Berberine Differentially Modulates the Activities of ERK, p38 MAPK, and JNK to Suppress Th17 and Th1 T Cell Differentiation in Type 1 Diabetic Mice

• Published in: The Journal of biological chemistry 2009-10, Vol.284 (41), p.28420-28429
• Main Authors: Cui, Guoliang, Qin, Xia, Zhang, Yuebo, Gong, Zhenwei, Ge, Baoxue, Zang, Ying Qin
• Format: Article
• Language: English
• Subjects: Animals; Berberine - immunology; Berberine - therapeutic use; Cell Differentiation - physiology; Cytokines - immunology; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - physiopathology; Disease Models, Animal; Disease Progression; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Humans; Interleukin-17 - immunology; JNK Mitogen-Activated Protein Kinases - metabolism; Lymph Nodes - cytology; Lymph Nodes - immunology; Mice; Mice, Inbred NOD; Molecular Basis of Cell and Developmental Biology; Nuclear Receptor Subfamily 1, Group F, Member 3; p38 Mitogen-Activated Protein Kinases - metabolism; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Receptors, Thyroid Hormone - genetics; Receptors, Thyroid Hormone - metabolism; Spleen - cytology; Spleen - immunology; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Th1 Cells - cytology; Th1 Cells - immunology; Th1 Cells - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.012674

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 β 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 RORγt expression.