Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a group of autoimmune diseases characterized by nonspecific inflammation in the gastrointestinal tract. Recent investigations suggest that activation of Th17 cells and/or deficiency of regulatory T cells (Treg) is involved in the pathogenesis of IBD. Heme oxygenase (HO)-1 is a protein with a wide range of anti-inflammatory and immune regulatory function, which exerts significantly protective roles in various T cell-mediated diseases. In this study, we aim to explore the immunological regulation of HO-1 in the dextran sulfate sodium-induced model of experimental murine colitis. BALB/c mice were administered 4% dextran sulfate sodium orally; some mice were intraperitoneally pretreated with HO-1 inducer hemin or HO-1 inhibitor stannum protoporphyrin IX. The results show that hemin enhances the colonic expression of HO-1 and significantly ameliorates the symptoms of colitis with improved histological changes, accompanied by a decreased proportion of Th17 cells and increased number of Tregs in mesenteric lymph node and spleen. Moreover, induction of HO-1 down-regulates retinoic acid-related orphan receptor γt expression and IL-17A levels, while promoting Treg-related forkhead box p3 (Foxp3) expression and IL-10 levels in colon. Further study in vitro revealed that up-regulated HO-1 switched the naive T cells to Tregs when cultured under a Th17-inducing environment, which involved in IL-6R blockade. Therefore, HO-1 may exhibit anti-inflammatory activity in the murine model of acute experimental colitis via regulating the balance between Th17 and Treg cells, thus providing a possible novel therapeutic target in IBD.
Highlights
Heme oxygenase-1 (HO-1) is an inducible enzyme with pleiotropic immunomodulatory effects
After mice were sacrificed on day 7, the colons were taken for RNA and protein extraction. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blot assays confirmed that the HO-1 mRNA expression and protein level were enhanced in the dextran sulfate sodium (DSS) group as compared with the control group (Fig. 1, A and B), accompanying the increase of HO-1 enzyme activity (Fig. 1C)
The levels of HO-1 mRNA and protein in colon were significantly increased after administration of hemin and Sn-protoporphyrin IX (SnPP) (Fig. 1, A and B)
Summary
Heme oxygenase-1 (HO-1) is an inducible enzyme with pleiotropic immunomodulatory effects. Results: Induction of HO-1 inhibits Th17-mediated responses in experimental colitis and switches the naive T cells to Tregs under Th17-skewing conditions in vitro. Conclusion: HO-1 ameliorates dextran sulfate sodium (DSS)-induced colitis via blocking IL-6/IL-6R signaling to regulate Th17/Treg cell balance. We aim to explore the immunological regulation of HO-1 in the dextran sulfate sodiuminduced model of experimental murine colitis. Further study in vitro revealed that up-regulated HO-1 switched the naive T cells to Tregs when cultured under a Th17-inducing environment, which involved in IL-6R blockade. HO-1 may exhibit anti-inflammatory activity in the murine model of acute experimental colitis via regulating the balance between Th17 and Treg cells, providing a possible novel therapeutic target in IBD
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