- Email: [email protected]
Complexity of transcriptional regulation of the tumor necrosis factor–α gene
Journal of Molecular and Cellular Cardiology 35 (2003) 1179–1181 www.elsevier.com/locate/yjmcc
Editorial
Complexity of transcriptional regulation of the tumor necrosis factor–a gene Recent studies suggest that the myocardial response to environmental stress comprises a homeostatic mechanism that allows cardiac myocytes to delimit cell injury through upregulation of cytoprotective factors. In response to various kinds of stimuli, the myocardium is capable of synthesizing a variety of cytoprotective factors, including growth factors and cytokines, which may contribute to the myocardial growth/remodeling and angiogenesis that occur after tissue injury [1–5]. Tumor necrosis factor–a (TNF-a) is a pro-inflammatory cytokine with pleiotropic-biological effects. Experimental studies have shown that the mammalian heart synthesizes TNF–a after stressful environmental conditions, such as hemodynamic overload [6], myocardial ischemia [7] and viral infection [8], and that this may contribute to important autocrine and/or paracrine homeostatic roles of cytoprotective factors in the diseased heart. The activities of TNF–a are mediated through two distinct cell surface receptors, TNF receptor 1 (p55) and TNF receptor 2 (p75), both of which exist on the surface of cardiac myocytes [9]. It has been reported that activation of both type 1 and 2 TNF receptors by TNF–a treatment confers resistance to hypoxic injury in adult cardiac myocytes [10]. It was further confirmed in in vivo model of myocardial infarction using mice lacking TNF receptors 1 and 2. Compared with control mice, these mice exhibit significantly greater infarct size after coronary ligation [11]. Recently, Wada et al. [12] reported interesting study demonstrating protective role of TNF–a in viral myocarditis. TNF-a gene-deficient mice are susceptible to viral infection and exhibit a poor prognosis. Injection of TNF–a into these mice improved survival, which suggested that TNF–a as a protective cytokine in the acute stage of viral myocarditis. These experimental studies suggest that TNF–a signaling gives rise to various cytoprotective signals that prevent the development of cardiac myocyte injury. However, recent studies in transgenic mice with targeted overexpression of the TNF–a gene in the heart showed that these mice developed progressive left ventricular dilation with a 6–month mortality of 25% [13]. Experimental studies in rats have also shown that circulating concentrations of TNF–a that overlap those observed in patients with heart failure are sufficient to produce persistent negative-inotropic effects that are detectable at the level of cardiac myocytes [14]. These seminal studies suggest that it is likely that the © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0022-2828(03)00247-5
short-term benefits of TNF–a will be lost if myocardial TNF-a expression becomes sustained and/or excessive. Kubota et al. [15] reported that overexpression of TNF–a activates both anti– and pro-apoptotic pathways in the myocardium, resulting in increase of apoptosis, primarily in nonmyocytes. The precise mechanism of myocardium-derived TNF–a expression was previously reported by Yokoyama et al. [16]. They examined TNF–a production in neonatal rat cardiac myocytes and fibroblasts after angiotensin II (Ang II) stimulation and compared it with that induced by lipopolysaccharide (LPS) or mechanical stretching. LPS, Ang II and mechanical stretch induced the production of TNF–a in cardiac fibroblasts, but only LPS stimulation induced TNF–a synthesis in cardiac myocytes. Subsequent experimental studies have indicated the importance of b-adrenergic receptormediated intracellular-cAMP elevation for inhibitory regulation of TNF–a synthesis. Last year, the molecular mechanism of Ang II-induced TNF–a regulation was examined using adult ferine hearts. Ang II-induced TNF–a mRNA expression and protein biosynthesis in the heart through the angiotensin type 1 receptor, in association with nuclear factor–jB (NF-jB) and activator protein-1 (AP-1) activation [17]. In this study, protein kinase C is proposed to be essential in Ang II-mediated induction of TNF–a in adult mammalian heart. The results obtained by Yokoyama et al. [16] suggest that increase in TNF–a expression by Ang II in adult ferine heart might be mediated mostly by cardiac fibroblasts. If transcriptional regulation of the TNF–a gene is cell-type specific, it would be difficult to identify critical transcription factor from the whole heart. Transcriptional regulation of the TNF–a gene is complex, with differences by specific stimulus, individual cell type and species. Moreover, significant differences have been noted between the regulatory mechanisms of the mouse and human TNF–a gene promoter. Most of the previous experimental studies involved the murine TNF–a gene, and indicated the importance of NF–jB in LPS-mediated transcriptional upregulation of the TNF–a gene [18]. However, it is reported that viral and LPS-mediated induction of the human TNF–a gene are not mediated by NF-jB [19]. Moreover, the sequence requirements of human TNF–a gene induction in different cell types differ significantly, indicating that transcriptional regulation of the human TNF–a gene is cell-type
