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Zinc finger transcription factors as molecular targets for nitric oxide-mediated immunosuppression: inhibition of IL-2 gene expression in murine lymphocytes.

AbstractBACKGROUND:
Nitric oxide (NO) has frequently been shown to display immunosuppressive activities. We describe here a molecular mechanism contributing to this effect.
MATERIALS AND METHODS:
Murine T cell lymphoma EL4-6.1 cells were activated with the physiological stimulus interleukin (IL)-1beta to express IL-2 mRNA in the presence or absence of subtoxic concentrations of the physiological spontaneous NO donor S-nitrosocysteine (SNOC). Subsequently, semiquantitative RT-PCR and gel shift assays with nuclear extracts were performed to analyze the effects of NO on IL-2 mRNA expression and on the activity of the dominant regulating transcription factors Sp1, EGR-1, and NFATc.
RESULTS:
NO inhibits IL-1beta-induced IL-2 mRNA expression in EL4-6.1 cells. The suppressive activity of NO was concentration dependent and found to be completely reversible. Importantly, NO at the concentrations used induced neither apoptosis nor necrosis. Dominant regulation of IL-2 gene expression is known to reside in the zinc finger transcription factors Sp1 or EGR-1 and in the non-zinc finger protein NFAT. NO abrogates the DNA binding activities of recombinant Sp1 and EGR-1. More importantly, gel shift assays also showed a lack of DNA binding of native Sp1 derived from NO-treated nuclear extracts and that from NO-treated viable lymphocytes. This effect is selective, as the DNA binding activity of recombinant NFATc was not affected by NO.
CONCLUSION:
Inactivation of zinc finger transcription factors by NO appears to be a molecular mechanism in the immunosuppressive activity of NO in mammals, thus contributing to NO-mediated inhibition of IL-2 gene expression after physiological stimuli. The exact understanding of the molecular mechanism leading to NO-mediated, fully reversible suppression of immune reactions may lead to use of this naturally occurring tool as an aid in inflammatory diseases.
AuthorsD Berendji, V Kolb-Bachofen, P F Zipfel, C Skerka, C Carlberg, K D Kröncke
JournalMolecular medicine (Cambridge, Mass.) (Mol Med) Vol. 5 Issue 11 Pg. 721-30 (Nov 1999) ISSN: 1076-1551 [Print] UNITED STATES
PMID10656874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Interleukin-1
  • Interleukin-2
  • NFATC Transcription Factors
  • Nitric Oxide Donors
  • Nitroso Compounds
  • Nuclear Proteins
  • RNA, Messenger
  • S-Nitrosothiols
  • Sp1 Transcription Factor
  • Transcription Factors
  • Nitric Oxide
  • S-nitrosocysteine
  • Hydrogen Peroxide
  • Cysteine
Topics
  • Animals
  • Cysteine (analogs & derivatives, pharmacology)
  • DNA, Neoplasm (metabolism)
  • DNA-Binding Proteins (metabolism)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Hydrogen Peroxide (pharmacology)
  • Immunosuppression
  • Interleukin-1 (pharmacology)
  • Interleukin-2 (genetics)
  • Lymphocytes (cytology, drug effects, metabolism)
  • Mice
  • NFATC Transcription Factors
  • Nitric Oxide (physiology)
  • Nitric Oxide Donors (pharmacology)
  • Nitroso Compounds (pharmacology)
  • Nuclear Proteins (metabolism)
  • Protein Binding (drug effects)
  • RNA, Messenger (drug effects, genetics, metabolism)
  • S-Nitrosothiols
  • Sp1 Transcription Factor (metabolism)
  • Transcription Factors (metabolism)
  • Tumor Cells, Cultured
  • Zinc Fingers

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