Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice.
Berberine, an alkaloid derivative from Berberis vulgaris L., has been used extensively in traditional Chinese medicine to treat diarrhea and diabetes, but the underlying mechanisms for treating diabetes are not fully understood. Recent studies suggested that berberine has many beneficial biological effects, including anti-inflammation. Because type 1 diabetes is caused by T cell-mediated destruction of beta cells and severe islet inflammation, we hypothesized that berberine could ameliorate type 1 diabetes through its immune regulation properties. Here we reported that 2 weeks of oral administration of berberine prevented the progression of type 1 diabetes in half of the NOD mice and decreased Th17 and Th1 cytokine secretion. Berberine suppressed Th17 and Th1 differentiation by reducing the expression of lineage markers. We found that berberine inhibited Th17 differentiation by activating ERK1/2 and inhibited Th1 differentiation by inhibiting p38 MAPK and JNK activation. Berberine down-regulated the activity of STAT1 and STAT4 through the suppression of p38 MAPK and JNK activation, and it controlled the stability of STAT4 through the ubiquitin-proteasome pathway. Our findings indicate that berberine targets MAPK to suppress Th17 and Th1 differentiation in type 1 diabetic NOD mice. This study revealed a novel role of ERK in Th17 differentiation through down-regulation of STAT3 phosphorylation and RORgamma t expression.
Cui
Guoliang
G
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031.
Qin
Xia
X
Shanghai Institute of Immunology, Shanghai Jiaotong University Medical School, 280 South Chongqing Road, Shanghai 200031, China.
Zhang
Yuebo
Y
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031.
Gong
Zhenwei
Z
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031.
Ge
Baoxue
B
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031.
Zang
Ying Qin
YQ
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031. Electronic address: yqin@sibs.ac.cn.
D000818:Animals; D001599:Berberine / Q000276:immunology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016207:Cytokines; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D001599:Berberine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases