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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C
Andrew Sawczenko1, Omeia Azooz, Joanna Paraszczuk
1Research Centre for Gastroenterology, Institute of Cell and Molecular Science, University of London, London E1 2AD, United Kingdom.
Insights
Interleukin-6 (IL-6) elevation in Crohn's disease children significantly impairs growth by suppressing insulin-like growth factor I (IGF-I). Specific IL-6 gene variants influence growth failure in pediatric Crohn's disease patients.
Area of Science:
- Pediatric Gastroenterology
- Inflammatory Bowel Disease Research
- Endocrinology and Growth
Background:
- Inflammatory diseases, including Crohn's disease, are known to impede linear growth in children.
- Elevated Interleukin-6 (IL-6) levels, even without inflammation, can retard growth by suppressing Insulin-like Growth Factor I (IGF-I).
- Intestinal inflammation in Crohn's disease is suspected to contribute to growth impairment via IL-6.
Purpose of the Study:
- To investigate the role of IL-6 in growth suppression associated with intestinal inflammation.
- To determine if blocking IL-6 can restore linear growth and IGF-I levels in an animal model of colitis.
- To examine the association between the IL-6 -174 gene promoter polymorphism and growth failure in children with Crohn's disease.
Main Methods:
- Administered anti-IL-6 antibody to rats with trinitrobenzene-sulphonic acid-induced colitis to assess effects on growth and IGF-I.
- Analyzed nutrient intake and inflammation markers in treated and untreated rats.
- Genotyped 153 children with Crohn's disease for the IL-6 -174 G/C promoter polymorphism and correlated genotypes with height, IGF-I, and C-reactive protein levels.
Main Results:
- Anti-IL-6 antibody treatment in rats significantly restored linear growth and increased IGF-I levels without improving nutrient intake or reducing inflammation.
- Children with Crohn's disease and the IL-6 GG genotype exhibited greater growth retardation compared to GC or CC genotypes.
- Patients with the IL-6 GG genotype showed higher C-reactive protein levels, an IL-6-induced marker, but similar Crohn's disease risk.
Conclusions:
- IL-6 plays a critical role in mediating growth suppression in the context of intestinal inflammation.
- The IL-6 -174 G/C promoter polymorphism is a significant genetic factor influencing growth failure in pediatric Crohn's disease.
- Targeting IL-6 may be a therapeutic strategy to improve growth outcomes in children with Crohn's disease.
Abstract:
Inflammatory diseases frequently impair linear growth. Crohn's disease inhibits growth in up to one third of affected children. In rats with trinitrobenzenesulphonic acid-induced colitis, 40% of growth impairment is attributable to inflammation, with the rest being due to undernutrition. In transgenic mice without inflammation, raised IL-6 retards growth, suppressing insulin-like growth factor (IGF)-I. We hypothesized that IL-6, induced by intestinal inflammation, suppresses growth and inhibits IGF-I expression. Therefore, an anti-IL-6 Ab was given to rats with trinitrobenzene-sulphonic acid colitis. The Ab did not improve nutrient intake or decrease inflammation compared with untreated disease controls, but it significantly restored linear growth (P = 0.023) and increased IGF-I (P = 0.05). In humans, the IL-6 -174 G/C promoter polymorphism affects IL-6 transcription, with the GG genotype inducing the greatest IL-6 levels. Because IL-6 is increased in Crohn's disease, we further hypothesized that growth failure would vary with the IL-6 -174 genotype. At diagnosis, among 153 children with Crohn's disease, those with the IL-6 GG genotype were more growth-retarded than those with the GC or CC genotypes (height SD score, -0.51 vs. -0.10; P = 0.031). Also, the patients with the IL-6 GG genotype had higher circulating levels of C-reactive protein, an IL-6-induced product (36 vs. 18 mg/dl, P = 0.028). However, their risk of developing Crohn's disease was similar to other genotypes when compared with 351 healthy controls (P = 0.7). Thus, the IL-6 -174 genotype mediates growth failure in children with Crohn's disease.
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