Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Roles of TLR-4 and NF-κB in Interleukin-6 Expression Induced by Heat Shock Protein 90 in Vascular Smooth Muscle Cells

혈관평활근세포에서 HSP90에 의한 IL-6 발현에 TLR-4와 NF-κB의 작용

  • Rhim, Byung-Yong (Department of Pharmacology, School of Medicine - Pusan National University) ;
  • Kim, Kang-Seong (Department of Pharmacology, School of Medicine - Pusan National University) ;
  • Kim, Koan-Hoi (Department of Pharmacology, School of Medicine - Pusan National University)
  • 임병용 (부산대학교 의학전문대학원 약리학교실) ;
  • 김강성 (부산대학교 의학전문대학원 약리학교실) ;
  • 김관회 (부산대학교 의학전문대학원 약리학교실)
  • Published : 2008.12.30
Download PDF
⟨ Previous Next ⟩

Abstract

This study has investigated whether extracellular HSP90 predisposes vascular smooth muscle cells (VSMCs) to pro-inflammatory phenotype. Exposure of rat aortic smooth muscle cells to HSP90 not only enhanced IL-6 release but also profoundly induced IL-6 transcript via promoter activation. HSP90-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-3 and TIR-domain-containing adapter-inducing interferon-${\beta}$ (TRIF). Curcumin, which inhibits dimerization of TLR-4, also attenuated the IL-6 induction by HSP90. Mutation at the NF-${\kappa}B$- or C/EBP-binding site in the IL-6 promoter region suppressed the promoter activation in response to HSP90. The gene delivery of $I{\kappa}B$ using recombinant adenoviruses and treatment with resveratrol, which inhibit NF-${\kappa}B$ activity, attenuated the HSP90-induced IL-6 release from VSMCs. The present study proposes that extracellular HSP90 would contribute to inflammatory reaction in the stressed vasculature by inducing IL-6 in VSMCs, and that TLR-4 and NF-${\kappa}B$ would play active roles in the process.

HSP90에 노출된 혈관평활근세포에서 IL-6 transcript가 증가하고, IL-6 단백질의 분비가 증가하며, 또한 IL-6 유전자의 promote가 활성화되었다. HSP90에 의한 IL-6 유전자의 promoter 활성화는 dominant negative 형태의 TLR-4와 MyD88에 의하여 크게 감소되었지만, dominant negative 형태의 TLR-3와 TRIF의 영향을 받지 않았다. 그리고 TLR-4의 이합체화(dimerization)를 저해하는 curcumin은 HSP90에 의한 IL-6의 분비 및 IL-6 유전자 promoter 활성화를 억제하였다. 그리고 IL-6 유전자의 promoter의 NF-${\kappa}B$- 또는 C/EBP-binding sequence에 변이는 HSP90에 의한 IL-6 유전자의 promoter 활성화 억제하였다. 이러한 결과는 혈관평활근세포에서 HSP90에 의한 IL-6 유전자 활성화에 TLR-4와 NF-${\kappa}B$B가 관여함을 의미한다.

