Activation of NF‐κB by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers

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Abstract
The eukaryotic transcription factor NF-κB is activated by a large variety of stimuli. We have recently shown that ER stress, caused by an aberrant accumulation of membrane proteins within this organelle, also activates NF-κB. Here, we show that activation of NF-κB by ER stress requires an increase in the intracellular levels of both reactive oxygen intermediates (ROIs) and ca2+. Two distinct intracellular Ca2+ chelators and a panel of structurally unrelated antioxidants prevented NF-κB activation by various ER stress-eliciting agents, whereas only antioxidants but not the Ca2+ chelators prevented NF-κB activation by the inflammatory cytokine TNF-α. Consistent with an involvement of calcium, the ER-resident Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid (CPA), which trigger a rapid efflux of Ca2+ from the ER, also potently activated NF-κB. Pretreatment with a Ca2+ chelator abrogated this induction. The Ca2+ chelator BAPTA-AM inhibited ROI formation in response to thapsigargin and CPA treatment, suggesting that the Ca2+ increase preceded ROI formation during NF-κB activation. The selective inhibitory effect of the drug tepoxalin suggests that the peroxidase activity of cyclooxygenases or lipoxygenases was responsible for the increased ROI production in response to Ca2+ release by thapsigargin.