Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
권호 표지

Statin inhibits interferon-$\gamma$-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells

Chung, Hyo-Kyun;Lee, In-Kyu;Kang, Hyo-Kyung;Suh, Jae-Mi;Kim, Ho;Park, Ki-Cheol;Kim, Dong-Wook;Kim, Young-Kun;Ro, Heung-Kyu;Shong, Min-Ho

  • Published : 2002.12.31
⟨ Previous Next ⟩

Abstract

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Pathogenesis of atherosclerosis is multistep processes where transendothelial migration of various leukocytes including monocytes is a crucial step. Interferon$-{\gamma}\;(IFN-{\gamma})$ contributes in this process by activating macrophages and T-lymphocytes, and by inducing adhesion molecules in vascular endothelial and smooth muscle cells. In this study we investigated the expression of intercellular cell adhesion molecule- 1 (ICAM-1) in transformed endothelial cell line ECV304 cells as influenced by lovastatin, tumor necrosis factor-${\alpha}\;(TNF-{\alpha})$ and $IFN-{\gamma}$. Results show that lovastatin suppresses expression of ICAM-1 by inhibiting the $IFN-{\gamma}-induced$ extracellular signal-regulated kinase (ERK) p44/p42-STAT1 signaling pathway. In cells treated with lovastatin and $IFN-{\gamma}$, ICAM-1 was expressed at a lower level than in cells treated with $IFN-{\gamma}$ alone. However, lovastatin does not reduce $TNF-{\alpha}$ induced expression of ICAM-1. A similar result was observed in cells treated with the MEKK inhibitor PD98059 and $IFN-{\gamma}$. Cis-acting DNA sequence elements were identified in the 5'-flanking region of the ICAM-1 promoter that mediate inhibition by lovastatin; these sequences map to the $IFN-{\gamma}$ activated site which also binds the STAT1 homodimer. However, lovastatin did not inhibit $IFN-{\gamma}-mediated$ induction of the Y701 phosphorylated form of STAT1. But lovastatin does inhibit the $IFN-{\gamma}-mediated $ phosphorylation of ERK1/ERK2 (T202/Y204) and S727 phosphorylation of STAT1. $TNF-{\alpha}$ does not induce phosphorylation of ERK1/ERK2 and S727 in ECV304 and smooth muscle cells. The results provide the evidences that statins may have beneficial effects by inhibiting $IFN-{\gamma}$ action in atherosclerotic process

