HYPOXIA, BUT NOT REOXYGENATION, INDUCES INTERLEUKIN-6 GENE-EXPRESSIONTHROUGH NF-KAPPA-B ACTIVATION

Interleukin (IL) 6 is one of major mediators of inflammation, and IL-6 gene activation during hypoxia/reoxygenation has been implicated in t he pathogenesis of ischemia/reperfusion injury. However, molecular eve nts involved in IL-6 gene expression during hypoxia/reoxygenation rema in to be identified. We have previously shown that NF-kappa B plays an essential and indispensable role in the transcriptional activation of the IL-6 gene induced by various stimuli, including IL-1 and tumor ne crosis factor-alpha. We show here that hypoxia, but not reoxygenation, induces the activation of NF-kappa B through the degradation of a maj or inhibitor of NF-kappa B, I kappa B alpha. This hypoxia-induced NF-k appa B activation resulted in the KB-dependent transcriptional activat ion of the IL-6 gene. Interestingly, the time course of hypoxia-induce d NF-kappa B activation was rather slow as compared with those of NF-k appa B activation induced by other stimuli, such as IL-1: a significan t NF-kappa B activation was not observed before 1 hr of hypoxia treatm ent and persisted for up to 7 hr of hypoxia treatment. However, hypoxi a-induced NF-kappa B activation was not inhibited by cycloheximide, wh ich indicates that hypoxia directly triggers NF-kappa B activation. Fu rthermore, while hypoxia is unlikely to generate reactive oxygene inte rmediates, pretreatment of cells with antioxidants such as N-acetyl cy steine and alpha-tocopherol inhibited NF-kappa B activation induced by hypoxia. Thus, we discuss possible implications of these results for a postulated role of reactive oxygene intermediates in NF-kappa B acti vation.