IL-17 Stimulates Migration of Carotid Artery Vascular Smooth Muscle Cells in an MMP-9 Dependent Manner via p38 MAPK and ERK1/2-Dependent NF-κB and AP-1 Activation

  • Gao ChengEmail author
  • Liu Wei
  • Wang Xiurong
  • Liu Xiangzhen
  • Zhao Shiguang
  • Fu Songbin
Original Paper


Inappropriate vascular remodeling is thought to be the main cause of restenosis following angioplasty. Migration of vascular smooth muscle cells (VSMC) into lumina, which is promoted by degradation of the extracellular matrix by matrix metalloproteinases (MMPs) plays a causal role in pathological vascular remodeling. The aim of the present research is to explore the effects of a novel cytokine, IL-17, on migration of VSMC and MMP-9 secretion. Carotid artery VSMC was isolated from Sprague–Dawley rats. Expression of MMP-9 and cell migration induced by IL-17 and its related signal pathway were detected. The results showed that IL-17-induced migration of VSMC in an MMP-9-dependent manner. IL-17-induced MMP-9 expression was via p38 MAPK and ERK1/2 dependent NF-κB and AP-1 activation. The present results demonstrated that IL-17 may play a role in vascular remodeling and targeting IL-17 or its specific downstream mediators is a potentially novel therapeutic pathway for attenuating the post-angioplastic restenosis.


Vascular remodeling IL-17 MMP-9 Restenosis 



We would like to express our appreciations to Sun Zhidan for his excellent technical assistance and Li Wen for her revision of the draft. This research was sponsored partly by the Heilongjiang Youth Fund (QC07C100) and Special Fund of The First Affiliated Hospital of Harbin Medical University (2007035).


