Growth failure in children with inflammatory bowel disease: A prospective study

Motil, Kathleen J.; Grand, Richard J.; Davis-Kraft, Lee; Ferlic, Laura; Smith, E O

doi:10.1016/0016-5085(93)90883-e

Cited by 296 publications

(260 citation statements)

References 43 publications

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“…It is known that the most prominent factor affecting growth is inadequate nutritional intake. 30 Moreover, growth retardation in IBD patients can be correlated with an increase in systemic TNF-a and IL-6 levels. 31,32 The bodyweight alterations observed both in Muc2 À/À and Muc2/ IL-10 DKO mice support this paradigm, as the weights of these mice correlated with the severity of inflammation.…”

Section: Mucin 2-interleukin 10-deficient Mice: Double Trouble M Van mentioning

confidence: 99%

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Sluis

Bouma

Vincent

et al. 2008

Laboratory Investigation

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Expression of the mucin MUC2, the structural component of the colonic mucus layer, is lowered in ulcerative colitis. Furthermore, interleukin (IL)-10 knockout (IL-10 À/À ) mice develop colitis and have reduced Muc2 levels. Our aim was to obtain insight into the role of Muc2 and IL-10 in epithelial protection. Muc2-IL-10 double-knockout (Muc2/IL-10 DKO ) mice were characterized and compared to Muc2 knockout (Muc2 À/À ), IL-10 À/À and wild-type (WT) mice. Clinical symptoms, intestinal morphology and differences in epithelial-specific protein levels were analyzed. In addition, levels of the proinflammatory cytokines in colonic tissue and serum were determined. IL-10 À/À mice were indistinguishable from WT mice throughout this experiment and showed no clinical or histological signs of colitis. Muc2/IL-10 DKO and Muc2 À/À mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10 DKO mice had a high mortality rate (50% survival/5 weeks) compared to the other types of mice (100% survival). Microscopic analysis of the colon of Muc2/IL-10 DKO mice showed mucosal thickening, increased proliferation, superficial erosions and a diminished Muc4 expression. Furthermore, pro-inflammatory cytokines were significantly upregulated, both in tissue (mRNA) and systemically in Muc2/IL-10 DKO mice. In conclusion, Muc2/IL-10 DKO mice develop colitis, which is more severe in every aspect compared to Muc2 À/À and IL-10 À/À mice. These data indicate that (i) in case of Muc2 deficiency, the antiinflammatory cytokine IL-10 can control epithelial damage, though to a limited extent and (ii) the mucus layer is most likely a key factor determining colitis.

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Section: Mucin 2-interleukin 10-deficient Mice: Double Trouble M Van mentioning

confidence: 99%

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Sluis

Bouma

Vincent

et al. 2008

Laboratory Investigation

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“…Delayed linear growth and pubertal development are frequent in children with chronic inflammatory bowel diseases (CIBD) (Motil et al 1993, Savage et al 1999. The growth impairment can be ascribed to various factors such as malnutrition (Kelts et al 1979), prolonged treatment with steroids (Allen 1996), and chronic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1beta (IL-1beta) and IL-6 modulate insulin-like growth factor-binding protein (IGFBP) secretion in colon cancer epithelial (Caco-2) cells

Street

Miraki-Moud²,

Sanderson³

et al. 2003

Journal of Endocrinology

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Chronic inflammation is characterised by modifications in cytokine concentrations, whereas growth is mainly dependent on the GH-IGF axis. IGF-I bioavailability is modulated by a family of IGF-binding proteins (IGFBPs). The aim of the present study was to evaluate the interactions among interleukin-1 (IL-1 ), IL-6 and IGFBP secretion by intestinal cells to assess whether cytokines modulate IGFBP secretion, and in turn IGF-I and IGF-II bioavailability. The human colon carcinoma derived cell line Caco-2 was used as an in vitro model for its capacity to differentiate spontaneously. Experiments were carried out on day 4 (undifferentiated state) and day 14 (differentiated state) after plating. Carcinoembryonic antigen (CEA) was used as a marker of differentiation and increased in the conditioned media (CM) from days 4 to 14 (0·2 0·01 ng/ml per 10 5 cells vs 3·3 0·2 ng/ml per 10 5 cells, P,0·05). IGFBP-2 and IGFBP-4 secretion decreased concomitantly. Cells were stimulated with IL-1 and IL-6 at 1, 10 and 50 ng/ml, and with IL-1 and IL-6 in combination at the same dose of 1 and 10 ng/ml. IGF-I at 50 ng/ml was used as a control. Caco-2 cells expressed and secreted mainly IGFBP-2 and IGFBP-4 into the CM. On day 4, IL-1 (1 ng/ml) and IL-6 (10 and 50 ng/ml) reduced IGFBP-2 by 29 8%, and by 32 9 and 38 8% respectively (P,0·05). IGFBP-4 was also reduced by IL-1 at 1 and 50 ng/ml (-14 4% and -46 11% vs serum free medium (SFM) respectively, P,0·05), and IL-6 at 50 ng/ml (-46 15%, P,0·05). Both IGFBP-2 and IGFBP-4 were reduced by IL-1 and IL-6 in combination at 1 and 10 ng/ml (P,0·05). On day 14, IGFBP-2 band intensity was reduced at 10 ng/ml of IL-1 (-22 15% vs SFM, P,0·05) and at 50 ng/ml of both cytokines (-33% 8% and -13% 13% vs baseline respectively, P,0·05). IGFBP-4 band intensity decreased with 10 and 50 ng/ml of IL-1 (-35 11% and -46 15% vs SFM respectively) and IL-6 (-36% 10% and -46 15% vs SFM respectively). IL-1 and IL-6 in combination at 1 and 10 ng/ml reduced both IGFBP-2 and IGFBP-4.In conclusion, IGFBP-2 and IGFBP-4 secretion in CM decreased with Caco-2 cell differentiation. IGFBP-2 and IGFBP-4 were significantly decreased by IL-1 and IL-6 treatment in both the undifferentiated and differentiated state. Furthermore, these cytokines increased cell proliferation whereas total protein content was significantly reduced only at the higher concentrations of IL-6 and IL-1 . These findings suggest that interleukins modulate the IGF-IGFBP system in Caco-2 cells in vitro.

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“…For example, Crohn's disease, characterized by transmural inflammation of the gastrointestinal tract (1), severely inhibits growth in approximately one third of affected children (2)(3)(4)(5). A significant proportion of children with Crohn's disease become short adults (6,7).…”

mentioning

confidence: 99%

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

Sawczenko

Azooz

Paraszczuk

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

111

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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 trinitrobenzenesulphonic 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 G͞C 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 growthretarded 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 mg͞dl, 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.Crohn's disease ͉ height ͉ insulin-like growth factor I ͉ C-reactive protein ͉ food intake

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Growth failure in children with inflammatory bowel disease: A prospective study

Cited by 296 publications

References 43 publications

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Interleukin-1beta (IL-1beta) and IL-6 modulate insulin-like growth factor-binding protein (IGFBP) secretion in colon cancer epithelial (Caco-2) cells

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the –174 IL-6 G/C polymorphism in children

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