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

Abstract

Sustained inflammation and matrix metalloproteinase (MMP) activation contribute to vascular proliferative/occlusive disorders. The proinflammatory cytokine interleukin (IL)‐17 signals mainly via TRAF3 Interacting Protein 2 (TRAF3IP2), an upstream regulator of various transcription factors critical for inflammatory responses, including AP‐1 and NF‐κB. Here we investigated whether IL‐17A/TRAF3IP2 signaling promotes MMP‐13‐dependent human aortic smooth muscle cell (SMC) migration and proliferation, and whether RECK overexpression blunts its mitogenic and migratory potential. Indeed, IL‐17A treatment induced (i) AP‐1, NF‐κB, CREB and p38 MAPK activation, (ii) miR‐21 induction, (iii) miR‐27b and miR‐320 inhibition, (iv) MMP‐13 expression and activation, (v) RECK suppression, and (vi) SMC migration and proliferation, all in a TRAF3IP2‐dependent manner. RECK (REversion‐inducing‐Cysteine‐rich protein with Kazal motifs) is a membrane‐anchored MMP inhibitor, and forced expression of TRAF3IP2 suppressed its expression, but induced MMP‐13 expression and activation. Importantly, forced expression of RECK promoted IL‐17‐mediated MMP‐13/RECK physical association, reduced MMP13 activity and inhibited MMP‐13‐dependent SMC migration and proliferation. Further supporting its causative role in vascular proliferative diseases, addition of recombinant MMP‐13 stimulated SMC migration and proliferation, in part via ERK activation. These results indicate that increased MMP‐13 and decreased RECK contribute to IL‐17A/TRAF3IP2‐mediated 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.Support or Funding InformationVA‐I01‐BX002255IK6BX004016‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.