Abstract
Objective
Transmembrane protein 88 (TMEM88), a new protein of increasing concern existed in cell membrane, inhibits the typical Wnt/β-catenin signaling pathway to play a regulatory role on cell proliferation by binding to Dishevelled-1. Until recently, the connection between TMEM88 and alcoholic liver disease is unknown. In this research, we explored the effect of TMEM88 on the secretion of inflammatory cytokines in ethanol (EtOH)-induced RAW264.7 cells, moreover, the function of YAP signaling pathway in EtOH-induced RAW264.7 cells were investigated.
Methods
We administered TMEM88 adenovirus (ADV-TMEM88) by tail vein injection into C57BL/6J mice in vivo. In vitro, RAW264.7 murine macrophages were stimulated with EtOH and were transfected with pEGFP-C1-TMEM88 and TMEM88 siRNA, respectively, protein expression and mRNA expression of IL-6 and IL-1β were assessed by Western Blotting and RT-qPCR, respectively.
Results
Our group found that the overexpression of TMEM88 led to an up-regulation of IL-6 and IL-1β secretion, hinting that it had the possibility of linking with the initiation, the development, and the end of inflammation. In addition to that, TMEM88 silencing reduced the secretion of IL-6 and IL-1β in RAW264.7 cells. Moreover, we demonstrated that the YAP signaling pathway under the action of EtOH was activated by TMEM88.
Conclusions
All in all, these experimental outcomes indicated that TMEM88 had an indispensable impact on EtOH-induced secretion of inflammatory cytokines (IL-6 and IL-1β) in RAW264.7 cells through YAP signaling pathway.
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References
Zhao H, Lu F, Cui S, Zhang X, Wang W, Si E, et al. TMEM88 inhibits extracellular matrix expression in keloid fibroblasts. Biomed Pharmacother. 2017;95:1436–40.
Palpant NJ, Pabon L, Rabinowitz JS, Hadland BK, Stoick-Cooper CL, Paige SL, et al. Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development. Development. 2013;140:3799–808.
Zhang X, Yu X, Jiang G, Miao Y, Wang L, Zhang Y, et al. Cytosolic TMEM88 promotes invasion and metastasis in lung cancer cells by binding DVLS. Cancer Res. 2015;75:4527–37.
de Leon M, Cardenas H, Vieth E, Emerson R, Segar M, Liu Y, et al. Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer. Gynecol Oncol. 2016;142:539–47.
Zhang X, Wan JX, Ke ZP, Wang F, Chai HX, Liu JQ. TMEM88, CCL14 and CLEC3B as prognostic biomarkers for prognosis and palindromia of human hepatocellular carcinoma. Tumour Biol. 2017;39:1010428317708900.
Ge YX, Wang CH, Hu FY, Pan LX, Min J, Niu KY, et al. New advances of TMEM88 in cancer initiation and progression, with special emphasis on Wnt signaling pathway. J Cell Physiol. 2018;233:79–87.
Wang Y, Liu Y, Kirpich I, Ma Z, Wang C, Zhang M, et al. Lactobacillus rhamnosus GG reduces hepatic TNFalpha production and inflammation in chronic alcohol-induced liver injury. J Nutr Biochem. 2013;24:1609–15.
Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, et al. Alcoholic liver disease. Nat Rev Dis Prim. 2018;4:16.
Zhao YY, Xiao M, Zhang CL, Xie KQ, Zeng T. Associations between the tumor necrosis factor-alpha gene and interleukin-10 gene polymorphisms and risk of alcoholic liver disease: a meta-analysis. Clin Res Hepatol Gastroenterol. 2016;40:428–39.
Kasztelan-Szczerbinska B, Surdacka A, Celinski K, Rolinski J, Zwolak A, Miacz S, et al. Prognostic significance of the systemic inflammatory and immune balance in alcoholic liver disease with a focus on gender-related differences. PLoS One. 2015;10:e0128347.
Gobejishvili L, Ghare S, Khan R, Cambon A, Barker DF, Barve S, et al. Misoprostol modulates cytokine expression through a cAMP pathway: potential therapeutic implication for liver disease. Clin Immunol. 2015;161:291–9.
Wu G, Yang Q, Yu Y, Lin S, Feng Y, Lv Q, et al. Taurine inhibits kupffer cells activation induced by lipopolysaccharide in alcoholic liver damaged rats. Adv Exp Med Biol. 2017;975(Pt 2):789–800.
Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T, et al. The effect of inflammatory cytokines in alcoholic liver disease. Mediators Inflamm. 2013;2013:495156.
Xu T, Pan LX, Ge YX, Li P, Meng XM, Huang C, et al. TMEM88 mediates inflammatory cytokines secretion by regulating JNK/P38 and canonical Wnt/beta-catenin signaling pathway in LX-2 cells. Inflammopharmacology. 2018;26:1339–48.
Cai SP, Cheng XY, Chen PJ, Pan XY, Xu T, Huang C, et al. Transmembrane protein 88 attenuates liver fibrosis by promoting apoptosis and reversion of activated hepatic stellate cells. Mol Immunol. 2016;80:58–67.
