Leukocyte elastase induces lung epithelial apoptosis via a PAR-1-, NF-kappaB-, and p53-dependent pathway.

Abstract:

:Leukocyte elastase induces apoptosis of lung epithelial cells via alterations in mitochondrial permeability, but the signaling pathways regulating this response remain uncertain. Here we investigated the involvement of proteinase-activated receptor-1 (PAR-1), the transcription factor NF-kappaB, and the protooncogene p53 in this pathway. Elastase-induced apoptosis of lung epithelial cells correlated temporally with activation of NF-kappaB, phosphorylation, and nuclear translocation of p53, increased p53 up-regulated modulator of apoptosis (PUMA) expression, and mitochondrial translocation of Bax resulting in enhanced permeability. Elastase-induced apoptosis was also prevented by pharmacologic inhibitors of NF-kappaB and p53 and by short interfering RNA knockdown of PAR-1, p53, or PUMA. These inhibitors prevented elastase-induced PUMA expression, mitochondrial translocation of Bax, increased mitochondrial permeability, and attenuated apoptosis. NF-kappaB inhibitors also reduced p53 phosphorylation. We conclude that elastase-induced apoptosis of lung epithelial cells is mediated by a PAR-1-triggered pathway involving activation of NF-kappaB and p53, and a PUMA- and Bax-dependent increase in mitochondrial permeability leading to activation of distal caspases. Further, p53 contributes to elastase-induced apoptosis by both transcriptional and post-transcriptional mechanisms.

authors

Suzuki T,Yamashita C,Zemans RL,Briones N,Van Linden A,Downey GP

doi

10.1165/rcmb.2008-0157OC

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

742-55

issue

6

eissn

1044-1549

issn

1535-4989

pii

2008-0157OC

journal_volume

41

pub_type

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