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P021. Roxithromycin inhibits nuclear factor kappaB signaling and endoplasmic reticulum stress in intestinal epithelial cells, and ameliorates experimental colitis

S.-J. Koh1, J.W. Kim1, J.P. Im2, J.S. Kim2, 1Seoul National University Boramae Hospital, Internal Medicine, Seoul, Korea, Republic of, 2Seoul National University College of Medicine, Department of Internal Medicine and Liver Research Institute, Seoul, Korea, Republic of

Background

Roxithromycin is known to demonstrate anti-inflammatory and immunoregulatory activity. However, little information is available in the effect of roxithromycin on intestinal inflammation.

Methods

HCT116 cells were pretreated with roxithromycin and then stimulated with tumor necrosis factor-α (TNF-α). Interleukin-8 (IL-8) expression was determined by real-time RT-PCR. IκB phosphorylation/degradation and intranuclear translocation of nuclear factor kappaB (NF-κB) were evaluated by Western blot analysis. The molecular marker of endoplasmic reticulum (ER) stress, including p-JNK, p-eIF2α, CHOP, and XBP1 was evaluated using western blotting and PCR. In the dextran sulfate sodium (DSS) colitis model, mice were given 4% DSS for 5 days with or without roxithromycin. Using the extracted colon tissue, immunohistochemical staining for phospho-IκB kinase (IKK) antibody was performed.

Results

Roxithromycin significantly inhibited the upregulated expression of IL-8 in HCT116 cells stimulated with TNF-α. Pretreatment with roxithromycin attenuated IκB phsophorylation/degradation and NF-κB nuclear translocation. CHOP and XBP1 mRNA expression was enhanced in the presence of TNF-α, and it was dampened by pretreatment of roxithromycin. JNK phosphorylation and the level of p-eIF2α was also downregulated by the pretreatment of roxithromycin. Administration of roxithromycin significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histology. In addition, the DSS-induced phospho-IKK activation was significantly decreased in roxithromycin-pretreated mice.

Conclusion

These results indicate that roxithromycin inhibits NF-κB activation and ER stress in intestinal epithelial cells and that it ameliorates experimental murine colitis. These results suggest that roxithromycin is a potential therapeutic agent for the treatment of inflammatory bowel disease.