Advertisement

Archives of Pharmacal Research

, Volume 41, Issue 10, pp 995–1008 | Cite as

3, 5, 3′-Triiodothyroacetic acid (TRIAC) is an anti-inflammatory drug that targets toll-like receptor 2

  • Hae Chan Ha
  • Ji Min Jang
  • Dan Zhou
  • Han Gyeol Kim
  • Moon Jung Back
  • In Chul Shin
  • So Yoon Yun
  • Yongwei Piao
  • Jong Min Choi
  • Jong Hoon Won
  • Dae Kyong Kim
Research Article
  • 225 Downloads

Abstract

Drug repositioning is a strategy that explores new pharmaceutical applications of previously launched or failed drugs, and is advantageous since it saves capital and time. In this study, we examined the inhibition of TLR2 signaling by drug candidates. HEK-Blue™-hTLR2 cells were pretreated with drugs and stimulated using the TLR2 ligand, Pam3CSK4. Among the drugs that inhibited TLR2 signaling, we selected TRIAC, which is yet to be patented. Pretreatment with TRIAC decreased the TLR2 level and the phosphorylation of Akt and MAPKs in HEK-Blue™-hTLR2 cells. Since TLR2 is overexpressed in patients with acute hepatitis, we confirmed that TRIAC alleviates necrosis in a mouse model of Con A-induced acute hepatitis. The serum AST and ALT levels are indicators of liver damage, and are increased in Con A-induced hepatitis. Additionally, TLR2 and inflammatory cytokine levels are increased following administration of Con A and lead to liver damage. TRIAC decreased the serum levels of AST and ALT, and reduced liver tissue necrosis in mice with Con A-induced acute fulminant liver damage, by reducing the levels of inflammatory cytokines. In conclusion, TRIAC alleviates inflammation in mouse models of Con A-induced hepatitis by inhibiting the phosphorylation of Akt and MAPKs, the sub-mechanisms underlying TLR2 signaling.

Keywords

TRIAC TLR2 Acute hepatitis Akt MAPK 

Notes

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science, ICT & Future Planning (Grant Numbers NRF-2013M3A9B6075890, NRF-2015M3A9C7030121).

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflict of interest with respect to the authorship and/or publication of this article.

Supplementary material

12272_2018_1057_MOESM1_ESM.docx (692 kb)
Supplementary material 1 (DOCX 692 kb)

