Advertisement

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

[Limited Access]      HTML         Full Text-PDF

American Journal of BioMedicine  Volume 2, Issue 5, pages 555–566, May 2014


Robyn B Wonderge; Steliana  Penzkofer; Min Zhou; Catherine  Dimmeler; Evelyn G Hazen

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


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. [PubMed]

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. [Abstract/FREE Full Text]

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. [CrossRef]

4. Wang XY, Yang CT, Zheng D, Mo L, Lan A, 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. [Abstract/FREE Full Text]

5. Muzio M, Bosisio D, Polentarutti N, D'Amico G, Stoppacciaro A, Mancinelli R, van't Veer C, 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. [Abstract/FREE Full Text]

6. Vanhoutte F, Paget C, Breuilh L, Fontaine J, Vendeville C, et al. Toll-like receptor (TLR)2 and TLR3 synergy and cross-inhibition in murine myeloid dendritic cells. Immunology letters 2008;116: 86–94. [View Article]

7. 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. [PubMed]

8. Schroder M, Bowie AG. TLR3 in antiviral immunity: key player or bystander? Trends Immunol  2005; 26:462–468. [CrossRef]

9. Doyle S, Vaidya S, O'Connell R, Dadgostar H, Dempsey P, et al. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002;17: 251–263. [View Article]

10.  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.

11.  Lipshultz SE. Exposure to anthracyclines during childhood causes cardiac injury. Semin Oncol 2006;33:S8–14. [PubMed]

12.  Vanhoutte F, Paget C, Breuilh L, Fontaine J, Vendeville C, et al. Toll-like receptor (TLR)2 and TLR3 synergy and cross-inhibition in murine myeloid dendritic cells. Immunology letters 2008;116: 86–94. [View Article]

13.  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. [PubMed]  

14.  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. [PubMed]

15.  Minotti G, Cairo G, Monti E. Role of iron in anthracycline cardiotoxicity: new tunes for an old song? FASEB J 1999;13:199–212. [PubMed]

16.  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. [CrossRe]

17.  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. [Abstract/FREE Full Text]

18.  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. [PubMed]

19.  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. [PubMed]

20. Matsumoto M, Funami K, Tanabe M, Oshiumi H, Shingai M, Seto Y, Yamamoto A, and Seys T. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol 2003; 171: 3154–3162. [Abstract/FREE Full Text

21.   Bien S, Riad A, Ritter CA, Gratz M, Olshausen F, Westermann D, et al. The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. Cancer Res 2007; 67(21):10428-10435. [Abstract/FREE Full Text]

22. 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. [Abstract/FREE Full Text]

23.  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. [PubMed]

24. Honda K, Sakaguchi S, Nakajima C, Watanabe A, Yanai H, Matsumoto M, Ohteki T, 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. [Abstract/FREE Full Text]

25.  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. [View Article]

26. 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. [View Article]

27. 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. [View Article]

28.  Hoebe K, Du x Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 2003; 424: 743–748. [CrossRefMedline]

29.  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. [PubMed]

30.  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. [PubMed]

31. 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. [Abstract/Full-Text]

32. Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, 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. [Abstract/FREE Full Text]

33.  So EY, Kang MH, and 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. [CrossRef]

34.  Bjorkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, 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. [CrossRef]

35.  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. [Abstract/FREE Full Text]

36.  Yousif NG, Al-amran FG. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. BMC cardiovascular disorders 2011;11(1): 62. [PubMed]

37.  Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, and Akira S. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science  2003; 301: 640–643. [Abstract/FREE Full Text]

38.  Tissari J, Siren J, Meri S, Julkunen I, and 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, 2005. [Abstract/FREE Full Text]

39.  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. [Abstract/FREE Full Text]

40.  Yang X, Coriolan D, Murthy V, Schultz K, Golenbock DT, and Beasley D. Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling. Am J Physiol Heart Circ Physiol 2005; 289: H1069–H1076. [Abstract/FREE Full Text]

41.  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. [CrossRefMedline]

42.  Austin EW, Yousif NG, 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. [Article-AJBM]

 

American Journal of Biomedicine © 2017 Frontier Theme
%d bloggers like this: