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Changes in Radixin Expression and Interaction with Efflux Transporters in the Liver of Adjuvant-Induced Arthritic Rats

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Abstract

Scaffold proteins such as radixin help to modulate the plasma membrane localization and transport activity of the multidrug resistance-associated protein 2 (MRP2/ABCC2) and P-glycoprotein (P-gp/ABCB1) efflux transporters in the liver. We examined changes in radixin expression and interaction with efflux transporters in adjuvant-induced arthritic (AA) rats, an animal model of rheumatoid arthritis, as well as in human liver cancer (HepG2) cells because inflammation affects drug pharmacokinetics via the efflux transporters. The expression levels of radixin and phosphorylated radixin (p-radixin) were measured 24 h after treatment with inflammatory cytokines comprising tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 or sodium nitroprusside (SNP; a nitric oxide donor). The protein levels of radixin, MRP2, and P-gp in the rat liver were next examined. We also investigated whether inflammation affected the formation of complexes between radixin and MRP2 or P-gp. The mRNA and protein levels of radixin in HepG2 cells were significantly decreased by TNF-α treatment, while minimal changes were observed after treatment with IL-1β, IL-6 or SNP. TNF-α also significantly decreased the protein levels of p-radixin, suggesting that TNF-α inhibited the activation of radixin and thereby reduced the activity of the efflux transporters. Complex formation of radixin with MRP2 and P-gp was significantly decreased in AA rats but this was reversed by prednisolone and dexamethasone treatment, indicating that decreased interactions of radixin with MRP2 and P-gp likely occur during liver inflammation. These data suggest that liver inflammation reduces radixin function by decreasing its interactions with MRP2 and P-gp.

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References

  1. Stieger, B., K. Fattinger, J. Madon, G.A. Kullak-Ublick, and P.J. Meier. 2000. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 118: 422–430.

    Article  CAS  Google Scholar 

  2. Sato, N., N. Funayama, A. Nagafuchi, S. Yonemura, S. Tsukita, and S. Tsukita. 1992. A gene family consisting of ezrin, radixin and moesin. Its specific localization at actin filament/plasma membrane association sites. Journal of Cell Science 103 ( Pt 1: 131–143.

    CAS  PubMed  Google Scholar 

  3. Kojima, Hideyuki, Anne T. Nies, Jörg König, Wolfgang Hagmann, Herbert Spring, Masahito Uemura, Hiroshi Fukui, and Dietrich Keppler. 2003. Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis. Journal of Hepatology 39: 693–702.

    Article  CAS  Google Scholar 

  4. Gary, R., and A. Bretscher. 1995. Ezrin self-association involves binding of an N-terminal domain to a normally masked C-terminal domain that includes the F-actin binding site. Molecular Biology of the Cell 6: 1061–1075. https://doi.org/10.1091/mbc.6.8.1061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Reczek, D., M. Berryman, and A. Bretscher. 1997. Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. The Journal of Cell Biology 139: 169–179. https://doi.org/10.1083/jcb.139.1.169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Suda, Jo, Lixin Zhu, and Serhan Karvar. 2011. Phosphorylation of radixin regulates cell polarity and Mrp-2 distribution in hepatocytes. American Journal of Physiology. Cell Physiology 300: C416–C424. https://doi.org/10.1152/ajpcell.00467.2010.

    Article  CAS  PubMed  Google Scholar 

  7. Yonemura, Shigenobu, Takeshi Matsui, Shoichiro Tsukita, and Sachiko Tsukita. 2002. Rho-dependent and -independent activation mechanisms of ezrin/radixin/moesin proteins: An essential role for polyphosphoinositides in vivo. Journal of Cell Science 115: 2569–2580.

    CAS  PubMed  Google Scholar 

  8. Pietromonaco, S.F., P.C. Simons, A. Altman, and L. Elias. 1998. Protein kinase C-theta phosphorylation of moesin in the actin-binding sequence. The Journal of Biological Chemistry 273: 7594–7603.

    Article  CAS  Google Scholar 

  9. Kikuchi, Shojiro, Masaki Hata, Kanehisa Fukumoto, Yukari Yamane, Takeshi Matsui, Atsushi Tamura, Shigenobu Yonemura, Hisakazu Yamagishi, Dietrich Keppler, Shoichiro Tsukita, and Sachiko Tsukita. 2002. Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nature Genetics 31: 320–325. https://doi.org/10.1038/ng905.

