Tumor Necrosis Factor-α and Its Receptors 1 and 2

Abstract

HomeCirculationVol. 119, No. 10Tumor Necrosis Factor-α and Its Receptors 1 and 2 Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTumor Necrosis Factor-α and Its Receptors 1 and 2Yin and Yang in Myocardial Infarction? Rainer Schulz, MD and Gerd Heusch, MD Rainer SchulzRainer Schulz From the Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany. Search for more papers by this author and Gerd HeuschGerd Heusch From the Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany. Search for more papers by this author Originally published2 Mar 2009https://doi.org/10.1161/CIRCULATIONAHA.108.846105Circulation. 2009;119:1355–1357Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 2, 2009: Previous Version 1 In healthy hearts, tumor necrosis factor-α (TNF-α) concentration is low, and TNF-α is mainly located in endothelium and resident mast cells.1 TNF-α receptors (TNFRs) 1 (TNFR1) and 2 (TNFR2) are expressed on most cardiac cells, including cardiomyocytes.2 During myocardial ischemia, preformed TNF-α is released within minutes from resident mast cells and macrophages.3 With persistent ischemia, TNF-α also originates from cardiomyocytes.4 In rats after myocardial infarction (MI), TNFR1 density is increased for 10 days, whereas TNFR2 density remains unchanged.5 In contrast, TNFR1 and TNFR2 are both downregulated in the failing heart, whereas soluble TNFRs are increased6 owing to proteolytic cleavage of cardiomyocyte TNFR and release from circulating exosome-like vesicles.7 Increased soluble TNFRs decrease TNF-α bioactivity while at the same time prolonging its half-life.8Article p 1386TNF-α and Myocardial Ischemia/ Reperfusion InjuryTNF-α contributes to both reversible (contractile dysfunction4,9) and irreversible (MI) injury.1 Preischemic treatment with TNF-α antibodies10 or soluble TNFR1,11 permanent TNF-α knockout,12 or knockout of TNFR1 but not TNFR213 all reduce infarct size. The latter finding highlights the functional difference of TNFR1 and TNFR2 activation for ischemia/reperfusion injury: Only TNFR1 signaling is detrimental (Figure). Download figureDownload PowerPointFigure. Signaling cascade activated (→) or inhibited (⊣) by TNFR1 (red) or TNFR2 (blue) activation. sTNFR1 indicates soluble TNFR1; sTNFR2, soluble TNFR2; S1-P, sphingosine-1-phosphate; NF-κB, nuclear factor-κB; SOCS3, suppressor of cytokine signaling 3; ROS, reactive oxygen species; Akt-P, phosphorylated Akt, a homologue of the transforming v-Akt; NADPH-Ox, NADPH oxidase; STAT3-P, phosphorylated signal transducer and activator of transcription; Jnk-P, phosphorylated c-jun N-terminal kinase; p38-P, phosphorylated mitogen-activated protein kinase; Erk-P, phosphorylated extracellular signal-regulated kinase; PKC, protein kinase C; CamK, calcium/calmodulin-dependent kinase; MMP-2/9, matrix metalloproteinases 2 and 9; and IL-6, interleukin 6. Red indicates proteins involved in apoptosis; purple, proteins involved in growth; green, proteins involved in contractile function; blue, protein involved in inflammation; and yellow, proteins involved in extracellular matrix turnover.TNF-α and CardioprotectionAlthough TNF-α aggravates acute ischemia/reperfusion injury, preconditioning with TNF-α reduces infarct size.1 In addition, accumulation of endogenous TNF-α after coronary microembolization reduces infarct size.9 Finally, the protection of delayed ischemic preconditioning is absent after pretreatment with TNF-α antibodies and in TNF-α–, TNFR1-, and TNFR2-knockout mice13; the latter result reflects the involvement of both TNFRs in cardioprotection.13,14TNF-α and Permanent Coronary OcclusionTransfection with soluble TNFR1 reduces infarct size 3 weeks after MI in rats8 but not in mice.15 Neither genetic ablation of TNF-α16 nor knockout of TNFR117 or TNFR218 alters infarct size when measured 1 day17 or several weeks after coronary ligation.16–18 However, infarct size after 1 day is increased with knockout of both TNFRs and is associated with increased cardiomyocyte apoptosis in the area at risk.19With permanent coronary occlusion, 40% to 70% of mice die within 10 days after MI,15–18,20 and >50% of them die of cardiac rupture.15,16,18 Reduction of TNF-α bioactivity by adenoviral transfection with soluble TNFR1 promotes rather than attenuates cardiac rupture by inhibiting reactive fibrosis and reduces survival within 7 days after MI in male mice.15 In contrast, genetic ablation of TNF-α16 or TNFR1 knockout17,18 increases post-MI survival, without reducing the rate of cardiac rupture.18 In contrast to TNFR knockout, matrix metalloproteinase-2 knockout reduces cardiac rupture and increases survival after MI.20Elevated TNF-α contributes to chronic left ventricular (LV) dysfunction after MI through a local inflammatory response,16 increased matrix metalloproteinase-2 activity, matrix and collagen degradation,16,20 and cardiomyocyte apoptosis.16 TNF-α inhibition with etanercept immediately after MI reduces leukocyte infiltration and extracellular matrix degradation and preserves cardiac function 6 weeks after MI in rats.21 Similarly, TNF-α blockade with soluble TNFR2 attenuates hemodynamic derangements in the first week after MI in rats but does not attenuate LV dilatation 10 weeks after MI.22 In contrast, adenoviral transfection with soluble TNFR1 starting 7 days after MI exacerbates LV dysfunction and remodeling.15TNFR1 knockout attenuates contractile dysfunction after MI,17,18 whereas TNFR2 knockout exaggerates ventricular dilatation and dysfunction. Upregulated transcript levels of inflammatory markers after MI are reduced in TNFR1-knockout mice but further enhanced in TNFR2-knockout mice. Thus, TNF-α worsens LV remodeling via TNFR1 and improves it via TNFR2 after