Cardiotoxicity of anthracycline: Novel approach through down regulation of TLR-3 via TRAF/MAPK signaling pathway


 

Abstract

Cardiotoxicity is one of the most important complications doxorubicin (DOX) and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of cardiac-toxicity following DOX treatment. Male adult C57BL6 wild-type mice and TLR-3 knock-out (-/-) mice were subjected to 20 mg/kg; administered intraperitoneally. TLR-3 down-stream signaling was activated in WT mice lead to strong pro-inflammatory response with significant monocyte cells invasion. In contrast, this effect was attenuated in TLR-3-/- mice. Moreover, the TLR-3 activation resulted in cardiac damage that was associated with significantly reduced LV function and increased monocyte chemoattractant protein-1 (MCP)-1 expression in WT mice. This finding was confirmed by
increased MAPK and TRIF protein expression in WT mice. This study confirmed that the absence of TLR-3 is associated with lower heart injury and maintained LV function. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of cardiotoxicity of DOX.

Keywords: TLR-3; Cardiotoxicity; Doxorubicin; MAPK; TRIF

Copyright © 2015 by The American Society for BioMedicine and BM-Publisher, Inc.

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References

  1. Choi EH, Chang H-J, Cho JY, Chun HS. Cytoprotective effect of anthocyanins against doxorubicin-induced toxicity in H9c2 cardiomyocytes in relation to their antioxidant activities. Food Chem Toxicol 2007; 45:1873-1881.
    https://doi.org/10.1016/j.fct.2007.04.003
  2. Teraoka K, Hirano M, Yamaguchi K, Yamashina A. Progressive cardiac dysfunction in adriamycin-induced cardiomyopathy rats. Eur J Heart Fail 2000;2(4):373-378.
    https://doi.org/10.1016/S1388-9842(00)00111-2
  3. Mogensen TH, Paludan SR. Reading the viral signature by Toll-like receptors and other pattern recognition receptors. J Mol Med 2005;83:180-192.
    https://doi.org/10.1007/s00109-004-0620-6
  4. Wang XY, Yang CT, Zheng D, et al. Hydrogen sulfide protects H9c2 cells against doxorubicin-induced cardiotoxicity through inhibition of endoplasmic reticulum stress. Mol Cell Biochem 2012;363(1-2):419-26.
    https://doi.org/10.1007/s11010-011-1194-6
  5. Wang XY, Yang CT, Zheng D, et al. Hydrogen sulfide protects H9c2 cells against doxorubicin-induced cardiotoxicity through inhibition of endoplasmic reticulum stress. Mol Cell Biochem 2012;363(1-2):419-26.
    https://doi.org/10.1007/s11010-011-1194-6
  6. Muzio M, Bosisio D, Polentarutti N, et al. Differential expression and regulation of Toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 2000;164:5998-6004.
    https://doi.org/10.4049/jimmunol.164.11.5998
  7. Vanhoutte F, Paget C, Breuilh L, et al. Toll-like receptor (TLR)2 and TLR3 synergy and cross-inhibition in murine myeloid dendritic cells. Immunology letters 2008;116: 86-94.
    https://doi.org/10.1016/j.imlet.2007.11.014
  8. Iarussi D, Indolfi P, Casale F, et al. Recent advances in the prevention of anthracycline cardiotoxicity in childhood. Curr Med Chem 2001;8:1649-60.
    https://doi.org/10.2174/0929867013371888
  9. Schroder M, Bowie AG. TLR3 in antiviral immunity: key player or bystander? Trends Immunol 2005; 26:462-468.
    https://doi.org/10.1016/j.it.2005.07.002
  10. Doyle S, Vaidya S, O'Connell R, et al. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002;17:251-263.
    https://doi.org/10.1016/S1074-7613(02)00390-4
  11. Doyle S, Vaidya S, O'Connell R, et al. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002;17:251-263.
    https://doi.org/10.1016/S1074-7613(02)00390-4
  12. Kanter PM, Bullard GA, Ginsberg RA, et al. Comparison of the cardiotoxic effects of liposomal doxorubicin (TLC D-99) versus free doxorubicin in beagle dogs. In Vivo. 1993;7:17-26.