Keywords

References

  1. Akira, S. and K Takeda. 2004. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499-511 https://doi.org/10.1038/nri1391
  2. Basu, S., R. J. Binder, R. Suto, K M. Anderson and P. K. Srivastava. 2000. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int. Immunol. 12, 1539-1546 https://doi.org/10.1093/intimm/12.11.1539
  3. 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
  4. 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
  5. 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
  6. Ikeda, D., M. Ikeda, T. Oohara, A Oguchi, T. Kamitani, Y. Tsuruya and S. Kano. 1991. Interleukin 6 stimulates growth of vascular smooth muscle cells in a PDGF-dependent manner. Am. J. Physiol. 260, H1713-1717
  7. Kanwar, R. K, J. R. Kanwar, D. Wang, D. J. Ormrod. and G. W. Krissansen. 2001. Temporal expression of heat shock proteins 60 and 70 at lesion-prone sites during atherogenesis in ApoE-deficient mice. Arterioscler. Thromb. Vasco BioI. 21, 1991-1997 https://doi.org/10.1161/hq1201.100263
  8. Kawai, T. and S. Akira. 2005. Toll-like receptor downstream signaling. Arthritis Res. Ther. 7, 12-19 https://doi.org/10.1186/ar1469
  9. Kishimoto, T. and T. Hirano. 1988. Molecular regulation of B lymphocyte response. Annu Rev. Immunol. 6, 485-512 https://doi.org/10.1146/annurev.iy.06.040188.002413
  10. Lee, W. Y., M. A Allison, D. J. Kim, C. H. Song and E. Barrett-Connor. 2007. Association of interleukin-6 and C-reactive protein with subclinical carotid atherosclerosis (the Rancho Bernardo Study). Am. J. Cardiol. 99, 99-102 https://doi.org/10.1016/j.amjcard.2006.07.070
  11. Liao, D. F., Z. G. Jin, A S. Baas, G. Daum, S. P. Gygi, R. Aebersold and B. C. Berk. 2000. Purification and identification of secreted oxidative stress-induced factors from vascular smooth muscle cells. J. BioI. Chem. 275, 189-196 https://doi.org/10.1074/jbc.275.1.189
  12. Libby, P. 2002. Inflammation in atherosclerosis. Nature 420, 868-874 https://doi.org/10.1038/nature01323
  13. Libby, P., P. M. Ridker and A. Maseri. 2002. Inflammation and atherosclerosis. Circulation 105, 1135-1143 https://doi.org/10.1161/hc0902.104353
  14. Liu, Z., N. Dronadula and G. N. Rao. 2004. A novel role for nuclear factor of activated T cells in receptor tyrosine kinase and G protein-coupled receptor agonist-induced vascular smooth muscle cell motility. J. BioI. Chem. 279, 41218-41226 https://doi.org/10.1074/jbc.M406917200
  15. 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
  16. Pockley, A. G. 2003. Heat shock proteins as regulators of the immune response. Lancet 362, 469-476. https://doi.org/10.1016/S0140-6736(03)14075-5
  17. Roth, M., M. Nauck, M. Tamm, A. P. Perruchoud, R. Ziesche and L. H. Block. 1995. Intracellular interleukin 6 mediates platelet-derived growth factor-induced proliferation of nontransformed cells. Proc. Natl. Acad. Sci. U. S. A. 92, 1312-1316 https://doi.org/10.1073/pnas.92.5.1312
  18. Rus, H. G., R. Vlaicu and F. Niculescu. 1996. Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 127, 263-271 https://doi.org/10.1016/S0021-9150(96)05968-0
  19. Srivastava, P. 2002. Roles of heat-shock proteins in innate and adaptive immunity. Nat. Rev. Immunol. 2, 185-194 https://doi.org/10.1038/nri749
  20. Tedgui, A. and Z. Mallat. 2006. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol. Rev. 86, 515-581 https://doi.org/10.1152/physrev.00024.2005
  21. Whitley, D., S. P. Goldberg and W. D. Jordan. 1999. Heat shock proteins: a review of the molecular chaperones. J. Vasco Surg. 29, 748-751 https://doi.org/10.1016/S0741-5214(99)70329-0
  22. 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
  23. Yang, X., D. Coriolan, V. Murthy, K. Schultz, D. T. Golenbock and D. Beasley. 2005. Pro-inflammatory 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
  24. Yang, X., V. Murthy, K. Schultz, J. B. Tatro, K. A Fitzgerald and D. Beasley. 2006. Toll-like receptor 3 signaling evokes a pro-inflammatory 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
  25. Youn, H. S., J. Y. Lee, K. A Fitzgerald, H. A. Young, S. Akira and D. H. Hwang. 2005. Specific inhibition of MyD88-independent signaling pathways of TLR-3 and TLR-4 by resveratrol: molecular targets are TBK1 and RIP1 in TRIF complex. J. Immunol. 175, 3339-3346 https://doi.org/10.4049/jimmunol.175.5.3339
  26. Youn, H. S., S. I. Saitoh, K. Miyake and D. H. Hwang. 2006. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem. Pharmacol. 72, 62-69 https://doi.org/10.1016/j.bcp.2006.03.022
  27. Yudkin, J. S., M. Kumari, S. E. Humphries and V. Mohamed-Ali. 2000. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148, 209-214 https://doi.org/10.1016/S0021-9150(99)00463-3
  28. Zampetaki, A, Z. Zhang, Y. Hu and Q. XU. 2005. Biomechanical stress induces IL-6 expression in smooth muscle cells via Ras/Rac1-p38 MAPK-NF-kappaB signaling pathways. Am. J. Physiol. Heart Circ. Physiol. 288, H2946-2954 https://doi.org/10.1152/ajpheart.00919.2004
  29. Zhou, L G. H. Werstuck, S. Lhotak, A. B. de Koning, S. K. Sood, G. S. Hossain, J. Moller, M. Ritskes-Hoitinga, E. Falk and S. Dayal. 2004. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation 110, 207-213 https://doi.org/10.1161/01.CIR.0000134487.51510.97