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혈관평활근세포에서 glycated albumin에 의한 interleukin-6 증가에 관여하는 인자에 대한 연구

Glycated Serum Albumin Induces Interleukin-6 Expression in Vascular Smooth Muscle Cells

  • 백승일 (부산대학교 의학전문대학원 약리학교실) ;
  • 임병용 (부산대학교 의학전문대학원 약리학교실) ;
  • 김관회 (부산대학교 의학전문대학원 약리학교실)
  • Baek, Seung-Il (Department of Pharmacology, School of Medicine-Pusan National University) ;
  • Rhim, Byung-Yong (Department of Pharmacology, School of Medicine-Pusan National University) ;
  • Kim, Koan-Hoi (Department of Pharmacology, School of Medicine-Pusan National University)
  • 투고 : 2010.11.12
  • 심사 : 2011.01.10
  • 발행 : 2011.01.30

초록

Glycate화된 단백질이 혈관질환의 발생에 관여하는지 알아보기 위하여 glycated albumin (GA)이 혈관평활근 세포에서 인터루킨-6 발현에 영향을 주는지 조사하고 또한 그 기전을 구명하였다. GA에 노출된 혈관평활근세포에서 인터루킨-6 transcript가 증가하고, 인터루킨-6 단백질의 분비가 증가하고, 또한 인터루킨-6 유전자의 promoter가 활성화되었다. GA에 의한 인터루킨-6 유전자의 promoter 활성화는 dominant negative 형태의 Toll-like receptor (TLR)-4와 myeloid differentiation factor 88 (Myd88)에 의하여 크게 감소되었지만, dominant negative 형태의 TLR-2와 TIR-domain-containing adapter-inducing interferon-$\beta$ (TRIF)의 영향을 받지 않았다. 그리고 Extrcellular signal-related kinase (ERK) 억제 물질들은 GA에 의한 인터루킨-6의 분비 및 인터루킨-6 유전자 promoter 활성화를 억제하였다. 그리고 인터루킨-6 유전자의 promoter의 NF-${\kappa}B$-binding sequence에 변이는 GA에 의한 인터루킨-6 유전자의 promoter 활성화 억제하였다. 이러한 결과는 혈관평활근세포에서 GA에 의한 인터루킨-6 유전자 활성화에 TLR-4와 ERK 및 NF-${\kappa}B$가 관여함을 의미한다.

Diabetes mellitus is associated with vascular complications. Diabetic patients exhibit high levels of glycated adducts in serum compared to non-diabetic individuals. The aim of this study was to investigate whether extracellular glycated albumin (GA) predisposes vascular smooth muscle cells (VSMCs) to pro-inflammatory phenotype. Exposure of rat aortic smooth muscle cells (AoSMCs) to GA not only enhanced interleukin-6 (IL-6) release but also activated promoter activity of the IL-6 gene. GA-induced IL-6 promoter activation was suppressed by dominant-negative forms of Toll-like receptor (TLR)-4 and myeloid differentiation factor 88 (MyD88), but not by dominant-negative-forms of TLR-2 and TIR-domain-containing adapter-inducing interferon-$\beta$ (TRIF). Extracellular signal-regulated kinase (ERK) inhibition and diphenyleneiodium (DPI) also attenuated IL-6 induction by GA. Mutation at the nuclear factor-${\kappa}B$ (NF-${\kappa}B$)-binding site in the IL-6 promoter region suppressed promoter activation in response to GA. The present study proposes that GA would contribute to inflammatory reaction in the stressed vasculature by inducing IL-6 in VSMCs, and that TLR-4, EKR, and NF-${\kappa}B$ play active roles in the process.

