TY - JOUR
T1 - Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses
AU - LI, Yanhong
AU - XIAO, Haitao
AU - Hu, Dong Dong
AU - FATIMA, Sarwat
AU - Lin, Cheng Yuan
AU - Mu, Huai Xue
AU - Lee, Nikki P.
AU - BIAN, Zhaoxiang
N1 - Funding Information:
This work was supported by grants from the Food and Health Bureau of The Government of Hong Kong Special Administration Region [Health and Medical Research Fund ( HMRF10111971 )] and the Municipal Science and Technology Program of Shenzhen (Basic Research Fund [2015]1342). We thank Sally KW Lee and Nickie WK Chan for their excellent technical assistance in flow cytometry.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - Ulcerative colitis (UC) is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment has fueled the search for alternative therapeutic strategies. In recent studies, berberine, a plant alkaloid with a long history of medicinal use in Chinese medicine, has shown beneficial effects against animal models of acute UC. However, UC usually presents as a chronic condition with frequent relapse in patients. How berberine will act on chronic UC remains unclear. In the present study, we adopted dextran sulfate sodium (DSS)-induced chronic relapsing colitis model to assess the ameliorating activity of berberine. Colitis was induced by two cycles of 2.0% DSS for five days followed by 14 days of drinking water plus a third cycle consisting of DSS only for five days. The colitis mice were orally administered 20 mg/kg berberine from day 13 onward for 30 days and monitored daily. The body weight, stool consistency, and stool bleeding were recorded for determination of the disease activity index (DAI). At the end of treatment, animals were sacrificed and samples were collected and subjected to histological, RT-qPCR, Western blot, and LC-MS analyses. Lymphocytes were isolated from spleens and mesenteric lymph nodes (MLN) and cultured for flow cytometry analysis of IL-17 secretion from CD4+ cells and the Th17 cell differentiation. Results showed that berberine significantly ameliorated the DAI, colon shortening, colon tissue injury, and reduction of colonic expression of tight junction (TJ) protein ZO-1 and occludin of colitis mice. Notably, berberine treatment pronouncedly reduced DSS-upregulated Th17-related cytokine (IL-17 and ROR-γt) mRNAs in the colon. Furthermore, the mRNA expression of IL-6 and IL-23, and the phosphorylation of STAT3 in colon tissues from DSS-treated mice were pronouncedly inhibited by berberine. Moreover, the up-regulation of IL-17 secretion from CD4+ cells of spleens and MLNs caused by DSS were significantly reversed by berberine treatment. Furthermore, Th17 cell differentiation from naive CD4+ cells isolated from above DSS colitis mice were suppressed by berberine in a concentration-dependent manner. In summary, we demonstrated for the first time that berberine reduced the severity of chronic relapsing DSS-induced colitis by suppressing Th17 responses. The demonstration of activity in this mouse model supports the possibility of clinical efficacy of berberine in treating chronic UC.
AB - Ulcerative colitis (UC) is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment has fueled the search for alternative therapeutic strategies. In recent studies, berberine, a plant alkaloid with a long history of medicinal use in Chinese medicine, has shown beneficial effects against animal models of acute UC. However, UC usually presents as a chronic condition with frequent relapse in patients. How berberine will act on chronic UC remains unclear. In the present study, we adopted dextran sulfate sodium (DSS)-induced chronic relapsing colitis model to assess the ameliorating activity of berberine. Colitis was induced by two cycles of 2.0% DSS for five days followed by 14 days of drinking water plus a third cycle consisting of DSS only for five days. The colitis mice were orally administered 20 mg/kg berberine from day 13 onward for 30 days and monitored daily. The body weight, stool consistency, and stool bleeding were recorded for determination of the disease activity index (DAI). At the end of treatment, animals were sacrificed and samples were collected and subjected to histological, RT-qPCR, Western blot, and LC-MS analyses. Lymphocytes were isolated from spleens and mesenteric lymph nodes (MLN) and cultured for flow cytometry analysis of IL-17 secretion from CD4+ cells and the Th17 cell differentiation. Results showed that berberine significantly ameliorated the DAI, colon shortening, colon tissue injury, and reduction of colonic expression of tight junction (TJ) protein ZO-1 and occludin of colitis mice. Notably, berberine treatment pronouncedly reduced DSS-upregulated Th17-related cytokine (IL-17 and ROR-γt) mRNAs in the colon. Furthermore, the mRNA expression of IL-6 and IL-23, and the phosphorylation of STAT3 in colon tissues from DSS-treated mice were pronouncedly inhibited by berberine. Moreover, the up-regulation of IL-17 secretion from CD4+ cells of spleens and MLNs caused by DSS were significantly reversed by berberine treatment. Furthermore, Th17 cell differentiation from naive CD4+ cells isolated from above DSS colitis mice were suppressed by berberine in a concentration-dependent manner. In summary, we demonstrated for the first time that berberine reduced the severity of chronic relapsing DSS-induced colitis by suppressing Th17 responses. The demonstration of activity in this mouse model supports the possibility of clinical efficacy of berberine in treating chronic UC.
KW - Berberine
KW - Chemical compounds
KW - Chronic relapsing colitis
KW - Dextran sulfate sodium (DSS)
KW - Th17 responses
UR - http://www.scopus.com/inward/record.url?scp=84961179666&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2016.02.010
DO - 10.1016/j.phrs.2016.02.010
M3 - Journal article
C2 - 26969793
AN - SCOPUS:84961179666
SN - 1043-6618
VL - 110
SP - 227
EP - 239
JO - Pharmacological Research
JF - Pharmacological Research
ER -