TMEM88 modulates the secretion of inflammatory factors by regulating YAP signaling pathway in alcoholic liver disease

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

  1. 1.

    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.

    CAS  Article  Google Scholar 

  2. 2.

    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.

    CAS  Article  Google Scholar 

  3. 3.

    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.

    CAS  Article  Google Scholar 

  4. 4.

    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.

    Article  Google Scholar 

  5. 5.

    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.

    PubMed  Google Scholar 

  6. 6.

    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.

    CAS  Article  Google Scholar 

  7. 7.

    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.

    CAS  Article  Google Scholar 

  8. 8.

    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.

    Article  Google Scholar 

  9. 9.

    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.

    Article  Google Scholar 

  10. 10.

    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.

    Article  Google Scholar 

  11. 11.

    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.

    CAS  Article  Google Scholar 

  12. 12.

    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.

    CAS  Article  Google Scholar 

  13. 13.

    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.

    Article  Google Scholar 

  14. 14.

    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.

    CAS  Article  Google Scholar 

  15. 15.

    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.

    CAS  Article  Google Scholar 

  16. 16.

    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.

    Article  Google Scholar 

  17. 17.

    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.

    CAS  Article  Google Scholar 

  18. 18.

    Lucey MR. Liver transplantation for alcoholic liver disease. Nat Rev Gastroenterol Hepatol. 2014;11:300–7.

    Article  Google Scholar 

  19. 19.

    Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol. 2015;12:231–42.

    Article  Google Scholar 

  20. 20.

    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.

    PubMed  Google Scholar 

  21. 21.

    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.

    Article  Google Scholar 

  22. 22.

    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.

    CAS  Article  Google Scholar 

  23. 23.

    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.

    CAS  Article  Google Scholar 

  24. 24.

    Smith K. Liver disease: kupffer cells regulate the progression of ALD and NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10:503.

    Article  Google Scholar 

  25. 25.

    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.

    CAS  Article  Google Scholar 

  26. 26.

    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.

    CAS  Article  Google Scholar 

  27. 27.

    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.

    CAS  Article  Google Scholar 

  28. 28.

    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.

    Google Scholar 

  29. 29.

    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.

    CAS  Article  Google Scholar 

  30. 30.

    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.

    CAS  Article  Google Scholar 

  31. 31.

    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.

    CAS  Article  Google Scholar 

  32. 32.

    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.

    CAS  Article  Google Scholar 

  33. 33.

    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.

    Article  Google Scholar 

  34. 34.

    Konsavage WM Jr, Yochum GS. Intersection of Hippo/YAP and Wnt/beta-catenin signaling pathways. Acta Biochim Biophys Sin (Shanghai). 2013;45:71–9.

    CAS  Article  Google Scholar 

  35. 35.

    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.

    CAS  Article  Google Scholar 

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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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Authors

Contributions

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.

Corresponding author

Correspondence to Tao Xu.

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The data analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

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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Not applicable.

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The authors declare that they have no conflict of interest.

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Li, L., Yang, C., Li, S. 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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Keywords

  • TMEM88
  • EtOH
  • YAP
  • RAW264.7 cells