Tumor Necrosis Factor-α Regulates Heme Oxygenase-1 Expression in Endothelial Cells via the Phosphorylation of JNK/p38

Authors: Chan-Jung Liang, Shu-Huei Wang, Pei-Jhen Wu, Jaw-Shiun Tsai, Chau-Chung Wu, Yuh-Lien Chen

Abstract:

Heme oxygenase-1 (HO-1), an enzyme degrading heme to carbon monoxide, iron, and biliverdin, has been recognized as playing a crucial role in cellular defense against stressful conditions, not only related to heme release. In the present study, the effects of TNF-a on the expression of heme oxygenase-1 (HO-1) in human aortic endothelial cells (HAECs) as well as the related mechanisms were investigated. 10 ng/mL TNF-α treatment significantly increased HO-1 expression after 6h, then a further increase at 12h and declined at 24h. Treatment with 2 ng/mL of TNF-a after 12 h resulted in a significant increase in HO-1 expression, which peaked at 10 ng/mL, then declined at 20 ng/mL. TNF-α induced HO-1 expression and then HO-1 expression reduced  vascular cell adhesion molecule-1 (VCAM-1) expression. Phosphorylation studies of ERK1/2, JNK, and p38, three subgroups of mitogen-activated protein kinases (MAPKs) demonstrated TNF-α-induced ERK1/2, JNK, and p38 phosphorylation. The increase in HO-1 expression in response to TNF-α treatment was affected by pretreatment with SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), not with PD98059 (an ERK1/2 inhibitor). The expression of HO-1 was stronger in aortas of TNF-α-treated apo-E deficient mice when compared with control mice. These results suggest that low dose of TNF-α treatment notably induced HO-1 expression was mediated through JNK/p38 phosphorylation and may have a protective potential in cardiovascular diseases and inflammatory response through the regulation of HO-1 expression.

Keywords: Heme oxygenase-1 inflammation, endothelial cells, mitogen-activated protein kinases (MAPKs).

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1088426

References:

[1] F.H. Bach, “Heme oxygenase-1: a therapeutic amplification funnel,” FASEB J., vol. 19, no. 10, pp. 1216–1219, 2005.
[2] T. Morita, “Heme oxygenase and atherosclerosis,” Arterioscler Thromb Vasc Biol., vol. 25, no. 9, pp. 1786–1795, 2005.
[3] K.A. Nath, J.J. Haggard, A.J. Croatt, J.P. Grande, K.D. Poss, J. Alam, “The indispensability of heme oxygenase-1 in protecting against acute heme protein- induced toxicity in vivo,” Am J Pathol., vol. 156, no. 5, pp. 1527–1535, 2000.
[4] S.W. Ryter, J. Alam, A.M. Choi, “Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications,” Physiol Rev., vol. 86, no. 2, pp. 583–650, 2006.
[5] L.E. Otterbein , F.H. Bach, J. Alam, M. Soares, H. Tao Lu, M. Wysk, R.J. Davis, R.A. Flavell, A.M. Choi, “Carbon monoxide has antiinflammatory effects involving the mitogen-activated protein kinase pathway,” Nat Med., vol. 6, no. 4, pp. 422–428, 2000.
[6] Y. Togane, T. Morita, M. Suematsu, Y. Ishimura, J. I. Yamazaki, S. Katayama, “Protective roles of endogenous carbon monoxide in neointimal development elicited by arterial injury,” Am J Physiol., vol. 278, no. 2, pp. 623–632, 2000.
[7] K.D. Poss, S. Tonegawa, “Heme oxygenase 1 is required for mammalian iron reutilization,” Proc Natl Acad Sci U S A., vol. 94, no. 20, pp. 10919–10924, 1997.
[8] R. Stocker, M.A. Perrella, “Heme oxygenase-1: a novel drug target for atherosclerotic diseases? ” Circulation., vol. 114, no. 20, pp. 2178– 2189, 2006.
[9] P. Wiesel, A.P.Patel, N. Difonzo, P.B. Marria, C.U. Sim, A. Pellacani, K. Maemura, B.W. Leblanc, K. Marino, C.M. Doerschuk, S.F. Yet, M.E. Lee, M.A. Perrella, “Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1-deficientmice,”Circulation., vol. 102, no. 24, pp. 3015–3022, 2000.
[10] S.F. Yet, M.A. Perrella, M.D. Layne, C.M. Hsieh, K. Maemura, L. Kobzik, P. Wiesel, H. Christou, S. Kourembanas, M.E. Lee, “Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice,” J Clin Invest., vol. 103, no. 8, pp. 23–29, 1999.
[11] K.Sato, J. Balla, L. Otterbein, R.N. Smith, S. Brouard, Y. Lin, E. Csizmadia, J. Sevigny, S.C. Robson, G.Vercellotti, A.M. Choi, F.H. Bach, M.P. Soares, “Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants,” J Immunol., vol. 166, no. 6, pp. 4185–4194, 2001.
[12] S. Mishra, T. Fujita, V.N. Lama, D. Nam, H. Liao, M. Okada, K. Minamoto, Y. Yoshikawa, H. Harada, D.J. Pinsky, “Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes,” Proc Natl Acad Sci U S A., vol. 103, no. 13, pp. 5191–5196, 2006.
[13] Baud, M. Karin,“Signal transduction by tumor necrosis factor and itsrelatives,” Trends Cell Biol., vol. 11, no. 9, pp. 372-377, 2001.
[14] I.A. van den Oever, H.G. Raterman, M.T. Nurmohamed, S. Simsek,“Endothelial dysfunction, inflammation, and apoptosis in diabetes mellitus,” Mediators Inflamm., vol. 2010, no. 2010, e792393, 2010.
[15] Y.M. Kim, H.O. Pae, J.E. Park, Y.C. Lee, J.M. Woo, N.H. Kim, Y.K. Choi, B.S. Lee, S.R. Kim, H.T. Chung,“Heme oxygenase in the regulation of vascular biology: from molecular mechanisms to therapeutic opportunities,” Antioxid. RedoxSignal., vol. 14, no. 1, pp. 137–167, 2011.
[16] I.T. Lee, S.F. Luo, C.W. Lee, S.W. Wang, C.C. Lin, C.C. Chang, Y.L. Chen, L.Y. Chau, C.M. Yang, “Overexpression of HO- 1 protects against TNF-alpha-mediated airway inflammation by down-regulation of TNFR1- dependent oxidative stress,” Am J Pathol., vol. 175, no. 2, pp. 519-532, 2009.
[17] Y.H. Chen, S.J. Lin, H.H. Ku, M.S. Shiao, F.Y. Lin, J.W. Chen, Y.L. Chen,“Salvianolic acid B attenuates VCAM-1 and ICAM-1 expression in TNF-alpha-treated human aortic endothelial cells,” J. Cell. Biochem., vol. 82, no. 3 , pp. 512-521, 2001.
[18] E.J. Park, Y.M. Kim, S.W. Park, H.J. Kim, J.H. Lee, D.U. Lee, K.C. Chang, “Induction of HO-1 through p38 MAPK/ Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPSactivated RAW 264.7 cells and CLP- induced septic mice,” Food Chem Toxicol., vol. 55, pp. 386-395, 2013.
[19] Speciale, S. Anwar, R. Canali , J. Chirafisi, A. Saija, F. Virgili, F. Cimino, “Cyanidin-3-O-glucoside counters the response to TNF-alpha of endothelial cells by activating Nrf2 pathway,” Mol. Nutr. Food Res., vol. 00, pp.1-9, 2013.