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P039. Reprogramming of intestinal epithelial cells by interleukin-22

L. Lebenheim1, B. Siegmund1, J.-D. Schulzke1, M. Schumann1, 1Charité – University Medicine Berlin, Germany, Gastroenterology, Infectiology and Rheumatology, Berlin, Germany

Background

Interleukin-22 (IL-22) is known to elicit epithelia-specific effects via the IL22R1/IL10R2 receptor. Since IL-22 has been associated with wound healing, it is believed to act mainly as an epithelia-protecting cytokine with rather barrier-supportive properties. However, others have associated rather oncogenic and pro-inflammatory functions to IL-22. Therefore, a broader characterization of IL-22's action on epithelia is needed.

Methods

To study effects of IL-22 on epithelial barrier function transepithelial resistance (Rt) of intestinal epithelial cell lines (HT-29 and Caco-2) was determined. Paracellular passage of biotin-NHS (MW 400 Da) and integrity of immunostained tight junction (TJ) proteins were visualized by confocal microscopy. Rat ileal and colonic mucosae were mounted to Ussing chambers and exposed basolaterally to IL-22. The effect of IL-22 on mobility on intestinal epithelial cells was determined in cell culture-based models for wound-healing as well as epithelial invasion. Epithelial polarity was examined in 3-dimensional Caco-2 cysts, grown in matrigel.

Results

IL-22 induced a significant and dose-dependent (1, 10, 100 ng/ml) reduction in Rt in both, Caco-2 and HT-29 cells, which was abolished by inhibition of PI-3 kinase and MAP kinase, but not by STAT inhibitors. Paracellular passage of biotin was elevated accordingly. In IL-22 treated rat ileum and colon complex changes including the subepithelial layer were found, indicating either protective or pro-inflammatory changes according to the concentration used. Preliminary data revealed a dose dependent reduction of the mucosal surface area in ileal and colonic specimen. IL-22-mediated epithelial wound healing was confirmed in the HT-29 model. Furthermore, epithelial invasion was dramatically increased in IL-22-treated intestinal epithelial cells. On the other hand, epithelial apoptosis was also modestly increased. The TJ proteins ZO-1 and JAM-A localized to intracellular pools and not to TJs. Caco-2 matrigel cysts displayed an increase in multiple lumen, atypical mitoses and basal actin protrusions.

Conclusion

By reducing epithelial polarity, IL-22 reprograms intestinal epithelia to gain migratory/invasive properties and at the same time to lose barrier properties. This has implications not only for wound healing but also for inflammation-associated carcinogenesis.