  1. Bettelli E, Oukka M, Kuchroo VK (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8:345–350. doi: 10.1038/ni0407-345 CrossRefPubMedGoogle Scholar
  2. Chandrasekar B, Mummidi S, Mahimainathan L, Patel DN, Bailey SR, Imam SZ, Greene WC, Valente AJ (2006) Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kappaB- and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatin. J Biol Chem 281:15099–15109. doi: 10.1074/jbc.M600200200 CrossRefPubMedGoogle Scholar
  3. Cho A, Reidy MA (2002) Matrix metalloproteinase-9 is necessary for the regulation of smooth muscle cell replication and migration after arterial injury. Circ Res 91:845–851. doi: 10.1161/01.RES.0000040420.17366.2E CrossRefPubMedGoogle Scholar
  4. Cortez DM, Feldman MD, Mummidi S, Valente AJ, Steffensen B, Vincenti M, Barnes JL, Chandrasekar B (2007) IL-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK- and ERK1/2-dependent C/EBP-beta, NF-kappaB, and AP-1 activation. Am J Physiol Heart Circ Physiol 293:H3356–H3365. doi: 10.1152/ajpheart.00928.2007 CrossRefPubMedGoogle Scholar
  5. Eberhardt W, Huwiler A, Beck KF, Walpen S, Pfeilschifter J (2000) Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. J Immunol 165:5788–5797PubMedGoogle Scholar
  6. Galis ZS, Khatri JJ (2002) Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90:251–262PubMedGoogle Scholar
  7. Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior RM, Ivan E (2002) Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res 91:852–859. doi: 10.1161/01.RES.0000041036.86977.14 CrossRefPubMedGoogle Scholar
  8. Gibbons GH, Dzau VJ (1994) The emerging concept of vascular remodeling. N Engl J Med 330:1431–1438. doi: 10.1056/NEJM199405193302008 CrossRefPubMedGoogle Scholar
  9. Hashmi S, Zeng QT (2006) Role of interleukin-17 and interleukin-17-induced cytokines interleukin-6 and interleukin-8 in unstable coronary artery disease. Coron Artery Dis 17:699–706. doi: 10.1097/01.mca.0000236288.94553.b4 CrossRefPubMedGoogle Scholar
  10. Ikeda U, Shimada K (2003) Matrix metalloproteinases and coronary artery diseases. Clin Cardiol 26:55–59. doi: 10.1002/clc.4960260203 CrossRefPubMedGoogle Scholar
  11. Liang KC, Lee CW, Lin WN, Lin CC, Wu CB, Luo SF, Yang CM (2007) Interleukin-1beta induces MMP-9 expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear factor-kappaB signaling pathways in human tracheal smooth muscle cells. J Cell Physiol 211:759–770. doi: 10.1002/jcp.20992 CrossRefPubMedGoogle Scholar
  12. Mnjoyan ZH, Doan D, Brandon JL, Felix K, Sitter CL, Rege AA, Brock TA, Fujise K (2008) The critical role of the intrinsic VSMC proliferation and death programs in injury-induced neointimal hyperplasia. Am J Physiol Heart Circ Physiol 294:H2276–H2284. doi: 10.1152/ajpheart.91527.2007 CrossRefPubMedGoogle Scholar
  13. Moon SK, Cha BY, Kim CH (2004) ERK1/2 mediates TNF-alpha-induced matrix metalloproteinase-9 expression in human vascular smooth muscle cells via the regulation of NF-kappaB and AP-1: Involvement of the ras dependent pathway. J Cell Physiol 198:417–427. doi: 10.1002/jcp.10435 CrossRefPubMedGoogle Scholar
  14. Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14:155–174. doi: 10.1016/S1359-6101(03)00002-9 CrossRefPubMedGoogle Scholar
  15. Patel DN, King CA, Bailey SR, Holt JW, Venkatachalam K, Agrawal A, Valente AJ, Chandrasekar B (2007) Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem 282:27229–27238. doi: 10.1074/jbc.M703250200 CrossRefPubMedGoogle Scholar
  16. Rahman MS, Yamasaki A, Yang J, Shan L, Halayko AJ, Gounni AS (2006) IL-17A induces eotaxin-1/CC chemokine ligand 11 expression in human airway smooth muscle cells: role of MAPK (Erk1/2, JNK, and p38) pathways. J Immunol 177:4064–4071PubMedGoogle Scholar
  17. Ross R (1999a) Atherosclerosis is an inflammatory disease. Am Heart J 138:S419–S420. doi: 10.1016/S0002-8703(99)70266-8 CrossRefPubMedGoogle Scholar
  18. Ross R (1999b) Atherosclerosis–an inflammatory disease. N Engl J Med 340:115–126. doi: 10.1056/NEJM199901143400207 CrossRefPubMedGoogle Scholar
  19. Schwartz SM (1997) Perspectives series: cell adhesion in vascular biology. Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest 99:2814–2816. doi: 10.1172/JCI119472 CrossRefPubMedGoogle Scholar
  20. Shen F, Hu Z, Goswami J, Gaffen SL (2006) Identification of common transcriptional regulatory elements in interleukin-17 target genes. J Biol Chem 281:24138–24148. doi: 10.1074/jbc.M604597200 CrossRefPubMedGoogle Scholar
  21. Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, Cohen JI, Spriggs MK (1995) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3:811–821. doi: 10.1016/1074-7613(95)90070-5 CrossRefPubMedGoogle Scholar
  22. Yao JS, Zhai W, Fan Y, Lawton MT, Barbaro NM, Young WL, Yang GY (2007) Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells. J Cereb Blood Flow Metab 27:510–520. doi: 10.1038/sj.jcbfm.9600365 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Gao Cheng
    • 1
    Email author
  • Liu Wei
    • 2
  • Wang Xiurong
    • 3
  • Liu Xiangzhen
    • 1
  • Zhao Shiguang
    • 1
  • Fu Songbin
    • 4
  1. 1.Department of NeurosurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Department of CardiologyThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
  3. 3.Harbin Veterinary Institute Key Laboratory of Ministry of Agriculture of ChinaHarbinChina
  4. 4.Department of GeneticsHarbin Medical UniversityHarbinChina

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