1180
Editorial / Journal of Molecular and Cellular Cardiology 35 (2003) 1179–1181
specific. Therefore, cell-type– and inducer-specific transcriptional regulation of the human TNF–a gene involves multiple promoter regions and factors that act in a cell-type-specific manner. In the present issue of Journal of Molecular and Cellular Cardiology on pages 1197–1205, Sato et al. [20] report the transcriptional regulation of the human TNF–a gene by LPS and Ang II stimulation in cardiac fibroblasts. Ang II presented significantly increased promoter activity of the TNF–a gene, as observed after LPS and endothelin-1 stimulation. Although Ang II is known to induce TNF–a through the activation of NF-jB and AP-1 in other cell types, binding of ATF-2/c–jun to the CRE (cAMP responsive element) site was required for TNF–a gene induction in cardiac fibroblasts. A growing body of studies has revealed the importance of various neurohumoral factors in the development of cardiac remodeling and heart failure. In addition to TNF–a, a series of important studies demonstrated that the interleukin 6 (IL-6) family of cytokines, such as cardiotrophin-1 (CT-1), leukemia inhibitory factor (LIF) and IL-6, provided homeostatic responses to environmental stress, including hypertrophic growth, neovascularization and increased free radical scavenging through increased expression of manganese superoxide dismutase [21–24]. However, as in the case of TNF–a, the short-term beneficial effects of IL-6 may be lost if myocardial IL-6 expression becomes sustained and excessive, in which case the salutary effects of IL-6 may be lost [25]. Elevated circulating level of TNF in patients with congestive heart failure (CHF) was primarily reported by Levine et al. in 1990 [26]. Thereafter, it was reported that proinflammatory cytokines, including TNF–a and IL-6, are expressed in direct relation to worsening NYHA functional classification [27]. Recently, increased circulating level of CT-1 has been reported in patients with CHF, and is known to correlate with left ventricular mass index in patients with dilated cardiomyopathy [28]. In addition, enhanced expression of LIF and CT-1 was observed in the left ventricles of patients with CHF in association with diminished gp130– dependent signal transduction [22,29]. The observation that a variety of redundant inflammatory mediators are activated in heart failure has also potential therapeutic implications for anti-inflammatory strategies. Many cytokines are involved in many types of cells in the pathogenesis of the heart failure. Even in the case of TNF–a production, cell-type-specific transcriptional regulation of the human TNF–a gene involves multiple factors that act in a cell-type-specific manner with Ang II stimulation. Although it is difficult to predict the in vivo transcriptional regulatory properties of promoter elements from their in vitro binding activities, further experimental study would be expected to identify transcriptional factor, which enhances salutary effect of TNF–a without sustained expression.
References [1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18] [19]
Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993;75:977–84. van Wamel AJ, Ruwhof C, van der Valk-Kokshoom LE, Schrier PI, van der Laarse A. The role of angiotensin II, endothelin-1, and transforming growth factor b as autocrine/paracrine mediators of stretchinduced cardiomyocyte hypertrophy. Mol Cell Biochem 2001;218: 113–24. Ren J, Samson WK, Sowers JR. IGF-1 as a cardiac hormone: physiological and pathological implications in heart disease. J Mol Cell Cardiol 1999;31:2049–61. Yamauchi-Takihara K, Ihara Y, Ogata A, Yoshizaki K, Azuma J, Kishimoto T. Hypoxic stress induces cardiac myocyte-derived interleukin-6. Circulation 1995;91:1520–4. Hishinuma S, Funamoto M, Fujio Y, Kunisada K, Yamauchi-Takihara K. Hypoxic stress induces cardiotrophin-1 expression in cardiac myocytes. Biochem Biophys Res Commun 1999;264:436–40. Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, et al. Tumor necrosis factor–a and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704–11. Gurevitch J, Frolkis I, Yuhas Y, Paz Y, Matsa M, Mohr R, et al. Tumor necrosis factor–a is released from the isolated heart undergoing ischemia and reperfusion. J Am Coll Cardiol 1996;28:247–52. Shioi T, Matsumori A, Sasayama S. Persistant expression of cytokines in the chronic stage of viral myocarditis in mice. Circulation 1996;94: 2930–7. Mann DL. Tumor necrosis factor-induced signal transduction and left ventricular remodeling. J Card Fail 2002;8:S379–86. Nakano M, Knowlton AA, Dibbs Z, Mann DL. Tumor necrosis factor–a confers resistance to hypoxic injury in the adult mammalian cardiac myocyte. Circulation 1998;97:1392–400. Kurrelmeyer KM, Michael LH, Baumgarten G, Taffet GE, Peschon JJ, Sivasubramanian N, et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci USA 2000;97:5456–61. Wada H, Saito K, Kanda T, Kobayashi I, Fujii H, Fujigaki S, et al. Tumor necrosis factor-alpha (TNF–a) plays a protective role in acute viral myocarditis in mice. Circulation 2001;103:743–9. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor–a. Circ Res 1997;81:627–35. Bozkurt B, Kribbs S, Clubb Jr FJ, Michael LH, Didenko VV, Hornsby PJ, et al. Pathophysiologically relevant concentrations of tumor necrosis factor–a promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97:1382–91. Kubota T, Miyagishima M, Frye CS, Alber SM, Bounoutas GS, Kadokami T, et al. Overexpression of tumor necrosis factor–a activates both anti– and pro-apoptotic pathways in the myocardium. J Mol Cell Cardiol 2001;33:1331–44. Yokoyama T, Sekiguchi K, Tanaka T, Tomaru K, Arai M, Suzuki T, et al. Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts. Am J Physiol 1999;276:H1968–76. Kalra D, Sivasubramanian N, Mann DL. Angiotensin II induced tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C–dependent pathway. Circulation 2002; 105:2198–205. Lenardo MJ, Baltimore D. NF–jB: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 1989;58:227–9. Goldfeld AE, Doyle C, Maniatis T. Human tumor necrosis factor a gene regulation by virus and lipopolysaccharide. Proc Natl Acad Sci USA 1990;87:9769–73.
Editorial / Journal of Molecular and Cellular Cardiology 35 (2003) 1179–1181 [20] Sato H, Watanabe A, Tanaka T, Koitabashi N, Arai M, Kurabayashi M, et al. Regulation of the human tumor necrosis factor–a promoter by angiotensin II and lipopolisaccharide in cardiac fibroblasts; different cis–acting promoter sequences and transcriptional factors. J Mol Cell Cardiol 2003;35 1197–1205, in this issue. [21] Yamauchi-Takihara K, Kishimoto T. Cytokines and their receptors in cardiovascular diseases-role of gp130 signalling pathway in cardiac myocyte growth and maintenance. Int J Exp Path 2000;81:1–16. [22] Wang F, Seta Y, Baumgarten G, Engel DJ, Sivasubramanian N, Mann DL. Functional significance of hemodynamic overload-induced expression of leukemia-inhibitory factor in the adult mammalian heart. Circulation 2001;103:1296–302. [23] Funamoto M, Fujio Y, Kunisada K, Negoro S, Tone E, Osugi T, et al. Signal transducer and activator of transcription 3 is required for glycoprotein 130–mediated induction of vascular endothelial growth factor in cardiac myocytes. J Biol Chem 2000;275:10561–6. [24] Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI, Eizirik DL, et al. Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenationinduced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 2001;104:979–81. [25] Tanaka T, Kanda T, McManus BM, Kanai H, Akiyama H, Sekiguchi K, et al. Overexpression of interleukin-6 aggravates viral myocarditis: impaired increase in tumor necrosis factor–a. J Mol Cell Cardiol 2001;33:1627–35. [26] Levine B, Kalman J, Mayer L, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. New Engl J Med 1990;323:236–41.
1181
[27] Aukrust P, Ueland T, Lien E, Bendtzen K, Muller F, Andreassen AK, et al. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1999; 83:376–82. [28] Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, et al. Relationship between plasma level of cardiotrophin-1 and left ventricular mass index in patients with dilated cardiomyopathy. J Am Coll Cardiol 2001;38:1485–90. [29] Podewski EK, Hilfiker-Kleiner D, Hilfiker A, Morawietz H, Lichtenberg A, Wollert KC, et al. Alterations in Janus kinase (JAK)–signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy. Circulation 2003; 107:798–802.
Keiko Yamauchi-Takihara* Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2–2 Yamadaoka, Suita, Osaka 565 0871, Japan E-mail address: [email protected] Received 17 July 2003; accepted 18 July 2003 * Corresponding author. Tel.: +81-6-6879-3835; fax: +81-6-6879-3839.
