title: Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children.
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.
authors.affiliation: Research Centre for Gastroenterology, Institute of Cell and Molecular Science, University of London, London E1 2AD, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sawczenko
authors.forename: Omeia
authors.initials: O
authors.lastname: Azooz
authors.forename: Joanna
authors.initials: J
authors.lastname: Paraszczuk
authors.forename: Maja
authors.initials: M
authors.lastname: Idestrom
authors.forename: Nick M
authors.initials: NM
authors.lastname: Croft
authors.forename: Martin O
authors.initials: MO
authors.lastname: Savage
authors.forename: Anne B
authors.initials: AB
authors.lastname: Ballinger
authors.forename: Ian R
authors.initials: IR
authors.lastname: Sanderson
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D016022:Case-Control Studies; D002648:Child; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy; D003424:Crohn Disease / Q000235:genetics; D004195:Disease Models, Animal; D005838:Genotype; D006130:Growth Disorders / Q000209:etiology*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007410:Intestinal Diseases / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D000906:Antibodies; D015850:Interleukin-6; D007334:Insulin-Like Growth Factor I; D014302:Trinitrobenzenesulfonic Acid