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Activation of NF‐κB by ER stress requires both Ca 2+ and reactive oxygen intermediates as messengers
Author(s) -
Pahl Heike L.,
Baeuerle Patrick A.
Publication year - 1996
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(96)00800-9
Subject(s) - thapsigargin , cyclopiazonic acid , chemistry , reactive oxygen species , intracellular , second messenger system , unfolded protein response , biochemistry , microbiology and biotechnology , endoplasmic reticulum , biology
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 ca 2+ . Two distinct intracellular Ca 2+ chelators and a panel of structurally unrelated antioxidants prevented NF‐κB activation by various ER stress‐eliciting agents, whereas only antioxidants but not the Ca 2+ chelators prevented NF‐κB activation by the inflammatory cytokine TNF‐α. Consistent with an involvement of calcium, the ER‐resident Ca 2+ ‐ATPase inhibitors thapsigargin and cyclopiazonic acid (CPA), which trigger a rapid efflux of Ca 2+ from the ER, also potently activated NF‐κB. Pretreatment with a Ca 2+ chelator abrogated this induction. The Ca 2+ chelator BAPTA‐AM inhibited ROI formation in response to thapsigargin and CPA treatment, suggesting that the Ca 2+ 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 Ca 2+ release by thapsigargin.