| First Author | Lu Z | Year | 2018 |
| Journal | Hepatology | Volume | 67 |
| Issue | 3 | Pages | 1027-1040 |
| PubMed ID | 29023933 | Mgi Jnum | J:271926 |
| Mgi Id | MGI:6283397 | Doi | 10.1002/hep.29573 |
| Citation | Lu Z, et al. (2018) MicroRNA 15a/16-1 suppresses aryl hydrocarbon receptor-dependent interleukin-22 secretion in CD4(+) T cells and contributes to immune-mediated organ injury. Hepatology 67(3):1027-1040 |
| abstractText | Interleukin-22 (IL-22), as a link between leukocytic and nonleukocytic cells, has gained increasing attention for its pronounced tissue-protective properties. MicroRNAs, emerging as crucial immune modulators, have been reported to be involved in the production and action of various cytokines. However, the precise control of IL-22 by microRNAs and its subsequent actions remained to be elucidated. In this study, we found a negative correlation between the expression of microRNA 15a/16-1 (miR-15a/16-1) and IL-22 in the model of concanavalin A-induced, immune-mediated liver injury. Knockout of miR-15a/16-1 ameliorated liver injury in an IL-22-dependent manner. Further results revealed that cluster of differentiation 4-positive (CD4(+) ) T cells were the major source of IL-22 during liver injury and that the aryl hydrocarbon receptor was the direct target of miR-15a/16-1 in CD4(+) T cells. In vivo and in vitro data showed that miR-15a/16-1 knockout CD4(+) T cells produced more IL-22, while overexpression of miR-15a/16-1 down-regulated the IL-22 production by inhibiting the aryl hydrocarbon receptor. Moreover, transfer of miR-15a/16-1 knockout CD4(+) T cells promoted tissue repair compared to wild-type CD4(+) T cells by up-regulating IL-22. In addition, as a synergistic effect, IL-22 could down-regulate miR-15a/16-1 expression by activating phosphorylated signal transducer and activator of transcription 3-c-myc signaling, and the decrease of miR-15a/16-1 in damaged hepatocytes contributed to IL-22-mediated tissue repair by reducing cell apoptosis and promoting cell proliferation. As further proof, we demonstrated the role of miR-15a/16-1 in controlling IL-22 production and IL-22-mediated reconstruction of the intestinal epithelial barrier in a dextran sodium sulfate-induced colitis model. CONCLUSION: Our results suggest that miR-15a/16-1 acts as a essential regulator of IL-22 and that the miR-15a/16-1-aryl hydrocarbon receptor-IL-22 regulatory axis plays a central role in tissue repair; modulation of miR-15a/16-1 might hold promise in developing new strategies to enhance IL-22-mediated tissue repair. (Hepatology 2018;67:1027-1040). |