    Article  CAS  PubMed  Google Scholar 

  10. Wang, Wei, Carol J. Soroka, Albert Mennone, Christoph Rahner, Kathy Harry, Marc Pypaert, and James L. Boyer. 2006. Radixin is required to maintain apical canalicular membrane structure and function in rat hepatocytes. Gastroenterology 131: 878–884. https://doi.org/10.1053/j.gastro.2006.06.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kano, Takashi, Sho Wada, Kaori Morimoto, Yukio Kato, and Takuo Ogihara. 2011. Effect of knockdown of ezrin, radixin, and moesin on P-glycoprotein function in HepG2 cells. Journal of Pharmaceutical Sciences 100: 5308–5314. https://doi.org/10.1002/jps.22718.

    Article  CAS  PubMed  Google Scholar 

  12. Belpaire, F.M., F. de Smet, B. Chindavijak, N. Fraeyman, and M.G. Bogaert. 1989. Effect of turpentine-induced inflammation on the disposition kinetics of propranolol, metoprolol, and antipyrine in the rat. Fundamental & Clinical Pharmacology 3: 79–88.

    Article  CAS  Google Scholar 

  13. Piquette-Miller, M., and F. Jamali. 1993. Selective effect of adjuvant arthritis on the disposition of propranolol enantiomers in rats detected using a stereospecific HPLC assay. Pharmaceutical Research 10: 294–299.

    Article  CAS  Google Scholar 

  14. Laethem, Martine E., Frans M. Belpaire, Pascal Wijnant, Marie-Therese Rosseel, and Marc G. Bogaert. 1994. Influence of endotoxin on the stereoselective pharmacokinetics of oxprenolol, propranolol, and verapamil in the rat. Chirality 6: 405–410. https://doi.org/10.1002/chir.530060508.

    Article  CAS  PubMed  Google Scholar 

  15. Piquette-Miller, M., and F. Jamali. 1992. Effect of adjuvant arthritis on the disposition of acebutolol enantiomers in rats. Agents and Actions 37: 290–296.

    Article  CAS  Google Scholar 

  16. Schneider, R.E., H. Bishop, M.J. Kendall, and C.P. Quarterman. 1981. Effect of inflammatory disease on plasma concentrations of three beta-adrenoceptor blocking agents. International Journal of Clinical Pharmacology, Therapy, and Toxicology 19: 158–162.

    CAS  PubMed  Google Scholar 

  17. Kawase, A., Y. Tsunokuni, and M. Iwaki. 2006. Effects of alterations in CAR on bilirubin detoxification in mouse collagen-induced arthritis. Drug Metabolism and Disposition 35: 256–261. https://doi.org/10.1124/dmd.106.011536.

    Article  CAS  PubMed  Google Scholar 

  18. Kawase, Atsushi, Sari Norikane, Ayaka Okada, Mamiko Adachi, Yukio Kato, and Masahiro Iwaki. 2014. Distinct alterations in ATP-binding cassette transporter expression in liver, kidney, small intestine, and brain in adjuvant-induced arthritic rats. Journal of Pharmaceutical Sciences 103: 2556–2564. https://doi.org/10.1002/jps.24043.

    Article  CAS  PubMed  Google Scholar 

  19. Uraki, Misato, Atsushi Kawase, Hiroyuki Sayama, Yuka Matsushima, and Masahiro Iwaki. 2017. Effects of adjuvant-induced inflammation on disposition of diclofenac and its metabolites in perfused rat liver. Journal of Pharmaceutical Sciences 106: 1175–1182. https://doi.org/10.1016/j.xphs.2016.12.021.

    Article  CAS  PubMed  Google Scholar 

  20. Williams, R.C. 1992. Rheumatoid factors: Historical perspective, origins and possible role in disease. The Journal of Rheumatology. Supplement 32: 42–45.

    PubMed  Google Scholar 

  21. Cai, X., Y.F. Wong, H. Zhou, Y. Xie, Z.Q. Liu, Z.H. Jiang, Z.X. Bian, H.X. Xu, and L. Liu. 2006. The comparative study of Sprague–Dawley and Lewis rats in adjuvant-induced arthritis. Naunyn-Schmiedeberg’s Archives of Pharmacology 373: 140–147. https://doi.org/10.1007/s00210-006-0062-5.