Keywords

References

  1. Exp Mol Med v.29 Hormonal regulation of ICAM-1 gene expression in thyroid cells, FRTL-5 An, B.S.;Ku, B.J.;Park, S.Y.;Shin, J.K.;Lee, J.H.;Kim, Y.K.;Shong, M.H.;Ro, H.K. https://doi.org/10.1038/emm.1997.7
  2. Endocrinology v.141 Thyrotropin modulates interferon-gamma-mediated intercellular adhesion molecule-1 gene expression by inhibiting Janus kinase-1 and signal transducer and activator of transcription-1 activation in thyroid cells Chung, J.;Park, E.S.;Kim, D.;Suh, J.M.;Chung, H.K.;Kim, J.;Kim, H.;Park, S.J.;Kwon, O.Y.;Ro, H.K.;Shong, M. https://doi.org/10.1210/en.141.6.2090
  3. J Exp Med v.191 P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice Collins, R.G.;Velji, R.;Guevara, N.V.;Hicks, M.J.;Chan, L.;Beaudet, A.L. https://doi.org/10.1084/jem.191.1.189
  4. Science v.277 STATs and gene regulation Darnell, J.E. Jr. https://doi.org/10.1126/science.277.5332.1630
  5. Science v.269 Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins David, M.;Petricoin, E. 3rd.;Benjamin, C.;Pine, R.;Weber, M.J.;Larner, A.C. https://doi.org/10.1126/science.7569900
  6. Oncogene v.19 Serine phosphorylation of STATs Decker, T.;Kovarik, P. https://doi.org/10.1038/sj.onc.1203481
  7. J Immunol v.137 Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1) Dustin, M.L.;Rothlein, R.;Bhan, A.K.;Dinarello, C.A.;Springer, T.A.
  8. J Biol Chem v.270 Stat1 Depends on Transcriptional Synergy with Sp1 Look, Dwight C.;Pelletier, Mark R.;Tidwell, Rose M.;Roswit, William T.;Holtzman, Michael J. https://doi.org/10.1074/jbc.270.51.30264
  9. EMBO J v.18 p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons Goh, K.C.;Haque, S.J.;Williams, B.R. https://doi.org/10.1093/emboj/18.20.5601
  10. Am J Cardiol v.87 Statin therapy: where are we? Where do we go next? Gotto, A.M. Jr. https://doi.org/10.1016/S0002-9149(01)01450-3
  11. Circ Res v.83 3-Hydroxy-3methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture Guijarro, C.;Blanco-Colio, L.M.;Ortego, M.;Alonso, C.;Ortiz, A.;Plaza, J.J.;Diaz, C.;Hernandez, G.;Edigo, J. https://doi.org/10.1161/01.RES.83.5.490
  12. J Clin Invest v.99 IFN-gamma potentiates atherosclerosis in ApoE knock-out mice Gupta, S.;Pablo, A.M.;Jiang, X.C.;Wang, N.;Tall, A.R.;Schindler, C. https://doi.org/10.1172/JCI119465
  13. Proc Natl Acad Sci USA v.88 Cell cycle-specific effects of lovastatin Jakobisiak, M.;Bruno, S.;Skierski, J.S.;Darzynkiewicz, Z. https://doi.org/10.1073/pnas.88.9.3628
  14. J Biol Chem v.274 Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner Jain, N.;Zhang, T.;Kee, W.H.;Li, W.;Cao, X. https://doi.org/10.1074/jbc.274.34.24392
  15. Oncogene v.19 Lovastatin induces apoptosis in a primitive neuroectodermal tumor cell line in association with RB down-regulation and loss of the G1 checkpoint Kim, J.S.;Pirnia, F.;Choi, Y.H.;Nguyen, P.M.;Knepper, B.;Tsokos, M.;Schulte, T.W.;Birrer, M.J.;Blagosklonny, M.V.;Schaefer, O.;Mushinski, J.F.;Trepel, J.B. https://doi.org/10.1038/sj.onc.1204008
  16. Nat Med v.6 The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals Kureishi, Y.;Luo, Z.;Shiojima, I.;Bialik, A.;Fulton, D.;Lefer, D.J.;Sessa, W.C.;Walsh, K. https://doi.org/10.1038/79510
  17. Nat Med v.6 Statins as a newly recognized type of immunomodulator Kwak, B.;Mulhaupt, F.;Myit, S.;Mach, F. https://doi.org/10.1038/82219
  18. Trends Cardiovasc Med v.10 Direct vascular effects of HMG-CoA reductase inhibitors Laufs, U.;Liao, J.K. https://doi.org/10.1016/S1050-1738(00)00044-X
  19. J Biol Chem v.269 Selective interaction of a subset of interferon-gamma response element-binding proteins with the intercellular adhesion molecule-1 (ICAM-1) gene promoter controls the pattern of expression on epithelial cells Look, D.C.;Pelletier, M.R.;Holtzman, M.J.
  20. Exp Cell Res v.252 Lovastatin inhibits G1/S transition of normal human B-Iymphocytes independent of apoptosis Naderi, S.;Blomhoff, R.;Myklebust, J.;Smeland, E.B.;Erikstein, B.;Norum, K.R.;Blomhoff, H.K. https://doi.org/10.1006/excr.1999.4608
