MicroRNA124-IL6R Mediates the Effect of Nicotine in Inflammatory Bowel Disease by Shifting Th1/Th2 Balance Toward Th1

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Background: Although it is generally believed that smoking protects against Th2-type ulcerative colitis (UC) and worsens Th1-type Crohn's disease (CD), the mechanism remains elusive. Nicotine is the main component of bidirectional regulation of tobacco on inflammatory bowel disease (IBD). Our previous studies have revealed that nicotine specifically elevates miR-124 level and protects against dextran sulfate sodium (DSS) colitis (resembling UC), while others reported that miR-124 is also highly expressed in CD, but it worsens CD. We speculated that miR-124 might mediate the dual role of nicotine in IBD by regulating Th1/Th2 balance. Methods: Murine inflammation performance was evaluated by body weight change, disease activity index score (DAI), colon length, HE staining and score. Th1/Th2 balance was detected by flow cytometry (FCM), cytometric bead array (CBA), ELISA and western blot in isolated peripheral blood lymphocytes and murine colon tissues. Findings: Results showed that miR-124 overexpression protected against DSS-induced colitis with a Th1 polarization in murine peripheral blood lymphocytes and colon tissues, while miR-124 knockdown showed opposite effect. Similar results were obtained in human peripheral blood lymphocytes. Furthermore, miR-124 knockdown could abolish Th1 polarization effect of nicotine on DSS mice and human peripheral blood lymphocytes. IL-6R interference could significantly attenuate the role of miR-124 in Th1 polarization, indicating it is a downstream target of miR-124 on Th1/Th2 balance. Interpretation: Nicotine shifts Th1/Th2 balance toward Th1 through miR-124-IL-6R pathway, which might be responsible for its dual role in IBD. Funding Statement: National Natural Science Foundation of China (81773726, 81603116) and Shanghai Sailing Program (19YF1459500). Declaration of Interests: The authors declare no financial or competing interests. Ethics Approval Statement: Human peripheral blood lymphocytes were collected from normal blood samples in Changhai Hospital, in accordance with the ethical standards of the institutional committee.