Editorial
Complexity of transcriptional regulation of the tumor necrosis factor–a gene Recent studies suggest that the myocardial response to environmental stress comprises a homeostatic mechanism that allows cardiac myocytes to delimit cell injury through upregulation of cytoprotective factors. In response to various kinds of stimuli, the myocardium is capable of synthesizing a variety of cytoprotective factors, including growth factors and cytokines, which may contribute to the myocardial growth/remodeling and angiogenesis that occur after tissue injury [1–5]. Tumor necrosis factor–a (TNF-a) is a pro-inflammatory cytokine with pleiotropic-biological effects. Experimental studies have shown that the mammalian heart synthesizes TNF–a after stressful environmental conditions, such as hemodynamic overload [6], myocardial ischemia [7] and viral infection [8], and that this may contribute to important autocrine and/or paracrine homeostatic roles of cytoprotective factors in the diseased heart. The activities of TNF–a are mediated through two distinct cell surface receptors, TNF receptor 1 (p55) and TNF receptor 2 (p75), both of which exist on the surface of cardiac myocytes [9]. It has been reported that activation of both type 1 and 2 TNF receptors by TNF–a treatment confers resistance to hypoxic injury in adult cardiac myocytes [10]. It was further confirmed in in vivo model of myocardial infarction using mice lacking TNF receptors 1 and 2. Compared with control mice, these mice exhibit significantly greater infarct size after coronary ligation [11]. Recently, Wada et al. [12] reported interesting study demonstrating protective role of TNF–a in viral myocarditis. TNF-a gene-deficient mice are susceptible to viral infection and exhibit a poor prognosis. Injection of TNF–a into these mice improved survival, which suggested that TNF–a as a protective cytokine in the acute stage of viral myocarditis. These experimental studies suggest that TNF–a signaling gives rise to various cytoprotective signals that prevent the development of cardiac myocyte injury. However, recent studies in transgenic mice with targeted overexpression of the TNF–a gene in the heart showed that these mice developed progressive left ventricular dilation with a 6–month mortality of 25% [13]. Experimental studies in rats have also shown that circulating concentrations of TNF–a that overlap those observed in patients with heart failure are sufficient to produce persistent negative-inotropic effects that are detectable at the level of cardiac myocytes [14]. These seminal studies suggest that it is likely that the © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0022-2828(03)00247-5
short-term benefits of TNF–a will be lost if myocardial TNF-a expression becomes sustained and/or excessive. Kubota et al. [15] reported that overexpression of TNF–a activates both anti– and pro-apoptotic pathways in the myocardium, resulting in increase of apoptosis, primarily in nonmyocytes. The precise mechanism of myocardium-derived TNF–a expression was previously reported by Yokoyama et al. [16]. They examined TNF–a production in neonatal rat cardiac myocytes and fibroblasts after angiotensin II (Ang II) stimulation and compared it with that induced by lipopolysaccharide (LPS) or mechanical stretching. LPS, Ang II and mechanical stretch induced the production of TNF–a in cardiac fibroblasts, but only LPS stimulation induced TNF–a synthesis in cardiac myocytes. Subsequent experimental studies have indicated the importance of b-adrenergic receptormediated intracellular-cAMP elevation for inhibitory regulation of TNF–a synthesis. Last year, the molecular mechanism of Ang II-induced TNF–a regulation was examined using adult ferine hearts. Ang II-induced TNF–a mRNA expression and protein biosynthesis in the heart through the angiotensin type 1 receptor, in association with nuclear factor–jB (NF-jB) and activator protein-1 (AP-1) activation [17]. In this study, protein kinase C is proposed to be essential in Ang II-mediated induction of TNF–a in adult mammalian heart. The results obtained by Yokoyama et al. [16] suggest that increase in TNF–a expression by Ang II in adult ferine heart might be mediated mostly by cardiac fibroblasts. If transcriptional regulation of the TNF–a gene is cell-type specific, it would be difficult to identify critical transcription factor from the whole heart. Transcriptional regulation of the TNF–a gene is complex, with differences by specific stimulus, individual cell type and species. Moreover, significant differences have been noted between the regulatory mechanisms of the mouse and human TNF–a gene promoter. Most of the previous experimental studies involved the murine TNF–a gene, and indicated the importance of NF–jB in LPS-mediated transcriptional upregulation of the TNF–a gene [18]. However, it is reported that viral and LPS-mediated induction of the human TNF–a gene are not mediated by NF-jB [19]. Moreover, the sequence requirements of human TNF–a gene induction in different cell types differ significantly, indicating that transcriptional regulation of the human TNF–a gene is cell-type
