: Background/Aim : Several reports have indicated that environmental factors and defects in innate immunity are central to the pathogenesis of inflammatory bowel disease (IBD). Although bacteria producing lipopolysaccharide (LPS), which is a Toll -like receptor (TLR) 4 agonist, play a crucial role in the development of experimental colitis, LPS tolerance following initial exposure to LPS can result in a state of hyporesponsiveness to subsequent LPS challenge. Therefore, we initiated this study to explore the role of LPS tolerance in the development of colitis. Methods : Dextran sulfate sodium (DSS) colitis was induced in Balb/c mice with or without daily intraperitoneal administration of LPS. Disease activity and cytokine mRNA expression in the colon were evaluated. To confirm LPS tolerance, mouse conventional bone marrow -derived dendritic cells (BMDC) were preincubated with or without LPS, and were restimulated with LPS 24 h after first exposure. Cytokine production was measured by ELISA, and mRNA expression was evaluated by RT -PCR. Furthermore, we investigated the expression of negative regulators of LPS tolerance in BMDC. Results : Administration of LPS significantly suppressed colonic inflammation of DSS -induced colitis. After subsequent stimulation with LPS, TNF -α production was reduced in BMDC. IRAK -M, a negative regulator of TLR4 signaling, mRNA expression was upregulated in LPS -treated BMDC. Conclusion : LPS tolerance was able to protect mice from DSS -induced colitis, and IRAK -M participated in this tolerance. Taken together, these observations suggest that loss of exposure to LPS is involved in the pathogenesis of IBD.

AIMS :To investigate whether Imiquimod (IMQ) as TLR7 ligand protects mice from colonic inflammation and the mechanisms underlying in such immunoregulatory conditions. METHODS : Murine colitis was induced to Balb/c mice by administration of trinitrobenzene sulfonic acid (TNBS) with or without daily intraperitoneal administration of IMQ. Colitis was evaluated by body weight decreases and by histological score. Also colonic mRNA expression was measured by RT -PCR. To confirm the induction of Regulatory T cells (Tregs) by type -1 IFN from pDCs, we generated mouse bone marrow -derived pDCs and co -cultured these with CD4 + T cells isolated from mouse spleen with or without IMQ stimulation. Cytokine production in the culture supernatant was measured by ELISA and the number of Tregs were analyzed by flow cytometry. Spleen and mesenteric lymph nodes (MLN) from IMQ -treated mice were collected, and mRNA expressions of cytokine were measured by RT -PCR and cytokine productions were measured by ELISA. Tregs and chemokine expressions were analyzed in colon of TNBS -induced colitis mouse by immunohistochemistry. RESULTS : Administration of IMQ significantly suppressed colonic inflammation of TNBS -induced colitis. In the colons of IMQ -treated mice, mRNA expression of TNF -α was decreased, and strong expressions of IL -6, IFN -β and TGF -β were detected. IL -10 and TGF -β productions were increased in the supernatant of co -cultured cells stimulated with IMQ, although we were unable to detect Treg differentiaton in IMQ -stimulated co -cultured cells. In MLN of IMQ -treated mice, strong expressions of TLR7, IFN -β, TGF -β and Foxp3 mRNA were detected. IL -10 production from MLN cells was also increased in the IMQ -treated group. Finally, Tregs in the inflamed colon and CCR9 in MLN of IMQ -treated mice were detected. CONCLUSION : These results suggest that IMQ protects mice from TNBS colitis through induction of CCR9, which regulates accumulation of Tregs in the inflamed colon.

Sixty-six rheumatoid arthritis (RA) patients were analyzed retrospectively to assess the incidence and risk factors for elevation of serum hepatic aminotransferases during methotrexate (MTX) therapy. The effect of folate supplementation on serum ALT and RA activity was evaluated prospectively in 14 patients who showed a sustained high serum level of ALT. The frequency of elevation of serum AST or ALT was 4-5 times greater than in patients taking other DMARDs. Multivariate linear regression analysis demonstrated that elevation of ALT was independently associated with sex (female), obesity, baseline ALT, MTX dose, and gastrointestinal side effects. Folate supplementation caused ALT levels to decrease in all patients within 3 months. Eleven patients showed no change of RA activity, but 3 patients dropped out of the study because of the exacerbation of RA. These results suggest that careful monitoring of serum hepatic aminotransferases is necessary in patients with predisposing factors, especially those receiving more than 0.15 mg/kg of MTX weekly. Folate supplementation can reverse the sustained elevation of ALT, but might cause exacerbation of RA in some patients.

A 39-year-old man presented with diarrhea and abdominal pain. At 26 years of age, he was found to have eosinophilia and abnormal liver function parameters, for which prednisolone therapy was started. He subsequently underwent a liver biopsy and endoscopic retrograde cholangiopancreatography, and received a diagnosis of primary sclerosing cholangitis (PSC). On presentation to our hospital, he was further diagnosed with eosinophilic colitis based on aggravation of diarrhea and severe eosinophilic infiltration in the colonic mucosa. We herein report a rare case of concurrent PSC and eosinophilic colitis.

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