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. 2009 Dec;29(8):1161-8.
doi: 10.1007/s10571-009-9409-z.

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-kappaB and AP-1 activation

Gao Cheng  1 , Liu Wei, Wang Xiurong, Liu Xiangzhen, Zhao Shiguang, Fu Songbin
Affiliations

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-kappaB and AP-1 activation

Gao Cheng et al. Cell Mol Neurobiol. 2009 Dec.

Abstract

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-kappaB 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.

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Figures

Fig. 1
Fig. 1
IL-17 stimulates MMP-9 expression in CAVSMC. a Expression of IL-17RA was detected by RT-PCR in CAVSMC. b Dose-dependent manner of MMP-9 expression induced by IL-17. c Time-dependent manner of MMP-9 expression induced by IL-17. d Anti-IL-17 and IL-17RA neutralizing antibody attenuated mRNA expression of MMP-9. (*, P < 0.05 versus IL-17 group, AVONA)
Fig. 2
Fig. 2
MMP-9 expression was independent of IL-1β, IL-6 and TNF-α. a MMP-9 expression blocked by anti-1L-17 and IL-17RA neutralizing antibody. b No obvious influence on MMP-9 expression was observed by neutralizing antibody which targets IL-1β, IL-6 and TNF-α
Fig. 3
Fig. 3
IL-17-induced MMP-9 expression was dependent on NF-kB and AP-1. a Act D, while not CHX, inhibited IL-17 induced MMP-9 mRNA expression. b Nuclear transport of NF-kB and C-Jun was obtained with IL-17 stimulation. c Inhibition of NF-kB and AP-1 reduced expression of MMP-9 mRNA. (*, P < 0.05 versus IL-17 group, AVONA)
Fig. 4
Fig. 4
Role of p38 MAPK and ERK1/2 in TF activation and MMP-9 expression. a IL-17-induced activation of p38 MAPK and ERK1/2 was blunted by SB-203580 and PD-98059, respectively. b Nuclear transport of TF induced by IL-17 was blocked by SB-203580 and PD-98059, respectively. c mRNA expression of MMP-9 was attenuated by MAPK inhibitors (*, P < 0.05 versus IL-17 group, AVONA)
Fig. 5
Fig. 5
Role of IL-17 in migration of CAVSMC. a IL-17 induced migration of CAVASMC was independent of IL-1β, IL-6 and TNF-α. Anti-1L-17 and IL-17RA neutralizing antibody reduced the cell migration stimulated by IL-17. b MMP inhibitor (GM-6001) and siRNA targeting MMP2/9 reduced the IL-17-induced cell migration. The effects of inhibition of MMP-9 was more pronounced than that of MMP-2. (*, P < 0.05 versus IL-17 group. #, P < 0.05 versus MMP-9 group, AVONA)
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