Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers.
The eukaryotic transcription factor NF-kappaB 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-kappaB. Here, we show that activation of NF-kappaB 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-kappaB activation by various ER stress-eliciting agents, whereas only antioxidants but not the Ca2+ chelators prevented NF-kappaB activation by the inflammatory cytokine TNF-alpha. 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-kappaB. 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-kappaB 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.
Pahl
H L
HL
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Baeuerle
P A
PA
D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002614:Chelating Agents; D003847:Deoxyglucose / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013312:Stress, Physiological / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000975:Antioxidants; D002614:Chelating Agents; D007211:Indoles; D016328:NF-kappa B; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; D019284:Thapsigargin; D003847:Deoxyglucose; D011493:Protein Kinase C; D000252:Calcium-Transporting ATPases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; C073135:tepoxalin; C000543:cyclopiazonic acid