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Rho kinase Blockade Ameliorates DSS-Induced Ulcerative Colitis in Mice Through Dual Inhibition of the NF-κB and IL-6/STAT3 Pathways

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Abstract

Inflammatory bowel disease (IBD) has received much attention due to its increasing worldwide incidence and potential increased risk of colorectal cancer. The protective function of a Rho-associated protein kinase inhibitor (Y-27632) against 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced mouse colitis has been proven in previous studies, but the concrete therapeutic mechanism of Y-27632 is still not completely illuminated. This current research is intended for further investigation of the effect and mechanism of Y-27632 in a mouse model of acute experimental ulcerative colitis induced by dextran sulfate sodium (DSS). A total of 24 male BALB/c mice were randomly separated into the following three groups (n = 8 per group) and injected intraperitoneally with the corresponding reagents for 7 days: control group (PBS), DSS group (PBS), and Y-27632 group (PBS and Y-27632; 10 mg/kg). Our data indicated that Y-27632 could significantly improve the severity of colitis, as evidenced by the disease activity index (DAI) scores, histological damage, and colon length. Additionally, Y-27632 treatment significantly decreased CD68 and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-17F (IL-17F), and interleukin-6 (IL-6). Furthermore, Y-27632 potently and pleiotropically suppressed nuclear factor-κB (NF-κB) and signal transduction and transcriptional activator 3 (STAT3) activation as well as the activity of prosurvival genes that are dependent on these transcription factors. In summary, the study demonstrates that Y-27632 exerts ameliorative effects on colonic inflammation mediated through dual inhibition of the NF-κB and IL-6/STAT3 pathways and thus is likely to function as a prospective novel treatment for human ulcerative colitis (UC).

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Funding

The study was funded by the National Natural Science Foundation of China (no. 81774093 and no. 81573784).

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Author notes

  1. Yifan Wang, Xueyun Duan, Xingxing Liu and Yujin Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China

    Yifan Wang, Xingxing Liu, Yujin Liu, Heng Fan, Meng Xu, Qianyun Chen & Qing Tang

  2. Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China

    Xueyun Duan

  3. Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430074, China

    Xueyun Duan

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  1. Yifan Wang
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Contributions

Study concept and design: Yifan Wang, Meng Xu, and Qianyun Chen; data acquisition: Yifan Wang and Yujin Liu; Yifan Wang and Yujin Liu performed most of the experiments; Yifan Wang, Xueyun Duan, Qing Tang, Xingxing Liu, and Heng Fan wrote the manuscript.

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Correspondence to Heng Fan.

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Wang, Y., Duan, X., Liu, X. et al. Rho kinase Blockade Ameliorates DSS-Induced Ulcerative Colitis in Mice Through Dual Inhibition of the NF-κB and IL-6/STAT3 Pathways. Inflammation 43, 857–867 (2020). https://doi.org/10.1007/s10753-019-01171-2

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