References

  1. Adinolfi LE, Nevola R, Lus G, Restivo L, Guerrera B, Romano C, Zampino R, Rinaldi L, Sellitto A, Giordano M, Marrone A (2015) Chronic hepatitis C virus infection and neurological and psychiatric disorders: an overview. World J Gastroenterol 21:2269–2280CrossRefPubMedPubMedCentralGoogle Scholar
  2. Akira S (2003) Toll-like receptor signaling. J Biol Chem 278:38105–38108CrossRefPubMedGoogle Scholar
  3. Anastasiou O, Sydor S, Sowa JP, Manka P, Katsounas A, Syn WK, Fuhrer D, Gieseler RK, Bechmann LP, Gerken G, Moeller LC, Canbay A (2015) Higher thyroid-stimulating hormone, triiodothyronine and thyroxine values are associated with better outcome in acute liver failure. PLoS ONE 10:e0132189CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ashburn TT, Thor KB (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3:673–683CrossRefPubMedGoogle Scholar
  5. Barton GM, Medzhitov R (2003) Toll-like receptor signaling pathways. Science 300:1524–1525CrossRefPubMedGoogle Scholar
  6. Beutler B, Hoebe K, Du X, Ulevitch RJ (2003) How we detect microbes and respond to them: the Toll-like receptors and their transducers. J Leukoc Biol 74:479–485CrossRefPubMedGoogle Scholar
  7. Boldt DH, MacDermott RP, Jorolan EP (1975) Interaction of plant lectins with purified human lymphocyte populations: binding characteristics and kinetics of proliferation. J Immunol 114:1532–1536PubMedGoogle Scholar
  8. Bozza M, Bliss JL, Maylor R, Erickson J, Donnelly L, Bouchard P, Dorner AJ, Trepicchio WL (1999) Interleukin-11 reduces T-cell-dependent experimental liver injury in mice. Hepatology 30:1441–1447CrossRefPubMedGoogle Scholar
  9. Cameron AR, Nelson J, Forman HJ (1983) Depolarization and increased conductance precede superoxide release by concanavalin A-stimulated rat alveolar macrophages. Proc Natl Acad Sci USA 80:3726–3728CrossRefPubMedGoogle Scholar
  10. Chang S, Dolganiuc A, Szabo G (2007) Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol 82:479–487CrossRefPubMedGoogle Scholar
  11. Das K, Chainy GB (2001) Modulation of rat liver mitochondrial antioxidant defence system by thyroid hormone. Biochim Biophys Acta 1537:1–13CrossRefPubMedGoogle Scholar
  12. Heymann F, Hamesch K, Weiskirchen R, Tacke F (2015) The concanavalin A model of acute hepatitis in mice. Lab Anim 49:12–20CrossRefPubMedGoogle Scholar
  13. Horn S, Kersseboom S, Mayerl S, Muller J, Groba C, Trajkovic-Arsic M, Ackermann T, Visser TJ, Heuer H (2013) Tetrac can replace thyroid hormone during brain development in mouse mutants deficient in the thyroid hormone transporter mct8. Endocrinology 154:968–979CrossRefPubMedGoogle Scholar
  14. Huang MJ, Liaw YF (1995) Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol 10:344–350CrossRefPubMedGoogle Scholar
  15. Huang TH, Chen CC, Liu HM, Lee TY, Shieh SH (2017) Resveratrol pretreatment attenuates concanavalin a-induced hepatitis through reverse of aberration in the immune response and regenerative capacity in aged mice. Sci Rep 7:2705CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kaneko Y, Harada M, Kawano T, Yamashita M, Shibata Y, Gejyo F, Nakayama T, Taniguchi M (2000) Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis. J Exp Med 191:105–114CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kuzuhara H, Nishiyama S, Minowa N, Sasaki K, Omoto S (2000) Protective effects of soyasapogenol A on liver injury mediated by immune response in a concanavalin A-induced hepatitis model. Eur J Pharmacol 391:175–181CrossRefPubMedGoogle Scholar
  18. Lee JH, Won JH, Choi JM, Cha HH, Jang YJ, Park S, Kim HG, Kim HC, Kim DK (2014) Protective effect of ellagic acid on concanavalin A-induced hepatitis via toll-like receptor and mitogen-activated protein kinase/nuclear factor kappaB signaling pathways. J Agric Food Chem 62:10110–10117CrossRefPubMedGoogle Scholar
  19. Li J, Xia Y, Liu T, Wang J, Dai W, Wang F, Zheng Y, Chen K, Li S, Abudumijiti H, Zhou Z, Lu W, Zhu R, Yang J, Zhang H, Yin Q, Wang C, Zhou Y, Lu J, Guo C (2015) Protective effects of astaxanthin on ConA-induced autoimmune hepatitis by the JNK/p-JNK pathway-mediated inhibition of autophagy and apoptosis. PLoS ONE 10:e0120440CrossRefPubMedPubMedCentralGoogle Scholar
