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Ursodeoxycholic acid protects interstitial Cajal-like cells in the gallbladder from undergoing apoptosis by inhibiting TNF-α expression

Authors: Jiang-fan WAN1,2, Shi-feng CHU2, Xin ZHOU2, Yue-ting LI3, Wen-bin HE2, Feng TAN1, Piao LUO2,4, Qi-di AI2,4, Qi WANG1, Nai-hong CHEN1,2,4
1 Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510080, China
2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
3 Beijing Hospital of Integrated Traditional and Western Medicine, Beijing 100039, China
4 College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
Correspondence to: Nai-hong CHEN: chennh@imm.ac.cn,
DOI: 10.1038/aps.2017.206
Received: 21 August 2017
Accepted: 31 October 2017
Advance online: 17 May 2018

Abstract

Hypomotility is a common symptom of gallstone disease, which is accompanied by a loss of interstitial Cajal-like cells (ICLCs) in the gallbladder. Ursodeoxycholic acid (UDCA) is widely used in treating gallstone disease, and has shown anti-apoptotic and anti-inflammatory effects apart from its ability to dissolve gallstones. In this study, we investigated the anti-apoptotic and anti-inflammatory effects of UDCA on ICLCs in guinea pigs with gallstones. Guinea pigs were fed a high-cholesterol diet for 8 weeks to induce the formation of gallstones. A group of animals was administered UDCA (50 mg·kg-1·d-1, ig) simultaneously. At the end of 8 weeks, the animals were euthanized with anesthesia, cholecystectomy was performed immediately and gallbladder was collected for further analysis. We showed that in the model group the contractility of gallbladder muscle strips in response to both acetylcholine (ACh) and CCK-8 was severely impaired, which was significantly improved by UDCA administration. Furthermore, UDCA administration significantly reduced the apoptotic ratio of ICLCs, based on the observation of co-localization imaging of apoptotic cells and c-kit-positive cells. Western blotting analysis and real-time PCR results revealed that the TNF-α/Caspase8/Caspase3 pathway was suppressed in the UDCA-treated animals, confirming the anti-apoptotic effect of UDCA in the gallbladder. The H&E staining showed that UDCA administration significantly attenuated inflammatory cell infiltration in the gallbladder wall. In conclusion, UDCA can protect ICLCs in the gallbladder from undergoing apoptosis by inhibiting the TNF-α/Caspase8/caspase3 pathway.
Keywords: ursodeoxycholic acid; gallstones; interstitial Cajal-like cells

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