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Thiol modulation of TNF alpha and IL-1 induced MnSOD gene expression and activation of NF-kappa B.

TNF alpha and IL-1 each can activate NF-kappa B and induce gene expression of manganese superoxide dismutase (MnSOD), a mitochondrial matrix enzyme which can provide critical protection against hyperoxic lung injury. The regulation of MnSOD gene expression is not well understood. Since redox status can modulate NF-kappa B and potential kappa B site(s) exist in the MnSOD promoter, the effect of thiols (including NAC, DTT and 2-ME) on TNF alpha and IL-1 induced activation of NF-kappa B and MnSOD gene expression was investigated. Activation of NF-kB and increased MnSOD expression were potentiated by thiol reducing agents. In contrast, thiol oxidizing or alkylating agents inhibited both NF-kappa B activation and elevated MnSOD expression in response to TNF alpha or IL-1. Since protease inhibitors TPCK and TLCK can inhibit NF-kappa activation, we also investigated the effect of these compounds on MnSOD expression and NF-kappa B activation. TPCK and TLCK each inhibited MnSOD gene expression and NF-kappa B activation. Since the MnSOD promoter also contains an AP-1 binding site, the effect of thiols and thiol modifying agents on AP-1 activation was investigated. Thiols had no consistent effect on AP-1 activation. Likewise, some of the thiol modifying compounds inhibited AP-1 activation by TNF alpha or IL-1, whereas others did not. Since diverse agents had similar effects on activation of NF-kappa B and MnSOD gene expression, we have demonstrated that activation of NF-kappa B and MnSOD gene expression are closely associated and that reduced sulfhydryl groups are required for cytokine mediation of both processes.