    Article  CAS  PubMed  Google Scholar 

  22. Kawase, Atsushi, Misato Sakata, Nagisa Yada, Misaki Nakasaka, Takuya Shimizu, Yukio Kato, and Masahiro Iwaki. 2014. Decreased radixin function for ATP-binding cassette transporters in liver in adjuvant-induced arthritis rats. Journal of Pharmaceutical Sciences 103: 4058–4065. https://doi.org/10.1002/jps.24210.

    Article  CAS  PubMed  Google Scholar 

  23. Kawase, Atsushi, Akiyuki Fujii, Makiko Negoro, Ryosuke Akai, Miki Ishikubo, Hiroshi Komura, and Masahiro Iwaki. 2008. Differences in cytochrome P450 and nuclear receptor mRNA levels in liver and small intestines between SD and DA rats. Drug Metabolism and Pharmacokinetics 23: 196–206.

    Article  CAS  Google Scholar 

  24. Kawase, Atsushi, Ayano Yamada, Yuko Gamou, Chika Tahara, Fumiaki Takeshita, Kazuya Murata, Hideaki Matsuda, Keiichi Samukawa, and Masahiro Iwaki. 2013. Increased effects of ginsenosides on the expression of cholesterol 7α-hydroxylase but not the bile salt export pump are involved in cholesterol metabolism. Journal of Natural Medicines 67: 545–553. https://doi.org/10.1007/s11418-012-0713-4.

    Article  CAS  PubMed  Google Scholar 

  25. Yang, Qing, Reiko Onuki, Chikako Nakai, and Yuichi Sugiyama. 2007. Ezrin and radixin both regulate the apical membrane localization of ABCC2 (MRP2) in human intestinal epithelial Caco-2 cells. Experimental Cell Research 313: 3517–3525. https://doi.org/10.1016/j.yexcr.2007.07.033.

    Article  CAS  PubMed  Google Scholar 

  26. Kobori, Takuro, Shinichi Harada, Kazuo Nakamoto, and Shogo Tokuyama. 2014. Involvement of PtdIns(4,5)P2 in the regulatory mechanism of small intestinal P-glycoprotein expression. Journal of Pharmaceutical Sciences 103: 743–751. https://doi.org/10.1002/jps.23811.

    Article  CAS  PubMed  Google Scholar 

  27. Pokharel, Deep, Matthew Padula, Jamie Lu, Ritu Jaiswal, Steven Djordjevic, and Mary Bebawy. 2016. The role of CD44 and ERM proteins in expression and functionality of P-glycoprotein in breast Cancer cells. Molecules 21: 290. https://doi.org/10.3390/molecules21030290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sukhai, M., A. Yong, A. Pak, and M. Piquette-Miller. 2001. Decreased expression of P-glycoprotein in interleukin-1β and interleukin-6 treated rat hepatocytes. Inflammation Research 50: 362–370. https://doi.org/10.1007/PL00000257.

    Article  CAS  PubMed  Google Scholar 

  29. Jover, Ramiro, Roque Bort, M. José Gómez-Lechón, and José V. Castell. 2002. Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: Molecular mechanism and transcription factors involved. The FASEB Journal 16: 1799–1801. https://doi.org/10.1096/fj.02-0195fje.

    Article  CAS  PubMed  Google Scholar 

  30. Fernandez, Christine, Marion Buyse, Michèle German-Fattal, and François Gimenez. 2004. Influence of the pro-inflammatory cytokines on P-glycoprotein expression and functionality. Journal of Pharmacy & Pharmaceutical Sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 7: 359–371.

    CAS  Google Scholar 

  31. Le Vee, Marc, Philippe Gripon, Bruno Stieger, and Olivier Fardel. 2008. Down-regulation of organic anion transporter expression in human hepatocytes exposed to the proinflammatory cytokine interleukin 1beta. Drug Metabolism and Disposition: The Biological Fate of Chemicals 36: 217–222. https://doi.org/10.1124/dmd.107.016907.

    Article  CAS  Google Scholar 

  32. Vee, M.L., V. Lecureur, B. Stieger, and O. Fardel. 2009. Regulation of drug transporter expression in human hepatocytes exposed to the Proinflammatory cytokines tumor necrosis factor- or Interleukin-6. Drug Metabolism and Disposition 37: 685–693. https://doi.org/10.1124/dmd.108.023630.

