Abstract
Background
Biliary atresia (BA) is an etiologically perplexing disease, manifested by neonatal cholestasis, repeated cholangitis, and progressive biliary fibrosis. MiR-155 has been implicated to modulate the immune response, which contributes to biliary injury. However, its potential role in the pathogenesis of BA has not been addressed so far.
Methods
The microRNA changes from BA patients and controls were identified via microarray. The immunomodulatory function of miR-155 was investigated via cell transfection and reporter assay. The lentiviral vector pL-miR-155 inhibitor was transfected into a mouse model to investigate its role in BA.
Results
The expression of miR-155 in livers of BA patients was significantly increased, and an inverse correlation between miR-155 and suppressor of cytokine signaling 1 (SOCS1) was detected. MiR-155 overexpression promoted expressions of major histocompatibility complex (MHC) I, MHC II, Chemokine (C-X-C motif) ligand (CXCL) 9, CXCL10, monocyte chemotactic protein 1, and CXCL1 after IFN-γ stimulation, which could be suppressed by SOCS1 overexpression. Moreover, miR-155 overexpression activated JAK2/STAT3, thus enhancing the pro-inflammatory effect. Downregulating miR-155 reduced the incidence of BA in a rhesus monkey rotavirus-induced BA model.
Conclusion
Our results reveal a vital contribution of miR-155 upregulation and consequent SOCS1 downregulation to an immune response triggered via IFN-γ in BA.
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Acknowledgements
Statement of financial support
This study received financial support from the National Key Clinical Specialty Construction Programs of China (2014–2016), the Shanghai ‘Non Key-in-Key Discipline’ Clinical medical centers (2014–2016), the Shanghai Hospital Development Center (SHDC12014106), the Natural Science Foundation of China (Nos. 81200257, 81300517, and 81370472), the Shanghai Hospital Development Center (SHDC12014106), the Shanghai Rising-Star Program (A type) (No. 15QA1400800), and The Science Foundation of Shanghai (No. 16411952200).
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Zhao, R., Dong, R., Yang, Y. et al. MicroRNA-155 modulates bile duct inflammation by targeting the suppressor of cytokine signaling 1 in biliary atresia. Pediatr Res 82, 1007–1016 (2017). https://doi.org/10.1038/pr.2017.87
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DOI: https://doi.org/10.1038/pr.2017.87
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