MI.18Hamid and coworkers in their elegant study in the present issue of Circulation now further delineate the ambivalent role of TNFR1 and TNFR2 in post-MI remodeling in male mice.23 Knockout of TNFR1 improved LV ejection fraction; reduced LV dilatation, cardiomyocyte hypertrophy and apoptosis, fibrosis, and inflammation; and ultimately resulted in improved survival after MI. In contrast, knockout of TNFR2 increased LV dilatation, cardiomyocyte hypertrophy and apoptosis, and fibrosis in the remote myocardium but did not affect systolic LV function. However, survival was also increased in TNFR2-knockout mice, and both TNFR-knockout mice had less reactive oxygen species formation and improved diastolic LV pressure. Importantly, Hamid and coworkers23 analyzed the signaling of TNFR1 and TNFR2 activation (Figure) and highlighted the divergent effects of TNFR1 and TNFR2 activation on stress kinase activation, nuclear signaling, and cardiomyocyte death pathways.Some questions remain: Is blockade of TNF-α bioactivity beneficial or deleterious? Increased TNF-α induces contractile dysfunction1 up to heart failure,24,25 and TNFR1 activation is primarily responsible for these detrimental effects.25 However, basal TNF-α improves contractile function via TNFR1 activation,26 and endogenous TNF-α contributes to the protection afforded by preconditioning through both TNFRs13; in addition, elimination of both TNFRs increases cardiomyocyte apoptosis.19 Thus, apart from signaling through TNFR1 or TNFR2, TNF-α can exert both beneficial and deleterious actions, depending on its concentration and duration of exposure.Are time and localization of increased TNF-α important? TNF-α remains elevated for weeks in the infarcted area, whereas it decreases in the peri-infarct area 1 week after MI and remains only slightly above basal values.5 Contractile dysfunction and LV dilatation coincide with the peak increase of TNF-α after MI.22 TNF-α in the infarcted area contributes to cardiomyocyte apoptosis, whereas TNF-α in the peri-infarct area might stimulate fibroblasts,27 thereby stabilize the infarcted area, and attract stem cells28 for cardiac repair and suppression of inflammation.29 Elevated TNF-α in the peri-infarct area depresses contractile function, induces cardiomyocyte apoptosis, and triggers fibrosis; however, when subsequently reduced again, TNF-α in the peri-infarct area might contribute to preservation of contractile function.26What is the contribution of cardiac rupture and arrhythmias to the impact of TNF-α on mortality? Hamid and coworkers23 suggest that less cardiac rupture was responsible for improved survival in TNFR knockouts. However, neither TNFR1 nor TNFR2 knockout affects the rate of cardiac rupture after MI,18 and blockade of TNF-α bioactivity by adenoviral transfer of soluble TNFR1 even increases the rate of cardiac rupture.15 An alternative explanation for the improved survival after MI in TNFR knockouts relates to a reduced incidence of arrhythmias. In post-MI rats, ventricular arrhythmias coincide with the secretion of TNF-α,30 and TNF-α promotes action potential prolongation through formation of reactive oxygen species in rat ventricular myocytes.31 Thus, diminished reactive oxygen species formation in TNFR knockouts, as shown by Hamid and coworkers,23 could restore normal repolarization and reduce arrhythmias. ECG tracings of TNFR1 and TNFR2 knockouts after MI could help identify the underlying cause.Are gender and age important for the actions of TNF-α? The expression of myocardial TNFR is higher in male than in female hearts, and such differential expression may contribute to sex differences in the severity of congestive heart failure and mortality.2,17 Indeed, TNF-α infusion depresses contractile function in male but not female mouse hearts.32 TNF-α–overexpressing mice develop progressive cardiomyocyte hypertrophy and LV dilatation, as well as increased collagen synthesis and deposition, along with marked diastolic dysfunction. Anti-TNF-α treatment prevents changes in extracellular matrix and preserves diastolic function, as did TNFR1 and TNFR2 knockout in the present study; however, this beneficial effect is only observed in young and not in old mice,24 which suggests a sex- and age-dependent signaling cascade after TNFR activation.ConclusionsIndeed, TNF-α and TNFR activation have an ambivalent role in MI. Excessive TNF-α expression and subsequent cardiomyocyte TNFR1 activation are detrimental, whereas a lower TNF-α concentration and subsequent cardiomyocyte TNFR2 activation are protective. TNF-α–induced fibrosis and attraction of stem cells might stabilize the infarcted area, while contributing to structural remodeling and diastolic dysfunction in remote myocardium. Apart from its receptor subtype, the action of TNF-α depends on its concentration, duration of exposure, and localization, as well as on the sex and age of the affected individual. Therefore, it is not surprising that clinical trials in chronic heart failure patients using compounds that antagonize TNF-α, including the TNF-α antibody infliximab and the soluble recombinant TNF-α receptor etanercept, revealed disappointing results, which supports the ambivalent effect of TNF-α.33The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.DisclosuresNone.FootnotesCorrespondence to Professor Dr Rainer Schulz, Institut für Pathophysiologie, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail [email protected] References 1 Schulz R. TNFα in myocardial ischemia/reperfusion: damage vs. protection. J Mol Cell Cardiol. 2008; 45: 712–714.CrossrefMedlineGoogle Scholar2 Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM. Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. 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