Bertola A, Mathews S, Ki SH, Wang H, Gao B. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc. 2013;8:627–37.
Wei W, Jiang F, Liu XC, Su Q. TMEM9 mediates IL-6 and IL-1beta secretion and is modulated by the Wnt pathway. Int Immunopharmacol. 2018;63:253–60.
Lucey MR. Liver transplantation for alcoholic liver disease. Nat Rev Gastroenterol Hepatol. 2014;11:300–7.
Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol. 2015;12:231–42.
Cojocariu CE, Trifan AV, Girleanu I, Stanciu C. Alcoholic liver disease–epidemiology and risk factors. Rev Med Chir Soc Med Nat Iasi. 2014;118:910–7.
Kawaratani H, Moriya K, Namisaki T, Uejima M, Kitade M, Takeda K, et al. Therapeutic strategies for alcoholic liver disease: focusing on inflammation and fibrosis (Review). Int J Mol Med. 2017;40:263–70.
Vonghia L, Van Herck MA, Weyler J, Francque S. Targeting myeloid-derived cells: new frontiers in the treatment of non-alcoholic and alcoholic liver disease. Front Immunol. 2019;10:563.
Kim A, Saikia P, Nagy LE. miRNAs involved in M1/M2 hyperpolarization are clustered and coordinately expressed in alcoholic hepatitis. Front Immunol. 2019;10:1295.
Smith K. Liver disease: kupffer cells regulate the progression of ALD and NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10:503.
Hirano S, Zhou Q, Furuyama A, Kanno S. Differential regulation of IL-1beta and IL-6 release in murine macrophages. Inflammation. 2017;40:1933–43.
Segura-Cerda CA, Aceves-Sanchez MJ, Perez-Koldenkova V, Flores-Valdez MA. Macrophage infection with combinations of BCG mutants reduces induction of TNF-alpha, IL-6, IL-1beta and increases IL-4. Tuberculosis. 2019;115:42–8.
Lawrimore CJ, Crews FT. Ethanol, TLR3, and TLR4 agonists have unique innate immune responses in neuron-like SH-SY5Y and microglia-like BV2. Alcohol Clin Exp Res. 2017;41:939–54.
Satishchandran A, Ambade A, Rao S, Hsueh YC, Iracheta-Vellve A, Tornai D, et al. MicroRNA 122, regulated by GRLH2, protects livers of mice and patients from ethanol-induced liver disease. Gastroenterology. 2018;154(238–252):e7.
Machado MV, Michelotti GA, Pereira TA, Xie G, Premont R, Cortez-Pinto H, et al. Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. J Hepatol. 2015;63:962–70.
Grijalva JL, Huizenga M, Mueller K, Rodriguez S, Brazzo J, Camargo F, et al. Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2014;307:G196–204.
Yimlamai D, Fowl BH, Camargo FD. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J Hepatol. 2015;63:1491–501.
Mannaerts I, Leite SB, Verhulst S, Claerhout S, Eysackers N, Thoen LF, et al. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. J Hepatol. 2015;63:679–88.
Jin H, Lian N, Bian M, Zhang C, Chen X, Shao J, et al. Oroxylin A inhibits ethanol-induced hepatocyte senescence via YAP pathway. Cell Prolif. 2018;51:e12431.
Konsavage WM Jr, Yochum GS. Intersection of Hippo/YAP and Wnt/beta-catenin signaling pathways. Acta Biochim Biophys Sin (Shanghai). 2013;45:71–9.
Yu HX, Yao Y, Bu FT, Chen Y, Wu YT, Yang Y, et al. Blockade of YAP alleviates hepatic fibrosis through accelerating apoptosis and reversion of activated hepatic stellate cells. Mol Immunol. 2019;107:29–40.
Acknowledgements
We would like to thank Dr. He Chen, Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University for providing us with Serum biochemical analysis.
Funding
This project was supported by the National Natural Science Foundation of China (nos. 81700522, 81602344), the fund of Anhui medical university doctoral start research (no. 0601067101), Anhui Provincial Natural Science Foundation (1704a0802161, 1808085MH235). Soft science project of Anhui provincial science and technology department (1607a0202062).
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Liang-yun Li, Chen-chen Yang designed the study. Li-su Wen and Yu-min Liu participated in the collecting and analyzing of the data. Hao-dong Li and Shuang Hu finished the manuscript. Hong Zhou, Jin-liang Wang and Hang Shen revised and edited the manuscript. Xiao-ming Meng, Jun Li and Tao Xu reviewed the manuscript. All authors approved the final version of the manuscript for publication.
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The data analysed during the current study are available from the corresponding author on reasonable request.
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The animal testing procedures have been approved by the Code of Ethics and reviewed and implemented according to the guidelines of the Animal Care and Use Committee of Anhui Medical University (number: LLSC20150348).
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Li, Ly., Yang, Cc., Li, Sw. et al. TMEM88 modulates the secretion of inflammatory factors by regulating YAP signaling pathway in alcoholic liver disease. Inflamm. Res. 69, 789–800 (2020). https://doi.org/10.1007/s00011-020-01360-y
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DOI: https://doi.org/10.1007/s00011-020-01360-y