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Low-dose ganciclovir ameliorates dextran sulfate sodium-induced ulcerative colitis through inhibiting macrophage STING activation in mice

Affiliation
Department of General Surgery ,The Second Affiliated Hospital of Soochow University ,Suzhou ,China
Gong, Lin-Kong;
Affiliation
Department of General Surgery ,The Second Affiliated Hospital of Soochow University ,Suzhou ,China
Yang, Xiaodong;
Affiliation
Department of General Surgery ,The Second Affiliated Hospital of Soochow University ,Suzhou ,China
Yang, Juan;
Affiliation
Department of General Surgery ,The Second Affiliated Hospital of Soochow University ,Suzhou ,China
Wu, Shu;
Affiliation
Department of General Surgery ,The Second Affiliated Hospital of Soochow University ,Suzhou ,China
Chen, Yue;
Affiliation
Institute of Pain Medicine and Special Environmental Medicine ,Nantong University ,Nantong ,China
Zhang, Jiang-Tao;
Affiliation
Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience ,Soochow University ,Suzhou ,China
Wang, Zhi-Hong;
Affiliation
Department of Nutrition and Food Hygiene ,School of Public Health ,Nantong University ,Nantong ,China
Chen, Li-Hua;
Affiliation
Department of General Surgery ,The Second Affiliated Hospital of Soochow University ,Suzhou ,China
Xing, Chungen;
Affiliation
Institute of Pain Medicine and Special Environmental Medicine ,Nantong University ,Nantong ,China
Liu, Tong

Ganciclovir (GCV) is a prodrug nucleoside analogue and is clinically used as antiviral drug for the treatment of cytomegalovirus (CMV) and other infections. Based on the potential anti-inflammatory activity of GCV, this study aimed to investigate the therapeutic effects of ganciclovir on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC), which may involve cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways. Our results demonstrated that incubation of GCV (50 μM) inhibited cGAS-STING pathway in macrophage RAW264.7 cells. Then, it was found that intestinal cGAS-STING pathways were upregulated in UC patients, Crohn’s disease colitis (CD) patients, and DSS-induced colitis mice. Intraperitoneal injection of low-dose GCV (10 mg/kg/day) attenuated DSS-induced colitis and abdominal pain in mice. GCV treatment significantly inhibited the upregulation of cGAS-STING pathway in DSS-induced colitis mice. Moreover, DSS-induced colitis and gut dysbiosis was markedly attenuated in STING deficient mice compared with that of wild-type (WT) mice. Finally, there was lacking therapeutic effect of GCV on DSS-induced colitis in STING deficient mice. Together, our results indicated that low-dose GCV ameliorated DSS-induced UC in mice, possibly through inhibiting STING signaling in colonic macrophages, indicating that GCV may be useful for the treatment of UC.

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License Holder: Copyright © 2022 Gong, Yang, Yang, Wu, Chen, Zhang, Wang, Chen, Xing and Liu.

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