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γ-Irradiation-induced DNA damage enhances NO production via NF-κB activation in RAW264.7 cells
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Description
We investigated the mechanism of augmentation of nitric oxide (NO) production in the murine macrophage cell line RAW264.7 after gamma-irradiation. The cells treated with interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) showed enhanced NO production by gamma-irradiation in a dose-dependent manner, accompanying the induction of inducible nitric oxide synthase (iNOS) expression. Nuclear factor kappa B (NF-kappaB) activation was induced 1 h after gamma-irradiation dose-dependently, which was detected by the degradation of I-kappaB. Inhibitors of I-kappaB degradation, MG132 and N(alpha)-p-tosyl-L-lysine chloromethyl ketone (TLCK), suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production, showing that gamma-irradiation induced NO production via NF-kappaB activation. Although NF-kappaB is known to be a redox-sensitive transcription factor, the antioxidant agents N-acetyl-cysteine (NAC) and 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (trolox) showed no suppression and treatment with H(2)O(2) showed only slight enhancement of IFN-gamma-induced NO production. The DNA damaging agents camptothecin and etoposide enhanced IFN-gamma-induced NO production and showed I-kappaB degradation, indicating that the increase in NO production was due to direct DNA damage. Furthermore, 3-aminobenzamide (3AB) and benzamide, inhibitors of poly (ADP-ribose) polymerase (PARP) that are activated upon recognition of DNA strand breaks, suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production and the I-kappaB degradation by gamma-irradiation. We concluded that (1) the increase in NO production was due to direct DNA damage by gamma-irradiation, and that (2) PARP activation through DNA damage induced NF-kappaB activation, leading to iNOS expression and NO production.
Journal
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- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1593 (2-3), 159-167, 2003-02
Elsevier BV
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Keywords
- Lipopolysaccharides
- Time Factors
- Immunoblotting
- Nitric Oxide Synthase Type II
- Nitric Oxide
- NF-κB
- Cell Line
- Interferon-gamma
- Mice
- Animals
- Poly (ADP-ribose) polymerase
- γ-Irradiation
- Molecular Biology
- NF-kappa B
- Nitric oxide
- Cell Biology
- Enzyme Activation
- RAW264.7 cell
- Gamma Rays
- DNA damage
- Nitric Oxide Synthase
- Poly(ADP-ribose) Polymerases
- DNA Damage
- Signal Transduction
Details 詳細情報について
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- CRID
- 1363951794556441600
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- ISSN
- 01674889
- http://id.crossref.org/issn/00052728
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- PubMed
- 12581860
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- Data Source
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- Crossref
- OpenAIRE