ABSTRACT
IL-10 is a potent anti-inflammatory cytokine that inhibits the production of proinflammatory mediators. Signaling by IL-10 occurs through the IL-10 receptor (IL-10R), which is expressed in numerous cell types, including intestinal epithelial cells (IECs), where it is associated with development and maintenance of barrier function. Guided by an unbiased metabolomics screen, we identified tryptophan (Trp) metabolism as a major modifying pathway in interferon-γ (IFNγ)-dominant murine colitis. In parallel, we demonstrated that IFNγ induction of indoleamine 2,3-dioxygenase 1, an enzyme that catalyzes the conversion of Trp to kynurenine (Kyn), induces IL-10R1 expression. Based on these findings, we hypothesized that IL-10R1 expression on IEC is regulated by Trp metabolites. Analysis of the promoter region of IL-10R1 revealed a functional aryl hydrocarbon response element, which is induced by Kyn in luciferase-based IL-10R1 promoter assays. Additionally, this analysis confirmed that IL-10R1 protein levels were increased in response to Kyn in IEC in vitro. Studies using in vitro wounding assays revealed that Kyn accelerates IL-10-dependent wound closure. Finally, reduction of murine dextran sodium sulfate colitis through Kyn administration correlates with colonic IL-10R1 expression. Taken together, these results provide evidence on the importance of IL-10 signaling in intestinal epithelia and implicate AHR in the regulation of IL-10R1 expression in the colon.
Subject(s)
Colitis/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Interleukin-10 Receptor alpha Subunit/metabolism , Intestinal Mucosa/metabolism , Tryptophan/metabolism , Animals , Dextran Sulfate , Disease Models, Animal , Gene Expression Regulation , Humans , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-10 Receptor alpha Subunit/genetics , Kynurenine/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Promoter Regions, Genetic/genetics , Receptors, Aryl Hydrocarbon/metabolism , Signal Transduction , Wound HealingABSTRACT
BACKGROUND: Several open-label and retrospective studies have indicated that thalidomide may be beneficial in patients with refractory Crohn's disease (CD). AIM: To report our long-term experience with the use of thalidomide for adults with refractory Crohn's disease. METHODS: We conducted a retrospective study of long-term clinical and safety outcomes among adults treated with thalidomide for refractory Crohn's disease. Response was defined as a clinician's assessment of improvement after at least 7 days treatment of one or more of the following: bowel movement frequency, fistula output, rectal bleeding, abdominal pain, extraintestinal manifestations, or well-being. Remission required all of the following: <3 stools/day, no bleeding, abdominal pain or extraintestinal manifestations and increased well-being. RESULTS: Thirty-seven adults with refractory Crohn's disease were treated with thalidomide for a median of 4.4 months and followed up for a median of 58 months. Clinical response and remission rates were 54% and 19%, respectively. About 40% of patients were able to stop steroids. Response rates were higher for those treated with more than 50 mg/day (85%) than for those treated with a maximum of 50 mg/day (40%; P = 0.01). An adverse event occurred in 68% of patients. Approximately one-third of patients (38%) experienced neuropathy. CONCLUSIONS: Thalidomide appears to be safe and effective in some patients with refractory Crohn's disease. Although side effects may limit long-term use, thalidomide has potential to induce significant clinical responses.
