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P080. Desensitization of the IGF‑1 receptor signal transduction in rat colon with experimental colitis


I. Román-Curto1, M. Fernández-Moreno1, B. Hernández-Breijo1, M. Lobo2, P. Sanz-Hernanz1, C. Pastor1, L. Sebastián1, J.P. Gisbert3, L. Guijarro1

1Universidad De Alcalá, Alcalá De Henares, Madrid, Spain; 2Department of Cell Biology and Genetics, University of Alcalá, Madrid, Spain; 3Hospital De La Princesa, Department of Gastroenterology, Madrid, Spain



Background: Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract as a consequence of deregulation of tumor necrosis factor-α (TNF‑α) signal transduction. TNF‑α activates cell signalling cascades involved in desensitization processes to anabolic hormones, as insulin. Both, insulin and IGF‑1, are able to activate insulin receptor substrate‑1 (IRS‑1) and subsequent signalling cascades (MAPK and Akt), triggering metabolic and/or mitogenic effects. On the other hand, it has been observed a decrease in IGF‑1 serum levels in IBD patients. However, the changes of the IGF‑1 signal transduction in colon during colitis are unknown.

Aim: To study the IGF‑1R/Akt/GSK-3/β-catenin system in an experimental model of colitis.

Methods: We employed healthy rats and rats subjected to experimental colitis (treated with DSS, dextran sulphate sodium), with or without IGF‑1 stimulation. In an additional experimental group, rats were treated with the antibody anti-TNF‑α infliximab. To characterize the extent of disease, body weight, glucose level and colon mucosal integrity (PAS-staining, Periodic Acid Schiff) were assessed. In all groups, the receptor/transductor system from IGF‑1 (IGF‑1R, pY99, IRS 1/2, PI3K, Akt, GSK‑3, mTor and β‑catenin) was studied in colonic mucosa by Western blot and by immunohistochemistry.

Results: The immunohistochemical studies of animals with colitis showed: (i) A decrease in goblet cells of colonic mucosa (PAS reaction); (ii) An increase in GSK‑3 phosphorylation and of proteins phosphorylated in tyrosine residues (pY99). All these effects were reversed by the treatment with infliximab. By Western blot studies, we observed: (i) An increase in the phosphorylation of IGF‑1R, AKt, GSK‑3 and mTor in the colon of animals with colitis. (ii) An absence of stimulation of the phosphorylation of these components by IGF‑1 in animals with colitis. (iii) A stimulation of the cascade GSK‑3/β‑catenin by IGF‑1 in control animals. (iv) An abolition of the stimulatory effect of IGF‑I on GSK‑3/β‑catenin during experimental colitis.

Conclusions: Taken together, our results suggest that during experimental colitis there is a state of resistance to IGF‑1 in the colon. This can be reversed by infliximab treatment. It has been shown that the mitogenic ability of IGF‑1 depends on the activation of the cascade GSK-3/β-catenin; therefore, our results point out the importance of the desensitization to IGF‑1 in the pathogenesis of IBD.