  21. J Clin Invest v.100 Interferon-gamma deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse hearts Nagano, H.;Mitchell, R.N.;Taylor, M.K.;Hasegawa, S.;Tilney, N.L.;Libby, P. https://doi.org/10.1172/JCI119564
  22. Circulation v.101 Current perspectives on statins Maron, O.J.;Fazio, S.;Linton, M.F. https://doi.org/10.1161/01.CIR.101.2.207
  23. Thyroid v.9 Hormone-dependent regulation of intercellular adhesion molecule-1 gene expres-sion: cloning and analysis of 5'-regulatory region of rat intercellular adhesion molecule-1 gene in FRTL-5 rat thyroid cells Park, E.S.;You, S.H.;Kim, H.;Kwon, O.Y.;Ro, H.K.;Cho, B.Y.;Taniguchi, S.I.;Kohn, L.D.;Shong, M. https://doi.org/10.1089/thy.1999.9.601
  24. Am Heart J v.138 no.2 Statin trials and goals of cholesterol-lowering therapy after AMI Pedersen, T.R. https://doi.org/10.1016/S0002-8703(99)70340-6
  25. Nature v.362 The pathogenesis of atherosclerosis: a perspective for the 1990s Ross, R. https://doi.org/10.1038/362801a0
  26. J Immunol v.141 Induction of intercellular adhesion molecule 1 on primary and continuous cell lines by pro-inflammatory cytokines. Regulation by pharmacologic agents and neutralizing antibodies Rothlein, R.;Czajkowski, M.;O'Neill, M.M.;Marlin, S.D.;Mainolfi, E.;Merluzzi, V.J.
  27. J Immunol v.165 Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein Sadeghi, M.M.;Collinge, M.;Pardi, R.;Bender, J.R. https://doi.org/10.4049/jimmunol.165.5.2712
  28. J Biol Chem v.273 Interferon gamma activation of Raf-1 is Jak1-dependent and p21 rasindependent Sakatsume, M.;Stancato, L.F.;David, M.;Silvennoinen, O.;Saharinen, P.;Pierce, J.;Lamer, A.C.;Finbloom, D.S. https://doi.org/10.1074/jbc.273.5.3021
  29. Nature v.387 A family of cytokine-inducible inhibitors of signalling Starr, R.;Willson, T.A.;Viney, E.M.;Murray, L.J.;Rayner, J.R.;Jenkins, B.J.;Gonda, T.J.;Alexander, W.S.;Metcalf, D.;Nicola, N.A.;Hilton, D.J. https://doi.org/10.1038/43206
  30. Immunobiology v.193 Transcriptional regulation of the human intercellular adhesion molecule-1 gene: a short overview Stratowa, C.;Audette, M. https://doi.org/10.1016/S0171-2985(11)80558-9
  31. Physiol Rev v.81 Small GTP-binding proteins Takai, Y.;Sasaki, T.;Matozaki, T. https://doi.org/10.1152/physrev.2001.81.1.153
  32. J Biol Chem v.272 Targeted inhibition of interferon-gamma-dependent intercellular adhesion molecule-1 (ICAM-1) expression using dominant-negative Stat1 Walter, M.J.;Look, D.C.;Tidwell, R.M.;Roswit, W.T.;Holtzman, M.J. https://doi.org/10.1074/jbc.272.45.28582
  33. Cell v.82 Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation Wen, Z.;Zhong, Z.;Darnell, J.E. Jr. https://doi.org/10.1016/0092-8674(95)90311-9
  34. J Biol Chem v.267 Intercellular adhesion molecule-1 gene expression in human endothelial cells. Differential regulation by tumor necrosis factor-alpha and phorbol myristate acetate Wertheimer, S.J.;Myers, C.L.;Wallace, R.W.;Parks, T.P.
  35. Proc Natl Acad Sci USA v.93 The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner Xia, K.;Mukhopadhyay, N.K.;Inhorn, R.C.;Barber, D.L.;Rose, P.E.;Lee, R.S.;Narsimhan, R.P.;D'Andrea, A.D.;Griffin, J.D.;Roberts, T.M. https://doi.org/10.1073/pnas.93.21.11681
  36. Curr Biol v.10 Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR Yokogami, K.;Wakisaka, S.;Avruch, J.;Reeves, S.A. https://doi.org/10.1016/S0960-9822(99)00268-7
  37. Science v.267 Requirement of serine phosphorylation for formation of STATpromoter complexes Zhang, X.;Blenis, J.;Li, H.C.;Schindler, C.;Chen-Kiang, S. https://doi.org/10.1126/science.7701321
  38. Mol Cell Biol v.17 Stat 1 serine phosphorylation occurs independently of tyrosine phosphorylation and requires an activated Jak2 kinasem Zhu, X.;Wen, Z.;Xu, L.Z.;Darnell, J.E. Jr. https://doi.org/10.1128/MCB.17.11.6618