1180
Editorial / Journal of Molecular and Cellular Cardiology 35 (2003) 1179–1181
specific. Therefore, cell-type– and inducer-specific transcriptional regulation of the human TNF–a gene involves multiple promoter regions and factors that act in a cell-type-specific manner. In the present issue of Journal of Molecular and Cellular Cardiology on pages 1197–1205, Sato et al. [20] report the transcriptional regulation of the human TNF–a gene by LPS and Ang II stimulation in cardiac fibroblasts. Ang II presented significantly increased promoter activity of the TNF–a gene, as observed after LPS and endothelin-1 stimulation. Although Ang II is known to induce TNF–a through the activation of NF-jB and AP-1 in other cell types, binding of ATF-2/c–jun to the CRE (cAMP responsive element) site was required for TNF–a gene induction in cardiac fibroblasts. A growing body of studies has revealed the importance of various neurohumoral factors in the development of cardiac remodeling and heart failure. In addition to TNF–a, a series of important studies demonstrated that the interleukin 6 (IL-6) family of cytokines, such as cardiotrophin-1 (CT-1), leukemia inhibitory factor (LIF) and IL-6, provided homeostatic responses to environmental stress, including hypertrophic growth, neovascularization and increased free radical scavenging through increased expression of manganese superoxide dismutase [21–24]. However, as in the case of TNF–a, the short-term beneficial effects of IL-6 may be lost if myocardial IL-6 expression becomes sustained and excessive, in which case the salutary effects of IL-6 may be lost [25]. Elevated circulating level of TNF in patients with congestive heart failure (CHF) was primarily reported by Levine et al. in 1990 [26]. Thereafter, it was reported that proinflammatory cytokines, including TNF–a and IL-6, are expressed in direct relation to worsening NYHA functional classification [27]. Recently, increased circulating level of CT-1 has been reported in patients with CHF, and is known to correlate with left ventricular mass index in patients with dilated cardiomyopathy [28]. In addition, enhanced expression of LIF and CT-1 was observed in the left ventricles of patients with CHF in association with diminished gp130– dependent signal transduction [22,29]. The observation that a variety of redundant inflammatory mediators are activated in heart failure has also potential therapeutic implications for anti-inflammatory strategies. Many cytokines are involved in many types of cells in the pathogenesis of the heart failure. Even in the case of TNF–a production, cell-type-specific transcriptional regulation of the human TNF–a gene involves multiple factors that act in a cell-type-specific manner with Ang II stimulation. Although it is difficult to predict the in vivo transcriptional regulatory properties of promoter elements from their in vitro binding activities, further experimental study would be expected to identify transcriptional factor, which enhances salutary effect of TNF–a without sustained expression.
References [1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18] [19]
Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993;75:977–84. van Wamel AJ, Ruwhof C, van der Valk-Kokshoom LE, Schrier PI, van der Laarse A. The role of angiotensin II, endothelin-1, and transforming growth factor b as autocrine/paracrine mediators of stretchinduced cardiomyocyte hypertrophy. Mol Cell Biochem 2001;218: 113–24. Ren J, Samson WK, Sowers JR. IGF-1 as a cardiac hormone: physiological and pathological implications in heart disease. J Mol Cell Cardiol 1999;31:2049–61. Yamauchi-Takihara K, Ihara Y, Ogata A, Yoshizaki K, Azuma J, Kishimoto T. Hypoxic stress induces cardiac myocyte-derived interleukin-6. Circulation 1995;91:1520–4. Hishinuma S, Funamoto M, Fujio Y, Kunisada K, Yamauchi-Takihara K. Hypoxic stress induces cardiotrophin-1 expression in cardiac myocytes. Biochem Biophys Res Commun 1999;264:436–40. Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, et al. Tumor necrosis factor–a and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704–11. Gurevitch J, Frolkis I, Yuhas Y, Paz Y, Matsa M, Mohr R, et al. Tumor necrosis factor–a is released from the isolated heart undergoing ischemia and reperfusion. J Am Coll Cardiol 1996;28:247–52. Shioi T, Matsumori A, Sasayama S. Persistant expression of cytokines in the chronic stage of viral myocarditis in mice. Circulation 1996;94: 2930–7. Mann DL. Tumor necrosis factor-induced signal transduction and left ventricular remodeling. J Card Fail 2002;8:S379–86. Nakano M, Knowlton AA, Dibbs Z, Mann DL. Tumor necrosis factor–a confers resistance to hypoxic injury in the adult mammalian cardiac myocyte. Circulation 1998;97:1392–400. Kurrelmeyer KM, Michael LH, Baumgarten G, Taffet GE, Peschon JJ, Sivasubramanian N, et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci USA 2000;97:5456–61. Wada H, Saito K, Kanda T, Kobayashi I, Fujii H, Fujigaki S, et al. Tumor necrosis factor-alpha (TNF–a) plays a protective role in acute viral myocarditis in mice. Circulation 2001;103:743–9. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor–a. Circ Res 1997;81:627–35. Bozkurt B, Kribbs S, Clubb Jr FJ, Michael LH, Didenko VV, Hornsby PJ, et al. Pathophysiologically relevant concentrations of tumor necrosis factor–a promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97:1382–91. Kubota T, Miyagishima M, Frye CS, Alber SM, Bounoutas GS, Kadokami T, et al. Overexpression of tumor necrosis factor–a activates both anti– and pro-apoptotic pathways in the myocardium. J Mol Cell Cardiol 2001;33:1331–44. Yokoyama T, Sekiguchi K, Tanaka T, Tomaru K, Arai M, Suzuki T, et al. Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts. Am J Physiol 1999;276:H1968–76. Kalra D, Sivasubramanian N, Mann DL. Angiotensin II induced tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C–dependent pathway. Circulation 2002; 105:2198–205. Lenardo MJ, Baltimore D. NF–jB: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 1989;58:227–9. Goldfeld AE, Doyle C, Maniatis T. Human tumor necrosis factor a gene regulation by virus and lipopolysaccharide. Proc Natl Acad Sci USA 1990;87:9769–73.
Editorial / Journal of Molecular and Cellular Cardiology 35 (2003) 1179–1181 [20] Sato H, Watanabe A, Tanaka T, Koitabashi N, Arai M, Kurabayashi M, et al. Regulation of the human tumor necrosis factor–a promoter by angiotensin II and lipopolisaccharide in cardiac fibroblasts; different cis–acting promoter sequences and transcriptional factors. J Mol Cell Cardiol 2003;35 1197–1205, in this issue. [21] Yamauchi-Takihara K, Kishimoto T. Cytokines and their receptors in cardiovascular diseases-role of gp130 signalling pathway in cardiac myocyte growth and maintenance. Int J Exp Path 2000;81:1–16. [22] Wang F, Seta Y, Baumgarten G, Engel DJ, Sivasubramanian N, Mann DL. Functional significance of hemodynamic overload-induced expression of leukemia-inhibitory factor in the adult mammalian heart. Circulation 2001;103:1296–302. [23] Funamoto M, Fujio Y, Kunisada K, Negoro S, Tone E, Osugi T, et al. Signal transducer and activator of transcription 3 is required for glycoprotein 130–mediated induction of vascular endothelial growth factor in cardiac myocytes. J Biol Chem 2000;275:10561–6. [24] Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI, Eizirik DL, et al. Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenationinduced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 2001;104:979–81. [25] Tanaka T, Kanda T, McManus BM, Kanai H, Akiyama H, Sekiguchi K, et al. Overexpression of interleukin-6 aggravates viral myocarditis: impaired increase in tumor necrosis factor–a. J Mol Cell Cardiol 2001;33:1627–35. [26] Levine B, Kalman J, Mayer L, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. New Engl J Med 1990;323:236–41.
1181
[27] Aukrust P, Ueland T, Lien E, Bendtzen K, Muller F, Andreassen AK, et al. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1999; 83:376–82. [28] Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, et al. Relationship between plasma level of cardiotrophin-1 and left ventricular mass index in patients with dilated cardiomyopathy. J Am Coll Cardiol 2001;38:1485–90. [29] Podewski EK, Hilfiker-Kleiner D, Hilfiker A, Morawietz H, Lichtenberg A, Wollert KC, et al. Alterations in Janus kinase (JAK)–signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy. Circulation 2003; 107:798–802.
Keiko Yamauchi-Takihara* Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2–2 Yamadaoka, Suita, Osaka 565 0871, Japan E-mail address: [email protected] Received 17 July 2003; accepted 18 July 2003 * Corresponding author. Tel.: +81-6-6879-3835; fax: +81-6-6879-3839.