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

Authors

Srinivas Mummidi, The University of Texas Rio Grande Valley
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

Document Type

Article

Publication Date

12-2019

Abstract

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.

Comments

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Recommended Citation

Mummidi, S., Das, N. A., Carpenter, A. J., Yoshida, T., Yariswamy, M., Mostany, R., Izadpanah, R., Higashi, Y., Sukhanov, S., Noda, M., Siebenlist, U., Rector, R. S., & Chandrasekar, B. (2019). RECK suppresses interleukin-17/TRAF3IP2-mediated MMP-13 activation and human aortic smooth muscle cell migration and proliferation. Journal of cellular physiology, 234(12), 22242–22259. https://doi.org/10.1002/jcp.28792

Publication Title

Journal of cellular physiology

DOI

10.1002/jcp.28792

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics