INDUCTION OF THE STRESS-RESPONSE WITH PROSTAGLANDIN A(1) INCREASES I-KAPPA-B-ALPHA GENE-EXPRESSION

I-kappa B alpha is an intracellular protein that functions as a primar y inhibitor of the proinflammatory transcription factor NF-KB. Inducti on of the stress response with heat shock was previously demonstrated to induce I-kappa B alpha gene expression. Because the stress response can also be induced by nonthermal stimuli, we determined whether indu ction of the stress response with prostaglandin A(1) (PGA(1)) would in duce I-kappa B alpha gene expression. Treatment of human bronchial epi thelium (BEAS-2B cells) with PGA(1) induced nuclear translocation of h eat shock factor 1, thus confirming that PGA(1) induces the stress res ponse in BEAS-2B cells. Induction of the stress response with PGA(1) i ncreased I-kappa B alpha mRNA expression in a time-dependent manner an d increased I-kappa B alpha peptide expression. Transient transfection assays involving a human I-kappa B alpha promoter-luciferase reporter construct demonstrated that induction of the stress response with PGA 1 activated the I-kappa B alpha promoter. Induction of the stress resp onse with PGA1 and concomitant induction of I-kappa B alpha were assoc iated with inhibition of TNF-alpha-mediated secretion of interleukin 8 and with inhibition of TNF-alpha-mediated nuclear translocation and a ctivation of NF-kappa B. These data demonstrate that induction of the stress response, by a nonthermal stimulus, increases I-kappa B alpha g ene expression by a mechanism involving activation of the I-kappa B al pha promoter. Coupled with previous data demonstrating heat shock-medi ated induction of I-kappa B alpha gene expression, these data suggest that I-kappa B alpha may be considered to be one of the stress protein s. The functional consequences of stress response-mediated I-kappa B a lpha gene expression may involve attenuation of cellular proinflammato ry responses.