RECK suppresses interleukin-17/TRAF3IP2-mediated MMP-13 activation and human aortic smooth muscle cell migration and proliferation

Srinivas Mummidi, Nitin A. Das, Andrea J. Carpenter, Tadashi Yoshida, Manjunath Yariswamy, Ricardo Mostany, Reza Izadpanah, Yusuke Higashi, Sergiy Sukhanov, Makoto Noda, Ulrich Siebenlist, Randy S. Rector, Bysani Chandrasekar

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Sustained inflammation and matrix metalloproteinase (MMP) activation contribute to vascular occlusive/proliferative disorders. Interleukin-17 (IL-17) is a proinflammatory cytokine that signals mainly via TRAF3 Interacting Protein 2 (TRAF3IP2), an upstream regulator of various critical transcription factors, including AP-1 and NF-κB. Reversion inducing cysteine rich protein with kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Here we investigated whether IL-17A/TRAF3IP2 signaling promotes MMP-13-dependent human aortic smooth muscle cell (SMC) proliferation and migration, and determined whether RECK overexpression blunts these responses. Indeed, IL-17A treatment induced (a) JNK, p38 MAPK, AP-1, NF-κB, and CREB activation, (b) miR-21 induction, (c) miR-27b and miR-320 inhibition, (d) MMP-13 expression and activation, (e) RECK suppression, and (f) SMC migration and proliferation, all in a TRAF3IP2-dependent manner. In fact, gain of TRAG3IP2 function, by itself, induced MMP-13 expression and activation, and RECK suppression. Furthermore, treatment with recombinant MMP-13 stimulated SMC migration in part via ERK activation. Importantly, RECK gain-of-function attenuated MMP-13 activity without affecting its mRNA or protein levels, and inhibited IL-17A- and MMP-13-induced SMC migration. These results indicate that increased MMP-13 and decreased RECK contribute to IL-17A-induced TRAF3IP2-dependent SMC migration and proliferation, and suggest that TRAF3IP2 inhibitors or RECK inducers have the potential to block the progression of neointimal thickening in hyperplastic vascular diseases.

Original languageEnglish (US)
Pages (from-to)22242-22259
Number of pages18
JournalJournal of Cellular Physiology
Issue number12
StatePublished - Dec 2019


  • RECK
  • inflammation
  • matrix metalloproteinases
  • neointima
  • restenosis

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology


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