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Molecular and Cellular Biochemistry

, Volume 148, Issue 1, pp 45–57 | Cite as

Thiol modulation of TNFα and IL-1 induced MnSOD gene expression and activation of NF-κB

  • Kumuda C. Das
  • Yvette Lewis-Molock
  • Carl W. White
Article

Abstract

TNFα and IL-1 each can activate NF-κB 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-κB and potential κB site(s) exist in the MnSOD promoter, the effect of thiols (including NAC, DTT and 2-ME) on TNFα and IL-1 induced activation of NF-κB 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-κB activation and elevated MnSOD expression in response to TNFα or IL-1. Since protease inhibitors TPCK and TLCK can inhibit NF-κB activation, we also investigated the effect of these compounds on MnSOD expression and NF-κB activation. TPCK and TLCK each inhibited MnSOD gene expression and NF-κB activation. Since the MnSOD promoter also contains anAP-1 binding site, the effect of thiols and thiol modifying agents on AP-1 activation was investigated. Thiols had no consistent effect onAP-1 activation. Likewise, some of the thiol modifying compounds inhibited AP-1 activation by TNFα or IL-1, whereas others did not. Since diverse agents had similar effects on activation of NF-κB and MnSOD gene expression, we have demonstrated that activation of NF-κB and MnSOD gene expression are closely associated and that reduced sulfhydryl groups are required for cytokine mediation of both processes.

Key words

manganese superoxide dismutase gene expression hyperoxide lung injury nuclear factor kappa B 

Abbreviations

O2

Superoxide radical

H2O2

Hydrogen peroxide

NAC

N-acetyl L-cysteine

DTT

Dithiothreitol

2-ME

2-Mercaptoethanol

MnSOD

Manganese superoxide dismutase

NF-κB

Nuclear factor kappa B

AP-1

Activator protein-1

NBT

Nitroblue tetrazolium

CAT

Chloramphenicol acetyltransferase

TPCK

N-tosyl-L-phenylalanine chloromethyl ketone

TLCK

Na-p-tosyl-L-lysine chloromethyl ketone

TAME

N-α-p-tosyl-L-arginine methyl ester

NEM

N-ethyl maleimide

DEM

Diethyl maleate

CDNB

1-chloro-2,4-dinitrobenzene

DTTOX

Oxidized dithiothreitol

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Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Kumuda C. Das
    • 1
  • Yvette Lewis-Molock
    • 1
  • Carl W. White
    • 1
  1. 1.Department of PediatricsNational Jewish Center for Immunology and Respiratory MedicineDenverUSA

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