  20. Li X, Liu HC, Yao QY, Xu BL, Zhang SC, Tu CT (2016) Quercetin protects mice from ConA-induced hepatitis by inhibiting HMGB1-TLR expression and down-regulating the nuclear factor kappa B pathway. Inflammation 39:96–106CrossRefPubMedGoogle Scholar
  21. Lien E, Ingalls RR (2002) Toll-like receptors. Crit Care Med 30:S1–S11CrossRefPubMedGoogle Scholar
  22. Malik R, Hodgson H (2002) The relationship between the thyroid gland and the liver. QJM 95:559–569CrossRefPubMedGoogle Scholar
  23. Massol J, Martin P, Soubrie P, Puech AJ (1988) Triiodothyroacetic acid (TRIAC) potentiation of antidepressant-induced reversal of learned helplessness in rats. Eur J Pharmacol 152:347–351CrossRefPubMedGoogle Scholar
  24. Mullur R, Liu YY, Brent GA (2014) Thyroid hormone regulation of metabolism. Physiol Rev 94:355–382CrossRefPubMedPubMedCentralGoogle Scholar
  25. Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27–31CrossRefPubMedPubMedCentralGoogle Scholar
  26. Sang XX, Wang RL, Zhang CE, Liu SJ, Shen HH, Guo YM, Zhang YM, Niu M, Wang JB, Bai ZF, Xiao XH (2017) Sophocarpine protects mice from ConA-Induced hepatitis via inhibition of the IFN-Gamma/STAT1 Pathway. Front Pharmacol 8:140CrossRefPubMedPubMedCentralGoogle Scholar
  27. Sesmilo G, Simo O, Choque L, Casamitjana R, Puig-Domingo M, Halperin I (2011) Serum free triiodothyronine (T3) to free thyroxine (T4) ratio in treated central hypothyroidism compared with primary hypothyroidism and euthyroidism. Endocrinol Nutr 58:9–15CrossRefPubMedGoogle Scholar
  28. Shinderman-Maman E, Cohen K, Moskovich D, Hercbergs A, Werner H, Davis PJ, Ellis M, Ashur-Fabian O (2017) Thyroid hormones derivatives reduce proliferation and induce cell death and DNA damage in ovarian cancer. Sci Rep 7:16475CrossRefPubMedPubMedCentralGoogle Scholar
  29. Sodhi A, Tarang S, Kesherwani V (2007) Concanavalin A induced expression of Toll-like receptors in murine peritoneal macrophages in vitro. Int Immunopharmacol 7:454–463CrossRefPubMedGoogle Scholar
  30. Tiegs G, Hentschel J, Wendel A (1992) A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Inv 90:196–203CrossRefGoogle Scholar
  31. Visvanathan K, Skinner NA, Thompson AJ, Riordan SM, Sozzi V, Edwards R, Rodgers S, Kurtovic J, Chang J, Lewin S, Desmond P, Locarnini S (2007) Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 45:102–110CrossRefPubMedGoogle Scholar
  32. Wang ZL, Wu XH, Song LF, Wang YS, Hu XH, Luo YF, Chen ZZ, Ke J, Peng XD, He CM, Zhang W, Chen LJ, Wei YQ (2009) Phosphoinositide 3-kinase gamma inhibitor ameliorates concanavalin A-induced hepatic injury in mice. Biochem Biophys Res Commun 386:569–574CrossRefPubMedGoogle Scholar
  33. Xue J, Chen F, Wang J, Wu S, Zheng M, Zhu H, Liu Y, He J, Chen Z (2015) Emodin protects against concanavalin A-induced hepatitis in mice through inhibiting activation of the p38 MAPK-NF-kappaB signaling pathway. Cell Physiol Biochem 35:1557–1570CrossRefPubMedGoogle Scholar
  34. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522–1526CrossRefPubMedGoogle Scholar
  35. Zhang B, Zhang A, Zhou X, Webb P, He W, Xia X (2012) Thyroid hormone analogue stimulates keratinocyte proliferation but inhibits cell differentiation in epidermis. Int J Immunopathol Pharmacol 25:859–869CrossRefPubMedGoogle Scholar
  36. Zhou M, Zhu X, Ye S, Zhou B (2014) Blocking TLR2 in vivo attenuates experimental hepatitis induced by concanavalin A in mice. Int Immunopharmacol 21:241–246CrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2018

Authors and Affiliations

  • Hae Chan Ha
    • 1
  • Ji Min Jang
    • 1
  • Dan Zhou
    • 1
  • Han Gyeol Kim
    • 1
  • Moon Jung Back
    • 1
  • In Chul Shin
    • 1
  • So Yoon Yun
    • 1
  • Yongwei Piao
    • 1
  • Jong Min Choi
    • 1
  • Jong Hoon Won
    • 1
  • Dae Kyong Kim
    • 1
  1. 1.Department of Environmental & Health Chemistry, College of PharmacyChung-Ang UniversitySeoulSouth Korea

Personalised recommendations