Induction of the stress response with prostaglandin A1 increases I-kappaBalpha gene expression.
I-kappaBalpha is an intracellular protein that functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB. Induction of the stress response with heat shock was previously demonstrated to induce I-kappaBalpha gene expression. Because the stress response can also be induced by nonthermal stimuli, we determined whether induction of the stress response with prostaglandin A1 (PGA1) would induce I-kappaBalpha gene expression. Treatment of human bronchial epithelium (BEAS-2B cells) with PGA1 induced nuclear translocation of heat shock factor 1, thus confirming that PGA1 induces the stress response in BEAS-2B cells. Induction of the stress response with PGA1 increased I-kappaBalpha mRNA expression in a time-dependent manner and increased I-kappaBalpha peptide expression. Transient transfection assays involving a human I-kappaBalpha promoter-luciferase reporter construct demonstrated that induction of the stress response with PGA1 activated the I-kappaBalpha promoter. Induction of the stress response with PGA1 and concomitant induction of I-kappaBalpha were associated with inhibition of TNF-alpha-mediated secretion of interleukin 8 and with inhibition of TNF-alpha-mediated nuclear translocation and activation of NF-kappaB. These data demonstrate that induction of the stress response, by a nonthermal stimulus, increases I-kappaBalpha gene expression by a mechanism involving activation of the I-kappaBalpha promoter. Coupled with previous data demonstrating heat shock-mediated induction of I-kappaBalpha gene expression, these data suggest that I-kappaBalpha may be considered to be one of the stress proteins. The functional consequences of stress response-mediated I-kappaBalpha gene expression may involve attenuation of cellular proinflammatory responses.
Thomas
S C
SC
Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.wonghr@chmcc.org
Ryan
M A
MA
Shanley
T P
TP
Wong
H R
HR
D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D011454:Prostaglandins A / Q000633:toxicity*; D013268:Stimulation, Chemical; D013312:Stress, Physiological / Q000139:chemically induced*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011454:Prostaglandins A; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C100573:prostaglandin A1