Role of PKC-α in NF-κB-MT1-MMP-mediated activation of proMMP-2 by TNF-α in pulmonary artery smooth muscle cells.

Abstract:

:We sought to evaluate the mechanism(s) associated with pro matrix metalloprotease 2 (proMMP-2) activation in bovine pulmonary artery smooth muscle cells. Preincubation of cells with anti-TNFR1 antibody prevented tumour necrosis factor-α (TNF-α)-induced proMMP-2 activation and increase in membrane type 1 matrix metalloprotease (MT1-MMP) expression as well as inhibition of tissue inhibitor of metalloproteinase 2 (TIMP-2) expression, indicating the role of TNFR1 receptor during TNF-α stimulation. Anti-MT1-MMP antibody abrogated proMMP-2 activation by TNF-α-stimulated cell membrane, suggesting the involvement of MT1-MMP in proMMP-2 activation. Induction of MT1-MMP expression in response to TNF-α occurs via activation of nuclear factor (NF)-κB on inhibitory κB kinase (IKK) activation and subsequently phosphorylation/degradation of IκB-α. Inhibition of protein kinase C (PKC)-α activity by Go6976 and PKC-α siRNA prevented TNF-α-induced IKK activity, IκB-α phosphorylation/degradation and NF-κB activation. Inhibition of PKC-α activity also prevented TNF-α-induced MT1-MMP expression and proMMP-2 activation as well as down regulation of TIMP-2 expression. Inhibition of IκB-α phosphorylation by PS-1145, an IKK selective inhibitor, prevented TNF-α-induced increase in MT1-MMP expression and proMMP-2 activation, which although did not alter inhibition of TIMP-2 expression. Overall, we unravelled a hitherto unknown mechanism of the involvement of PKC-α in proMMP-2 activation and inhibition of TIMP-2 expression by NF-κB-MT1-MMP-dependent and -independent pathway, respectively, during TNF-α stimulation in pulmonary artery smooth muscle cells.

journal_name

J Biochem

journal_title

Journal of biochemistry

authors

Roy S,Chakraborti T,Chowdhury A,Chakraborti S

doi

10.1093/jb/mvs150

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

289-302

issue

3

eissn

0021-924X

issn

1756-2651

pii

mvs150

journal_volume

153

pub_type

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