  13. Lipshultz SE. Exposure to anthracyclines during childhood causes cardiac injury. Semin Oncol 2006;33:S8-14.
    https://doi.org/10.1053/j.seminoncol.2006.04.019
  14. Vanhoutte F, Paget C, Breuilh L, et al. Toll-like receptor (TLR)2 and TLR3 synergy and cross-inhibition in murine myeloid dendritic cells. Immunology letters 2008;116: 86-94.
    https://doi.org/10.1016/j.imlet.2007.11.014
  15. Vanhoutte F, Paget C, Breuilh L, et al. Toll-like receptor (TLR)2 and TLR3 synergy and cross-inhibition in murine myeloid dendritic cells. Immunology letters 2008;116: 86-94.
    https://doi.org/10.1016/j.imlet.2007.11.014
  16. Vanhoutte F, Paget C, Breuilh L, et al. Toll-like receptor (TLR)2 and TLR3 synergy and cross-inhibition in murine myeloid dendritic cells. Immunology letters 2008;116: 86-94.
    https://doi.org/10.1016/j.imlet.2007.11.014
  17. Lyass O, Uziely B, Ben-Yosef R, et al. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in meta-static breast carcinoma. Cancer 2000;89:1037-47.
    https://doi.org/10.1002/1097-0142(20000901)89:5<1037::AID-CNCR13>3.0.CO;2-Z
  18. Mrozek E, Rhoades CA, Allen J, et al. Phase I trial of liposomal encapsulated doxorubicin (Myocet; D-99) and weekly docetaxel in advanced breast cancer patients. Ann Oncol 2005;16:1087-93.
    https://doi.org/10.1093/annonc/mdi209
  19. Minotti G, Cairo G, Monti E. Role of iron in anthracycline cardiotoxicity: new tunes for an old song? FASEB J 1999;13:199-212.
    https://doi.org/10.1096/fasebj.13.2.199
  20. Spallarossa P, Garibaldi S, Altieri P, Fabbi P, Manca V, Nasti S, et al. Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. J Mol Cell Cardiol 2004;37(4):837-846.
    https://doi.org/10.1016/j.yjmcc.2004.05.024
  21. Weinstein DM, Mihm MJ, Bauer JA. Cardiac peroxynitrite formation and left ventricular dysfunction following doxorubicin treatment in mice. J Pharmacol Exp Ther 2000; 294(1):396-401.
  22. Minotti G, Ronchi R, Salvatorelli E, et al. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res 2001;61:8422-8.
  23. Mayhew E, Cimino M, Klemperer J, et al. Free and liposomal doxorubicin treatment of intraperitoneal colon 26 tumor: therapeutic and pharmacologic studies. Sel Cancer Ther 1990; 6:193-209.
    https://doi.org/10.1089/sct.1990.6.193
  24. Matsumoto M, Funami K, Tanabe M, et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol 2003; 171: 3154-3162.
    https://doi.org/10.4049/jimmunol.171.6.3154
  25. Bien S, Riad A, Ritter CA, et al. The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. Cancer Res 2007; 67(21):10428-10435.
    https://doi.org/10.1158/0008-5472.CAN-07-1344
  26. Jiang B, Xu S, Hou X, Pimentel DR, Brecher P, and Cohen RA. Temporal control of NF-kappaB activation by ERK differentially regulates interleukin-1beta-induced gene expression. J Biol Chem 2004; 279:1323-1329.
    https://doi.org/10.1074/jbc.M307521200
  27. Jiang B, Xu S, Hou X, Pimentel DR, Brecher P, Cohen RA. Temporal control of NF-kappaB activation by ERK differentially regulates interleukin-1beta-induced gene expression. J Biol Chem 2004; 279:1323-1329.
    https://doi.org/10.1074/jbc.M307521200
  28. Honda K, Sakaguchi S, Nakajima C, et al. Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double stranded RNA or viral infection. Proc Natl Acad Sci USA 2003;100: 10872-10877.
    https://doi.org/10.1073/pnas.1934678100
  29. Hause L, Al-Salleeh FM, Petro TM. Expression of IL-27 p28 by Theiler's virus-infected macrophages depends on TLR3 and TLR7 activation of JNK-MAP-kinases. Antiviral research 2007; 76: 159-167.
    https://doi.org/10.1016/j.antiviral.2007.06.013
  30. Hou L, Sasaki H, Stashenko P. Toll-like receptor 4-deficient mice have reduced bone destruction following mixed anaerobic infection. Infection and immunity 2000; 68: 4681-4687.
