Simvastatin Down-regulates Inflammatory Responses By Shifting The Th17/Treg Profile In TNBS Induced Colitis

Objective: Inflammatory bowel disease(IBD) is a chronic relapsing inflammatory of intestinal mucosa.However,the etiology of the disease is still unclear.Recently, it has been strongly suggested that the inflammatory response is mainly caused by inappropriate activation of intestinal mucosal immune system.Statins are 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitor and are used to treat hypercholesterolemia in patients with coronary artery and atherosclerotic diseases.Statins have indeed been proposed as immunomodulatory and antiinflammatory drugs by the effects on different immune pathways. To explore the effect and mechanism of Simvastatin in experimental colitis model induced by TNBS.Methods:The 40 Spragye-Dawley rats were randomly divided into 5 groups: control group, model group(TNBS),The drug treatment group,low dosage of simvastatin group(SL,5mg/kg) and high dosage of simvastatin group(SH,20mg/kg group),Sulfasalazine Enteric-coated group(SASP,400mg/kg).The colitis model was induced by intracolonic administration of 5% TNBS in 50% ethanol(v/v) except the control group.Corresponding doses of simvastatin and Sulfasalazine Enteric-coated treatment by intragastric administration started at day 1 after making modes every day. The model group were treatmented with an equal volume of saline by intragastric administration every day.the control group were given normal saline intracolonic instillation and normal saline intragastric administration for following days.During the experiment, the severity of colitis were assessed by body weight, disease activity index(DAI),colon injury index score(CMDI), and histological score(TDI).The level of IL-17 and IL-22,IL-10 in serum were detected by ELISA.Expressions of IL-17 and Foxp3 were detected by immunohistochemistry.The expession of RORγt、Foxp3 m RNA in colon mucosa were determined respectively by RT-PCR.Results: 1.Compared with control group, the DAI score, CMDI score and pathological scores in the TNBS group and the treatment group increased remarkably, The difference was statistically significant(P<0.05),so the colitis model was successfully established.2. Compared with control group,the level of IL-17 and IL-22 in serum of the group TNBS and the treatment group increased significantly,there were statistically significant differences between groups(P=0.000).There were also significant differences between the treatment groups and model group(P<0.05). the level of IL-10 was higher than the control group in each treatment groups and group TNBS,there were statistically significant differences between groups(P=0.000).Compared with group TNBS,each treatment group increased obviously, with significant difference(P<0.05).3.The expression of IL-17 in colonic mucosa of different group has a statistically significant difference(P<0.05).In group TNBS,IL-17 expression increased, with a significant difference compared with the control group(P=0.000).There were significantly differences between group TNBS and group SH(P=0.002), no statistical significance as compared with group SL and group SASP.The expression of Foxp3 in colonic mucosa of each group has a statistically significant difference after administration(P=0.000). Compared with the control group, the expression of Foxp3 in group TNBS increased, with significant difference(P=0.010).There were significantly differences between group TNBS and group SH(P=0.000).4.Foxp3 and RORγt m RNA was a small amount of expression in colon mucosa of rats in the control group. RORγt m RNA in group TNBS was obviously higher than the control group.Compared with the group TNBS, it was outstandingly lower in the group SH( P < 0.05). Foxp3 m RNA was a certain extent expression in colon tissue in the model group, after treatment, the expession of Foxp3 m RNA were significantly upregulated.There were significantly differences among groups with statistical significance(P=0.000).Conclusions: 1.The imbalance of Th17/Treg could contribute to the pathogenesis of experimental colitis induced by TNBS.2.Simvastatin could inhibit TNBS induced experimental colitis, the mechanism may be related to the up regulation of Treg-related cytokine of IL-10 and transcription factor(Foxp3) levels, inhibit the expression of Th17-related cytokine and transcription factor(RORγt) levels.