and 16 weeks after start of enteral nutrition and in addition to height velocity, at 0 and 6 months after intestinal resection. Study A: 14 patients, 9 male, 5 female, median age 12.5 years (range 7.0-17.2), puberty stage 1 (n = 13), stage 3 (n = 1). All had active Crohn's disease. Study B: 9 patients, 7 male, 2 female, median age 13.5 years (range 7.8-16.5), puberty stage 1 (n = 5), stages 2-4 (n = 4). All had Crohn's disease resistant to medical therapy. Crohn's disease was confirmed radiologically, endoscopically and histologically. Disease activity was scored using the Lloyd Still index (LSI). Study A: nutritional support was with a polymeric, casein-based formula feed AL 110. Study B: surgical procedures were small bowel resection (n = 2), right hemicolectomy (n = 5), subtotal colectomy (n = 2). Study A: weight SDS, CRP, IGF-1 and IGFBP-3 were measured at 0, 2, 8, 16 weeks after start of enteral feeding. Study B: height velocity, CRP, IGF-I and IGFBP-3 were measured 0, 6 months after intestinal resection. Medians and ranges were used. Significance of changes was calculated using the Wilcoxon rank test for the analysis of paired data. Study A: median LSI before treatment was 39 and increased after 8 weeks of enteral nutrition to 60 (P < 0.05). Weight SDS increased at 8 and 16 weeks (P < 0.05) compared to pretreatment. CRP was elevated at 0 weeks, falling during treatment. Median (range) values (normal < 5 mg/l) at 0 at 2, 8, 16 weeks were 53 mg/l (15-150), 8 mg/l (5-25), 7 mg/l (5-83) and 14 mg/l (5-39), all P < 0.001 compared with pretreatment. Median IGF-I-values increased during treatment. Median (range) values at 0, 2, 8, 16 weeks (all P < 0.005) compared to pretreatment, median (range) values at 0, 2, 8, 16 weeks were 78 micrograms/l (50-204), 131 micrograms/l (73-251), 119 micrograms/l (77-291) and 133 micrograms/l (67-497), all P < 0.005 compared to pre-treatment. IGFBP-3 levels increased during treatment. Median (range) values at 0, 2, 8, 16 weeks were 2.4 mg/l (1.4-3.1), 2.9 mg/l (1.8-4.6), 3.0 mg/l, 3.2 mg/l (1.8-4.5), all P < 0.01 compared to pretreatment. Study B: height velocity increased during 6 months after surgery. Median (range) values; 3.3 cm/year (0-8.3) before surgery, 8.4 cm/year (2-12.6) 6 months post-surgery, P < 0.01. Median (range) CRP values fell from 45 mg/l (5-150) to 8 mg/l (5-31) and IGF-I-values increased from 163 micrograms/l (64-286) to 226 micrograms/l (71-391). These changes were not statistically significant. IGFBP-3 values did not change. The IGF system, as shown by serum IGF-I and IGFBP-3, is responsive to therapeutic intervention in active Crohn's disease. It is likely that a combination of decreased inflammatory activity and improved nutrition contributes to these changes.
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            Energy balance, viral burden, insulin-like growth factor-1, interleukin-6 and growth impairment in children infected with human immunodeficiency virus.

            To determine the relationship between energy metabolism and growth abnormalities in HIV-infected children and to assess clinical or laboratory characteristics which may be contributing factors to their growth impairment.
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              Study of growth hormone secretion and action in growth-retarded children with juvenile chronic arthritis (JCA).

              The stimulated and spontaneous growth hormone (GH) secretion and the response to GH action were assessed in growth-retarded children with juvenile chronic arthritis (JCA), in order to determine the underlying mechanisms of growth retardation in such children. Six children (4 boys and 2 girls aged 10.7-13.8 years) with active JCA of systemic onset were included in the study which involved: (1) anthropometric measurements; (2) assessment of GH responses to insulin-induced hypoglycaemia and clonidine stimulation; (3) assessment of the nocturnal pulsatile GH secretion by measuring GH in blood samples obtained every 20 min from 20.00 to 08.00 h; and (4) the IGF-I generation test. As a control, the latter test was also performed in eight aged-matched children with physiological delay in puberty. Biosynthetic hGH (0.1 IU/kg BW) was administered s. c. for 4 days and blood samples were taken at baseline and the morning after the last GH injection for measurement of IGF-I and IGFBP-3. All six children with JCA were prepubertal and their growth velocity was <3 cm/year. The GH responses to both stimulation tests were normal (peak GH >20 mU/l). Analysis of the pulsatile GH secretion during the night revealed three-to-four GH pulses of normal amplitude (>20 mU/l). IGF-I (26.7+/-4.6 nmol/l, mean+/-SD) and IGFBP-3 (2.1+/-0.2 mg/l) levels were lower in the patients compared with the controls (43.0+/-3.7 nmol/l and 2.8+/-0.2 mg/l, respectively, P<0.01). Following stimulation with exogenous hGH, there was a significant increase in IGF-I and IGFBP-3 levels in the control group (85 and 73%, respectively), but only a small increase in the patients (31 and 14%). It appears that stimulated and spontaneous GH secretion is normal in children with active systemic JCA, but the response to endogenous and exogenous GH with regard to IGF-I and IGFBP-3 production is impaired, indicating a degree of GH insensitivity in such children.
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                Author and article information

                Journal
                Hormone Research in Paediatrics
                Horm Res Paediatr
                S. Karger AG
                1663-2818
                1663-2826
                September 1 2002
                2002
                November 17 2004
                : 58
                : 1
                : 24-27
                Article
                10.1159/000064757
                64b34370-e153-496e-818f-e83cd1487a65
                © 2004

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