title: Hyperthermia promotes and prevents respiratory epithelial apoptosis through distinct mechanisms.
abstract: Hyperthermia has been shown to confer cytoprotection and to augment apoptosis in different experimental models. We analyzed the mechanisms of both effects in the same mouse lung epithelial (MLE) cell line (MLE15). Exposing MLE15 cells to heat shock (HS; 42°C, 2 h) or febrile-range hyperthermia (39.5°C) concurrent with activation of the death receptors, TNF receptor 1 or Fas, greatly accelerated apoptosis, which was detectable within 30 minutes and was associated with accelerated activation of caspase-2, -8, and -10, and the proapoptotic protein, Bcl2-interacting domain (Bid). Caspase-3 activation and cell death were partially blocked by inhibitors targeting all three initiator caspases. Cells expressing the IκB superrepessor were more susceptible than wild-type cells to TNF-α-induced apoptosis at 37°C, but HS and febrile-range hyperthermia still increased apoptosis in these cells. Delaying HS for 3 hours after TNF-α treatment abrogated its proapoptotic effect in wild-type cells, but not in IκB superrepressor-expression cells, suggesting that TNF-α stimulates delayed resistance to the proapoptotic effects of HS through an NF-κB-dependent mechanism. Pre-exposure to 2-hour HS beginning 6 to16 hours before TNF-α treatment or Fas activation reduced apoptosis in MLE15 cells. The antiapoptotic effects of HS pretreatment were reduced in TNF-α-treated embryonic fibroblasts from heat shock factor-1 (HSF1)-deficient mice, but the proapoptotic effects of concurrent HS were preserved. Thus, depending on the temperature and timing relative to death receptor activation, hyperthermia can exert pro- and antiapoptotic effects through distinct mechanisms.
authors.affiliation: Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Nagarsekar
authors.forename: Mohan E
authors.initials: ME
authors.lastname: Tulapurkar
authors.forename: Ishwar S
authors.initials: IS
authors.lastname: Singh
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
authors.forename: Nirav G
authors.initials: NG
authors.lastname: Shah
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D016328:NF-kappa B; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases