Abstract
As one of the ligands of aryl hydrocarbon receptor (AhR), baicalein, isolated from Scutellaria baicalensis Georgi, has been proved to exert potential therapeutic effects on ulcerative colitis (UC), but its therapeutic mechanism remains obscure. Authentically, ulcerative colitis can be alleviated by regulating the differentiation of naïve CD4+ T cells via AhR activation. So, our study planned to prove the hypothesis that baicalein protected mice against UC by regulating the balance of Th17/Treg cells via AhR activation. Immunofluorescence and western blot results showed that baicalein could promote AhR activation and induce it to transfer to the nucleus. We further determined the effect of baicalein on naïve CD4+ T cell differentiation in vitro by magnetic cell separation and drug intervention. The results showed that baicalein could promote Treg cell differentiation by activating AhR. In vivo study, UC mice were established by free drinking of dextran sulfate sodium (DSS) for 7 days and then were orally administrated by baicalein (10, 20, and 40 mg/kg), TCDD (AhR agonist), and CH223191 (antagonist). The results demonstrated that baicalein improved the symptoms of UC mice, regulated the balance of Th17/Treg cells, and restored the balance of proinflammatory cytokines such as IL-17, IL-6, and TNF-α; anti-inflammatory cytokines such as IL-10 and TGF-β; and epithelial protective cytokine IL-22 in UC mice, and these effects were related to AhR. Taken together, our research found that baicalein might be a potential drug for UC via regulating Treg cell differentiation and maintaining immune homeostasis and attempted to shed a light on the pivotal role of AhR in these effects.
Highlights
It is known that ulcerative colitis (UC) is a chronic nonspecific inflammatory disease, and its main diseased regions are the colon and rectum [1]
IL-10 and IL-17A enzyme-linked immune sorbent assay (ELISA) kits were purchased from MultiSciences Biotech (Hangzhou, China); IL-6, tumour necrosis factor-α (TNF-α), TGF-β, and IL-22 ELISA kits were purchased from Neobioscience Technology Co, Ltd
We found that aryl hydrocarbon receptor (AhR) of the baicalein-treated EL-4 cells transferred from cytoplasm to the nucleus, which fails to be observed in the CH223191 and CH223191+baicalein groups (Figure 1(g))
Summary
It is known that ulcerative colitis (UC) is a chronic nonspecific inflammatory disease, and its main diseased regions are the colon and rectum [1]. It is acknowledged that multiple factors cause antigens in intestinal luminal to cross the damaged epithelial barrier, which leads to the abnormal activation of the intestinal immune system and imbalance between anti-inflammatory and proinflammatory signals. The current mainstream treatment concept is to affect the intestinal immune system, such as antieffector T cell activation or promoting anti-inflammatory signaling pathways [6]. CD4+ CD25+ Treg cells have multiple immune inhibitory functions, mainly reflecting in (1) expressing CD39 and CD73 to disrupt the metabolism of effector T cells, (2) secreting perforin and granzyme B to exert cytotoxic effects on effector T cells, and (3) promoting the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β, thereby restraining the function of Th17 and Th1 cells [12]. CD4+ CD25+ Treg cells play a significant role in maintaining intestinal immune tolerance and alleviate inflammation [13], and a therapeutic strategy of using Tregs for controlling excessive immune response in UC has been proposed in recent years [14]
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