Abstract
Although it is generally believed that nicotine accounts for the beneficial effect of smoking on ulcerative colitis, the underlying mechanisms remain not well understood. Our previous finding that nicotine inhibits inflammatory responses through inducing miR-124 prompted us to ask whether the miRNA is involved in the protective action of nicotine against UC. Our present study found that miR-124 expression is upregulated in colon tissues from UC patients and DSS colitis mice. Nicotine treatment further augmented miR-124 expression in lymphocytes isolated from human ulcerative colonic mucosa and ulcerative colon tissues from DSS mice, both in infiltrated lymphocytes and epithelial cells. Moreover, knockdown of miR-124 significantly diminished the beneficial effect of nicotine on murine colitis and IL-6-treated Caco-2 colon epithelial cells. Further analysis indicated that nicotine inhibited STAT3 activation in vivo and in IL-6 treated Caco-2 cells and Jurkat human T lymphocytes, in which miR-124 knockdown led to increased activation of STAT3. Blocking STAT3 activity alone is beneficial for DSS colitis and also abolished nicotine’s protective effect in this model. These data indicate that nicotine exerts its protective action in UC through inducing miR-124 and inhibiting STAT3, and suggest that the miR-124/STAT3 system is a potential target for the therapeutic intervention of UC.
Key message
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Nicotine upregulates miR-124 expression in ulcerative colon tissues and cells.
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MiR-124 is required for the protective role of nicotine in DSS colitis mice and epithelial cells.
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The protective effect of nicotine in murine DSS colitis depends on blocking STAT3 activation.
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MiR-124 mediates the inhibitory role of nicotine on STAT3/p-STAT3.
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Targeting miR-124 and STAT3 represents a novel approach for treating ulcerative colitis.
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Acknowledgments
We thank Xiu-Ming Guo (Department of Pharmacology, Second Military Medical University, China) and Can-Rong Ni (Changhai Hospital, Second Military Medical University, China) for their assistance in IHC and ISH and their help in evaluating HE tissue sections. This study was supported by the grants from the National Natural Science Foundation of China (81273606 and 81473259 to XL, 81230083 to DFS, 81570474 to PD and 81603116 to YS), and National Science and Technology Major Project (2014ZX09J14103-08C to XL).
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All animal experiments were undertaken with the approval of the Scientific Investigation Board of the Second Military Medical University. The study protocol was approved by the ethics committee of Shanghai Jiaotong University, and all subjects provided informed consent
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The authors declare that they have no competing interests.
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This article has been presented as a poster at Annual Meeting of the American Association of Immunology held in New Orleans, USA on May 8–12, 2015 and was included in the conference proceedings as a meeting abstract.
Zhen Qin and Jing-Jing Wan contributed equally to this work
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Qin, Z., Wan, JJ., Sun, Y. et al. Nicotine protects against DSS colitis through regulating microRNA-124 and STAT3. J Mol Med 95, 221–233 (2017). https://doi.org/10.1007/s00109-016-1473-5
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DOI: https://doi.org/10.1007/s00109-016-1473-5