    https://doi.org/10.1128/IAI.68.8.4681-4687.2000
  31. Sabbatucci M, Purificato C, Fantuzzi L, Gessani S. Toll-like receptor cross-talk in human monocytes regulates CC-chemokine production, antigen uptake and immune cell recruitment. Immunobiology 2011; 216: 1135-1142.
    https://doi.org/10.1016/j.imbio.2011.04.005
  32. Hoebe K, Du x Georgel P, Janssen E, et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 2003; 424: 743-748.
    https://doi.org/10.1038/nature01889
  33. Lyass O, Uziely B, Ben-Yosef R, et al. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in meta-static breast carcinoma. Cancer 2000;89:1037-47.
    https://doi.org/10.1002/1097-0142(20000901)89:5<1037::AID-CNCR13>3.0.CO;2-Z
  34. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991;324:808-15.
    https://doi.org/10.1056/NEJM199103213241205
  35. Zhang R, Singh S, Ha X, Cowsik G, Lavezzi O, Caudell H, Ohura R. TLR3 exaggerated sepsis induced cardiac dysfunction via activation of TLR4-mediated NF-κB and TRIF/IRF signaling pathways. American journal of BioMedicine 2014;2(1):80-93.
    https://doi.org/10.18081/2333-5106/014-01/125-136
  36. Tabeta K, Georgel P, Janssen E, et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA 2004;101: 3516-3521.
    https://doi.org/10.1073/pnas.0400525101
  37. So EY, Kang MH, Kim BS. Induction of chemokine and cytokine genes in astrocytes following infection with Theiler's murine encephalomyelitis virus is mediated by the Toll-like receptor 3. Glia 2006; 53: 858-867.
    https://doi.org/10.1002/glia.20346
  38. Bjorkbacka H, Kunjathoor VV, Moore KJ, et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 2004;10:416-421.
    https://doi.org/10.1038/nm1008
  39. Cario E and Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 2000;68:7010-7017.
    https://doi.org/10.1128/IAI.68.12.7010-7017.2000
  40. Al-amran FG. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. BMC cardiovascular disorders 2011;11(1):62.
    https://doi.org/10.1186/1471-2261-11-62
  41. Yamamoto M, Sato S, Hemmi H, Hoshino K, et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 2003;301:640-643.
    https://doi.org/10.1126/science.1087262
  42. Tissari J, Siren J, Meri S, Julkunen I, Matikainen S. IFN-alpha enhances TLR3-mediated antiviral cytokine expression in human endothelial and epithelial cells by up-regulating TLR3 expression. J Immunol 2005;174:4289-4294.
    https://doi.org/10.4049/jimmunol.174.7.4289
  43. Yang X, Coriolan D, Schultz K, Golenbock DT, and Beasley D. Toll-like receptor 2 mediates persistent chemokine release by Chlamydia pneumoniae-infected vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2005;25:2308-2314.
    https://doi.org/10.1161/01.ATV.0000187468.00675.a3
  44. Yang R, Mark MR, Gray A, Huang A, Xie M, Zhang M, Goddard A, Wood WI, Gurney AL, and Godowski PJ. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signaling. Nature 1998;395:284-288.
    https://doi.org/10.1038/26239
  45. Austin EW, Ao L, Fullerton DA, Meng X. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. American journal of BioMedicine 2013;1(2):33-47.  https://doi.org/10.18081/ajbm/2333-5106-013-12/38-48

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Research Article
DOI: http://dx.doi.org/10.18081/2333-5106/015-2/423-432
American Journal of BioMedicine 2015, Volume 3, Issue 2, pages 23-32
Received January 22, 2015; Accepted April; 26, 2015, Published June 2, 2015

How to cite this article
Liang G, Lazenby D, Groden JD. Cardiotoxicity of anthracycline: Novel approach through down regulation of TLR-3 via
TRAF/MAPK signaling pathway. American Journal of BioMedicine 2015;3(2):11–22
Research Article
1. Abstract
2. Keywords
3. Introduction
5. Results
6. Discussion
7. References

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