Calcium-dependent and independent mechanisms of capsaicin receptor (TRPV1)-mediated cytokine production and cell death in human bronchial epithelial cells.
Activation of the capsaicin receptor (VR1 or TRPV1) in bronchial epithelial cells by capsaicinoids and other vanilloids promotes pro-inflammatory cytokine production and cell death. The purpose of this study was to investigate the role of TRPV1-mediated calcium flux from extracellular sources as an initiator of these responses and to define additional cellular pathways that control cell death. TRPV1 antagonists and reduction of calcium concentrations in treatment solutions attenuated calcium flux, induction of interleukin-6 and 8 gene expression, and IL-6 secretion by cells treated with capsaicin or resiniferatoxin. Most TRPV1 antagonists also attenuated cell death, but the relative potency and extent of protection did not directly correlate with inhibition of total calcium flux. Treatment solutions with reduced calcium content or chelators had no effect on cytotoxicity. Inhibitors of arachidonic acid metabolism and cyclo-oxygenases also prevented cell death indicating that TRPV1 agonists disrupted basal arachidonic acid metabolism and altered cyclo-oxygenase function via a TRPV1-dependent mechanism in order to produce toxicity. These data confirm previous results demonstrating calcium flux through TRPV1 acts as a trigger for cytokine production by vanilloids, and provides new mechanistic insights on mechanisms of cell death produced by TRPV1 agonists in respiratory epithelial cells.
Reilly
Christopher A
CA
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
Johansen
Mark E
ME
Lanza
Diane L
DL
Lee
Jeewoo
J
Lim
Ju-Ok
JO
Yost
Garold S
GS
D016718:Arachidonic Acid / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D007473:Ion Channels / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D050916:TRPV Cation Channels
D015850:Interleukin-6; D016209:Interleukin-8; D007473:Ion Channels; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D002211:Capsaicin; D002118:Calcium