STRESS-RESPONSE DECREASES NF-KAPPA-B NUCLEAR TRANSLOCATION AND INCREASES I-KAPPA-B-ALPHA EXPRESSION IN A549 CELLS

The stress response and stress proteins confer protection against dive rse forms of cellular and tissue injury, including acute lung injury. The stress response can inhibit nonstress protein gene expression, the refore transcriptional inhibition of proinflammatory responses could b e a mechanism of protection against acute lung injury. To explore this possibility, we determined the effects of the stress response on nucl ear translocation of the transcription factor NF-kappa B, an important regulator of proinflammatory gene expression. In A549 cells induction of the stress response decreased tumor necrosis factor-alpha (TNF-alp ha)-mediated NF-kappa B nuclear translocation. TNF-alpha initiates NF- kappa B nuclear translocation by causing dissociation of the inhibitor y protein I-kappa B alpha from NF-kappa B and rapid degradation of I-k appa B alpha. Prior induction of the stress response inhibited TNF-alp ha-mediated dissociation of I-kappa B alpha from NF-kappa B and subseq uent degradation of I-kappa B alpha. Induction of the stress response also increased expression of I-kappa B alpha. We conclude that the str ess response affects NF-kappa B-mediated gene regulation by two indepe ndent mechanisms. The stress response stabilizes I-kappa B alpha and i nduces expression of I-kappa B alpha. The composite result of these tw o effects is to decrease NF-kappa B nuclear translocation. We speculat e that the protective effect of the stress response against acute lung injury involves a similar effect on the I-kappa B/NF-kappa B pathway.