Interleukin (IL) 6 is one of major
mediators of inflammation, and
IL-6 gene activation during
hypoxia/reoxygenation has been implicated in the pathogenesis of
ischemia/reperfusion injury. However, molecular events involved in
IL-6 gene expression during
hypoxia/reoxygenation remain 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 necrosis factor-alpha. We show here that
hypoxia, but not reoxygenation, induces the activation of
NF-kappa B through the degradation of a major inhibitor of
NF-kappa B,
I kappa B alpha. This
hypoxia-induced
NF-kappa B activation resulted in the kappa B-dependent transcriptional activation of the
IL-6 gene. Interestingly, the time course of
hypoxia-induced
NF-kappa B activation was rather slow as compared with those of
NF-kappa B activation induced by other stimuli, such as IL-1: a significant
NF-kappa B activation was not observed before 1 hr of
hypoxia treatment and persisted for up to 7 hr of
hypoxia treatment. However,
hypoxia-induced
NF-kappa B activation was not inhibited by
cycloheximide, which indicates that
hypoxia directly triggers
NF-kappa B activation. Furthermore, while
hypoxia is unlikely to generate
reactive oxygen intermediates, pretreatment of cells with
antioxidants such as N-acetyl
cysteine 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 oxygen intermediates in
NF-kappa B activation.