키워드

참고문헌

  1. Akira, S. and K. Takeda. 2004. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499-511. https://doi.org/10.1038/nri1391
  2. Brownlee, M. 2001. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813-820. https://doi.org/10.1038/414813a
  3. Bunn, H. F., K. H. Gabbay, and P. M. Gallop. 1978. The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 200, 21-27. https://doi.org/10.1126/science.635569
  4. Clements, R. S., Jr., W. G. Robison, Jr., and M. P. Cohen. 1998. Anti-glycated albumin therapy ameliorates early retinal microvascular pathology in db/db mice. J. Diabetes Complications 12, 28-33. https://doi.org/10.1016/S1056-8727(97)00051-2
  5. Cohen, M. P., R. S. Clements, J. A. Cohen, and C. W. Shearman. 1996. Glycated albumin promotes a generalized vasculopathy in the db/db mouse. Biochem. Biophys. Res. Commun. 218, 72-75. https://doi.org/10.1006/bbrc.1996.0014
  6. Derijard, B., J. Raingeaud, T. Barrett, I. H. Wu, J. Han, R. J. Ulevitch, and R. J. Davis. 1995. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science 267, 682-685. https://doi.org/10.1126/science.7839144
  7. Edfeldt, K., J. Swedenborg, G. K. Hansson, and Z. Q. Yan. 2002. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 105, 1158-1161.
  8. Eickelberg, O., M. Roth, R. Mussmann, J. J. Rudiger, M. Tamm, A. P. Perruchoud, and L. H. Block. 1999. Calcium channel blockers activate the interleukin-6 gene via the transcription factors NF-IL6 and NF-kappaB in primary human vascular smooth muscle cells. Circulation 99, 2276-2282. https://doi.org/10.1161/01.CIR.99.17.2276
  9. Hattori, Y., H. Kakishita, K. Akimoto, M. Matsumura, and K. Kasai. 2001. Glycated serum albumin-induced vascular smooth muscle cell proliferation through activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by protein kinase C. Biochem. Biophys. Res. Commun. 281, 891-896. https://doi.org/10.1006/bbrc.2001.4436
  10. Hattori, Y., M. Suzuki, S. Hattori, and K. Kasai. 2002. Vascular smooth muscle cell activation by glycated albumin (Amadori adducts). Hypertension 39, 22-28. https://doi.org/10.1161/hy1201.097300
  11. Herder, C., B. Haastert, S. Muller-Scholze, W. Koenig, B. Thorand, R. Holle, H. E. Wichmann, W. A. Scherbaum, S. Martin, and H. Kolb. 2005. Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). Diabetes 54, S11-17. https://doi.org/10.2337/diabetes.54.suppl_2.S11
  12. Higai, K., A. Shimamura, and K. Matsumoto. 2006. Amadori-modified glycated albumin predominantly induces E-selectin expression on human umbilical vein endothelial cells through NADPH oxidase activation. Clin. Chim. Acta. 367, 137-143. https://doi.org/10.1016/j.cca.2005.12.008
  13. Higgins, P. J. and H. F. Bunn. 1981. Kinetic analysis of the nonenzymatic glycosylation of hemoglobin. J. Biol. Chem. 256, 5204-5208.
  14. Hollestelle, S. C., M. R. De Vries, J. K. Van Keulen, A. H. Schoneveld, A. Vink, C. F. Strijder, B. J. Van Middelaar, G. Pasterkamp, P. H. Quax, and D. P. De Kleijn. 2004. Toll-like receptor 4 is involved in outward arterial remodeling. Circulation 109, 393-398. https://doi.org/10.1161/01.CIR.0000109140.51366.72
  15. Kawai, T. and S. Akira. 2005. Toll-like receptor downstream signaling. Arthritis Res. Ther. 7, 12-19. https://doi.org/10.1186/ar1469
  16. Libby, P. 2002. Inflammation in atherosclerosis. Nature 420, 868-874. https://doi.org/10.1038/nature01323
  17. Libby, P., P. M. Ridker, and A. Maseri. 2002. Inflammation and atherosclerosis. Circulation 105, 1135-1143. https://doi.org/10.1161/hc0902.104353
