Anti-apoptotic effects of Z alpha-1 antitrypsin in human bronchial epithelial cells

¹ Dept of Medicine, Respiratory Research Division, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and Both authors contributed equally to this work.
² Dept of Medicine, Respiratory Research Division, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland
³ Current address: Centre for Infection and Immunity, Whitla Medical Building, Queen's University Belfast

^* To whom correspondence should be addressed. E-mail: cmgreene{at}rcsi.ie.

	Abstract

Z alpha-1 antitrypsin (AAT) deficiency is a genetic disease, which manifests as early-onset emphysema or liver disease. Although the majority of AAT is produced by the liver, it is also produced, amongst others, by bronchial epithelial cells in the lung. Here, we investigate the effects of ZAAT expression on apoptosis in a human bronchial epithelial cell line (16HBE14o-) and delineate mechanisms involved.

Control, MAAT- or ZAAT-expressing cells were assessed for apoptosis, caspase-3 activity, cell viability, phosphorylation of Bad, NFB activation and induced expression of a selection of pro- and anti-apoptotic genes.

Expression of ZAAT in 16HBE14o- cells, like MAAT, inhibited basal and agonist-induced apoptosis. ZAAT expression also inhibited caspase-3 activity by 57% compared to control cells (p=0.05) and was a more potent inhibitor than MAAT. Whilst ZAAT had no effect on activity of Bad, its expression activated NFB-dependent gene expression above control or MAAT-expressing cells. In 16HBE14o- cells but not HEK293 cells, ZAAT up regulated expression of cIAP-1 an upstream regulator of NFB. cIAP1 expression was increased in ZAAT versus MAAT bronchial biopsies.

The data suggest a novel mechanism by which ZAAT may promote human bronchial epithelial cell survival.

Keywords:  Apoptosis, caspase-3, cIAP1, NFB, Z alpha-1 antitrypsin