    Article  CAS  PubMed  Google Scholar 

  33. Bauerová, K., E. Paulovičová, D. Mihalová, K. Švík, and S. Poništ. 2009. Study of new ways of supplementary and combinatory therapy of rheumatoid arthritis with immunomodulators. Glucomannan and Imunoglukán ® in adjuvant arthritis. Toxicology and Industrial Health 25: 329–335. https://doi.org/10.1177/0748233709102945.

    Article  PubMed  Google Scholar 

  34. Kolios, George, Vassilis Valatas, and Elias Kouroumalis. 2006. Role of Kupffer cells in the pathogenesis of liver disease. World Journal of Gastroenterology 12. Baishideng Publishing Group Inc: 7413–7420. https://doi.org/10.3748/wjg.v12.i46.7413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Campion, Sarah N., Rachel Johnson, Lauren M. Aleksunes, Michael J. Goedken, Nico van Rooijen, George L. Scheffer, Nathan J. Cherrington, and José E. Manautou. 2008. Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function. American Journal of Physiology-Gastrointestinal and Liver Physiology. American Physiological Society 295: G294–G304. https://doi.org/10.1152/ajpgi.00541.2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Song, Im-Sook, In-Kyoung Lee, Suk-Jae Chung, Sang-Geon Kim, Myung-Gull Lee, and Chang-Koo Shim. 2002. Effect of nitric oxide on the sinusoidal uptake of organic cations and anions by isolated hepatocytes. Archives of Pharmacal Research 25: 984–988.

    Article  CAS  Google Scholar 

  37. Cha, Seok Ho, Hong Pyo Kim, Nam-Hee Jung, Woon Ki Lee, Ju Young Kim, and Young-Nam Cha. 2002. Down-regulation of organic anion transporter 2 mRNA expression by nitric oxide in primary cultured rat hepatocytes. IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) 54: 129–135. https://doi.org/10.1080/15216540214534.

    Article  CAS  Google Scholar 

  38. Li, Yang, Chengyuan Ma, Xu Shi, Zhongmei Wen, Dan Li, Munan Sun, and Hui Ding. 2014. Effect of nitric oxide synthase on multiple drug resistance is related to Wnt signaling in non-small cell lung cancer. Oncology Reports 32: 1703–1708. https://doi.org/10.3892/or.2014.3351.

    Article  CAS  PubMed  Google Scholar 

  39. Sewer, M.B., T.B. Barclay, and E.T. Morgan. 1998. Down-regulation of cytochrome P450 mRNAs and proteins in mice lacking a functional NOS2 gene. Molecular Pharmacology 54: 273–279. https://doi.org/10.1124/mol.54.2.273.

    Article  CAS  PubMed  Google Scholar 

  40. Morgan, E.T. 2001. Regulation of cytochrome p450 by inflammatory mediators: Why and how? Drug Metabolism and Disposition: The Biological Fate of Chemicals 29: 207–212.

    CAS  Google Scholar 

  41. Zhou, Lei, Heng Zhang, and Jie Wu. 2016. Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells. Experimental and Therapeutic Medicine 11: 1875–1880. https://doi.org/10.3892/etm.2016.3128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Conforti, A., S. Lussignoli, S. Bertani, R. Ortolani, L. Cuzzolin, G. Benoni, and P. Bellavite. 2019. Cytokine and nitric oxide levels in a rat model of immunologic protection from adjuvant-induced arthritis. International Journal of Immunopathology and Pharmacology 14: 153–160 http://www.ncbi.nlm.nih.gov/pubmed/12604016. Accessed June 28.

    Google Scholar 

  43. Koss, McKenzie, Gordon R. Pfeiffer, Ying Wang, Sharon T. Thomas, Michael Yerukhimovich, William A. Gaarde, Claire M. Doerschuk, and Qin Wang. 2006. Ezrin/radixin/moesin proteins are phosphorylated by TNF-alpha and modulate permeability increases in human pulmonary microvascular endothelial cells. Journal of Immunology (Baltimore, Md. : 1950) 176: 1218–1227. https://doi.org/10.4049/jimmunol.176.2.1218.

    Article  CAS  Google Scholar 

  44. Ladner, Katherine J., Michael A. Caligiuri, and Denis C. Guttridge. 2003. Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for cytokine-induced loss of skeletal muscle gene products. The Journal of Biological Chemistry 278: 2294–2303. https://doi.org/10.1074/jbc.M207129200.