  18. Mansour, S. J., W. T. Matten, A. S. Hermann, J. M. Candia, S. Rong, K. Fukasawa, G. F. Vande Woude, and N. G. Ahn. 1994. Transformation of mammalian cells by constitutively active MAP kinase. Science 265, 966-970. https://doi.org/10.1126/science.8052857
  19. Medzhitov, R. 2001. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135-145. https://doi.org/10.1038/35100529
  20. Michelsen, K. S., M. H. Wong, P. K. Shah, W. Zhang, J. Yano, T. M. Doherty, S. Akira, T. B. Rajavashisth, and M. Arditi. 2004. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl. Acad. Sci. U.S.A. 101, 10679-10684. https://doi.org/10.1073/pnas.0403249101
  21. Ross, R. 1986. The pathogenesis of atherosclerosis-an update. N. Engl. J. Med. 314, 488-500. https://doi.org/10.1056/NEJM198602203140806
  22. Salazar, R., R. Brandt, and S. Krantz. 1995. Expression of fructosyllysine receptors on human monocytes and monocyte- like cell lines. Biochim. Biophys. Acta. 1266, 57-63. https://doi.org/10.1016/0167-4889(94)00221-Y
  23. Singh, R., A. Barden, T. Mori, and L. Beilin. 2001. Advanced glycation end-products: a review. Diabetologia 44, 129-146. https://doi.org/10.1007/s001250051591
  24. Sun, H. N., S. U. Kim, M. S. Lee, S. K. Kim, J. M. Kim, M. Yim, D. Y. Yu, and D. S. Lee. 2008. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of phosphoinositide 3-kinase and p38 mitogenactivated protein kinase signal pathways is required for lipopolysaccharide-induced microglial phagocytosis. Biol. Pharm. Bull. 31, 1711-1715. https://doi.org/10.1248/bpb.31.1711
  25. Wu, V. Y. and M. P. Cohen. 1995. Evidence for a ligand receptor system mediating the biologic effects of glycated albumin in glomerular mesangial cells. Biochem. Biophys. Res. Commun. 207, 521-528. https://doi.org/10.1006/bbrc.1995.1219
  26. Wu, V. Y., C. W. Shearman, and M. P. Cohen. 2001. Identification of calnexin as a binding protein for Amadori-modified glycated albumin. Biochem. Biophys. Res. Commun. 284, 602-606. https://doi.org/10.1006/bbrc.2001.4982
  27. Wu, Y. M., D. R. Robinson, and H. J. Kung. 2004. Signal pathways in up-regulation of chemokines by tyrosine kinase MER/NYK in prostate cancer cells. Cancer Res. 64, 7311-7320. https://doi.org/10.1158/0008-5472.CAN-04-0972
  28. Yang, X., D. Coriolan, V. Murthy, K. Schultz, D. T. Golenbock, and D. Beasley. 2005. Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling. Am. J. Physiol. Heart Circ. Physiol. 289, H1069-1076. https://doi.org/10.1152/ajpheart.00143.2005
  29. Yang, X., D. Coriolan, K. Schultz, D. T. Golenbock, and D. Beasley. 2005b. Toll-like receptor 2 mediates persistent chemokine release by Chlamydia pneumoniae-infected vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 25, 2308-2314. https://doi.org/10.1161/01.ATV.0000187468.00675.a3
  30. Yang, X., V. Murthy, K. Schultz, J. B. Tatro, K. A. Fitzgerald, and D. Beasley. 2006. Toll-like receptor 3 signaling evokes a proinflammatory and proliferative phenotype in human vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 291, H2334-2343. https://doi.org/10.1152/ajpheart.00252.2006
  31. Zernecke, A., E. Shagdarsuren, and C. Weber. 2008. Chemokines in atherosclerosis: an update. Arterioscler. Thromb. Vasc. Biol. 28, 1897-1908. https://doi.org/10.1161/ATVBAHA.107.161174
  32. Zuany-Amorim, C., J. Hastewell, and C. Walker. 2002. Toll-like receptors as potential therapeutic targets for multiple diseases. Nat. Rev. Drug Discov. 1, 797-807. https://doi.org/10.1038/nrd914