Hypoxia, but Not Reoxygenation, Induces Interleukin 6 Gene Expression Through Nf-??B Activation1

Abstract

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.

INHIBITON OF NF-κB ACTIVATION DURING ISCHEMIA REDUCES HEPATIC ISCHEMIA/REPERFUSION INJURY IN RATS

“…Indeed, NF-κB activated by ROS is markedly activated during ischemia, and the inhibition of XOD by the preadministration of allopurinol strongly diminished NF-κB activation (Matsui et al, 2000). Some reports have also revealed that NF-κB was activated during hypoxia, but not reoxygenation (Muraoka et al, 1997;Ricciardi et al, 2000). Moreover, we also demonstrated in this experiment that NF-κB was activated during ischemia, but not after reperfusion (Fig.…”

Role of Oxidants in NF-κB Activation and TNF-α Gene Transcription Induced by Hypoxia and Endotoxin

“…Previous studies have shown that NAC abolishes hypoxia-induced NF-B DNA-binding activity (26). In the present study, the antioxidants NAC (500 M) and PDTC (10 M) abolished NF-B DNA-binding activity and TNF-␣ mRNA levels in J774.1 cells FIGURE 5.…”

“…Hydrogen peroxide exposure can rapidly activate NF-B, and the thiol reductant pyrrolidinedithiocarbamic acid (PDTC), an effective antioxidant, can block NF-B activation in response to LPS, TNF-␣, and active phorbol ester in a number of different cell lines (24,25). The antioxidant N-actylcysteine (NAC) blocks activation of NF-B by hypoxia (26). However, these previous reports did not measure endogenous ROS production or describe the source of ROS generation required for the activation of NF-B by hypoxia or LPS (27).…”

Inhibition of endothelial cell migration through the down‑regulation of MMP-9 by A-kinase anchoring protein 12

“…HIF-1 has not been implicated in the regulation of MMP-9, although some in vitro studies have found this enzyme to be induced by hypoxia (18)(19)(20). The induction of MMP-9 may be due to NF-B induced by hypoxia (21,22). The correlation between HIF-1 and MMP-9 raises the possibility that HIF-1 may have a regulatory role in the expression of MMP-9.…”