    Article  CAS  PubMed  Google Scholar 

  45. Amoozadeh, Yasaman, Qinghong Dan, Jenny Xiao, Faiza Waheed, and Katalin Szászi. 2015. Tumor necrosis factor-α induces a biphasic change in claudin-2 expression in tubular epithelial cells: role in barrier functions. American Journal of Physiology 309. Cell Physiology. American Physiological Society: C38–C50. https://doi.org/10.1152/ajpcell.00388.2014.

    Article  CAS  PubMed  Google Scholar 

  46. Schmidt, Christian, Bailu Peng, Zhongkui Li, Guido M. Sclabas, Shuichi Fujioka, Jiangong Niu, Marc Schmidt-Supprian, Douglas B. Evans, James L. Abbruzzese, and Paul J. Chiao. 2003. Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation. Molecular Cell 12: 1287–1300.

    Article  CAS  Google Scholar 

  47. Yano, Kentaro, Takumi Tomono, Riyo Sakai, Takashi Kano, Kaori Morimoto, Yukio Kato, and Takuo Ogihara. 2013. Contribution of radixin to P-glycoprotein expression and transport activity in mouse small intestine in vivo. Journal of Pharmaceutical Sciences 102: 2875–2881. https://doi.org/10.1002/jps.23637.

    Article  CAS  PubMed  Google Scholar 

  48. Yano, Kentaro, Kyoma Otsuka, Yuko Kato, Hideaki Kawabata, Shinya Ohmori, Hiroshi Arakawa, and Takuo Ogihara. 2016. Different regulation of P-glycoprotein function between Caco-2 and Caki-1 cells by ezrin, radixin and moesin proteins. Journal of Pharmacy and Pharmacology 68: 361–367. https://doi.org/10.1111/jphp.12525.

    Article  CAS  PubMed  Google Scholar 

  49. Sekine, Shuichi, Kousei Ito, Junjiro Saeki, and Toshiharu Horie. 2011. Interaction of Mrp2 with radixin causes reversible canalicular Mrp2 localization induced by intracellular redox status. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1812: 1427–1434. https://doi.org/10.1016/j.bbadis.2011.07.015.

    Article  CAS  Google Scholar 

  50. Hegedüs, Tamás, Tamás Sessler, Robert Scott, William Thelin, Éva Bakos, András Váradi, Katalin Szabó, László Homolya, Sharon L. Milgram, and Balázs Sarkadi. 2003. C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins. Biochemical and Biophysical Research Communications 302: 454–461. https://doi.org/10.1016/S0006-291X(03)00196-7.

    Article  CAS  PubMed  Google Scholar 

  51. Morales, F.C., Y. Takahashi, E.L. Kreimann, and M.-M. Georgescu. 2004. Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Proceedings of the National Academy of Sciences 101: 17705–17710. https://doi.org/10.1073/pnas.0407974101.

    Article  CAS  Google Scholar 

  52. Morales, F.C., Y. Takahashi, S. Momin, H. Adams, X. Chen, and M.-M. Georgescu. 2007. NHERF1/EBP50 head-to-tail intramolecular interaction masks association with PDZ domain ligands. Molecular and Cellular Biology 27: 2527–2537. https://doi.org/10.1128/MCB.01372-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by Japan Society for the Promotion of Science Grant-in Aid for Scientific Research (C) Grant Number 18 K06806, the Japanese Ministry of Education, Culture, Sports Science, and Technology.

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan

    Atsushi Kawase, Misaki Nakasaka, Hatsune Bando, Saori Yasuda, Hiroaki Shimada & Masahiro Iwaki

  2. Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, Japan

    Masahiro Iwaki

  3. Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, Japan

    Masahiro Iwaki

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  1. Atsushi Kawase
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were Atsushi Kawase, Misaki Nakasaka, Hatsune Bando and Saori Yasuda. The first draft of the manuscript was written by Atsushi Kawase and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Kawase, A., Nakasaka, M., Bando, H. et al. Changes in Radixin Expression and Interaction with Efflux Transporters in the Liver of Adjuvant-Induced Arthritic Rats. Inflammation 43, 85–94 (2020). https://doi.org/10.1007/s10753-019-01097-9

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