Induction of CCAAT/enhancer-binding protein–homologous protein by cigarette smoke through the superoxide anion-triggered PERK–eIF2α pathway

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Cigarette smoke triggers apoptosis through oxidative stress- and endoplasmic reticulum (ER) stress-dependent induction of CCAAT/enhancer-binding protein–homologous protein (CHOP) (Tagawa et al., 2008. Free Radic. Biol. Med. 45, 50–59). We investigated roles of individual reactive oxygen/nitrogen species in the transcriptional induction of CHOP by cigarette smoke. Exposure of bronchial epithelial cells to O 2 −, ONOO − or H 2O 2 induced expression of CHOP, whereas NO alone did not. Induction of CHOP mRNA by cigarette smoke extract (CSE) was attenuated by scavengers for O 2 −, ONOO − or NO, whereas scavenging H 2O 2 did not affect the induction of CHOP. Like CSE, O 2 − and ONOO − caused activation of the CHOP gene promoter. Scavengers for O 2 −, ONOO − or NO attenuated CSE-triggered activation of the CHOP gene promoter. CSE, O 2 − and ONOO − induced phosphorylation of protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2α (eIF2α) and caused induction of downstream activating transcription factor 4 (ATF4). Scavengers for O 2 −, ONOO − or NO attenuated induction of ATF4 by CSE. Furthermore, dominant-negative inhibition of the PERK–eIF2α pathway exclusively suppressed CSE-triggered induction of CHOP and consequent apoptosis. These results suggest that O 2 − and ONOO − are selectively involved in CSE-triggered induction of CHOP and that the PERK–eIF2α pathway plays a crucial role in the induction of CHOP and apoptosis downstream of the particular reactive oxygen species.