Abstract
Dihydroartemisinin (DHA) is a derivative of the herb Artemisia annua L. that has prominent immunomodulatory activity; however, its underlying mechanism remains elusive. Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition characterized as an autoimmune disorder that includes dysfunctions in the T helper (Th)/T regulatory cell (Treg) balance, which normally plays pivotal roles in immune homeostasis. The aim of this study was to explore the potential of DHA to ameliorate IBD by restoring the Th/Treg cell balance. To this end, we established mouse models of colitis induced by oxazolone (OXA) and 2,4,6-trinitro-benzene sulfonic acid (TNBS). We then treated mice with DHA at 4, 8, or 16 mg/kg/day. DHA treatment ameliorated colitis signs and reduced lymphocyte infiltration and tissue fibrosis. Moreover, DHA decreased the numbers of Th1 and Th17 cells and Th9 and Th22 cells in TNBS- or OXA-induced colitis, respectively, and increased Tregs in both models. DHA (0.8 mg/mL) also inhibited activated CD4+ T lymphocytes, which was accompanied by apoptosis induction. Moreover, it promoted heme oxygenase-1 (HO-1) production in vitro and in vivo, concomitant with CD4+ T cell apoptosis and restoration of the Th/Treg balance, and these effects were blocked by treatment with the HO-1 inhibitor Sn-protoporphyrin IX. Overall, these results suggest that DHA is a novel and valuable candidate for IBD therapy or Th/Treg immunoregulation.
Highlights
Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is an idiopathic autoimmune disease characterized by non-specific, relapsing, and precarious inflammatory reactions in the gastrointestinal tract
Eosin)-stained colonic sections of DHA-treated mice showed reduced leukocyte infiltration and (Figure 1B and Figure S1A), whereas Sirius-Red staining revealed a lower degree of tissue fibrosis structural destruction (Figure 1Band S1A), whereas Sirius-Red staining revealed a lower degree of (Figure 1C and Figure S1B). These results indicated that DHA could ameliorate OXA-induced colitis in tissue fibrosis (Figure 1C and S1B)
Significantly decreased the numbers of TUNEL-positive cells (Figure 4G,H, Figure S4B and S4C). These results suggested that DHA induces activated CD4+ T cell apoptosis by regulating heme oxygenase-1 (HO-1) expression and production
Summary
Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is an idiopathic autoimmune disease characterized by non-specific, relapsing, and precarious inflammatory reactions in the gastrointestinal tract. The main symptoms of IBD include weight loss, diarrhea, hematochezia, abdominal pain. The morbidity of IBD has been increasing annually in various regions, resulting in substantial medical expenses [2]. Patients with IBD have an increased risk of other diseases such as anemia [3], acute arterial events [4], and colorectal cancer [5]. The mainstays of IBD treatment include dietary, surgical, and medical approaches [6]; many patients are still reluctant to receive treatment due to the associated high costs, toxic effects, and long-term uncertainty [7]. New alternative medical strategies for IBD are desperately needed
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