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.