Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration.
Oxidative stress is a characteristic of chronic inflammatory diseases. The reactive oxygen intermediate hydrogen peroxide (H(2)O(2)) is an important signaling molecule that modulates gene expression. We have demonstrated that H(2)O(2) significantly enhanced cytokine production in BEAS-2B cells, with a maximal effect at 4h. This did not result from enhanced NF-kappaB activation, but through decreased activity of histone deacetylase (HDAC)2. This results in increased inflammatory gene expression following acetylation of specific histone residues. Decreased HDAC2 activity was associated with tyrosine nitration status. Peroxynitrite and SIN-1, a peroxynitrite generator, were also able to reduce HDAC2 activity via tyrosine nitration. Our data suggest that oxidative stress contributes to worsening inflammation via reduction of HDAC2 activity through HDAC2 nitration. This novel mechanism of inflammation may be important in increasing the severity and chronicity of inflammatory diseases.
Ito
K
K
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
Hanazawa
T
T
Tomita
K
K
Barnes
P J
PJ
Adcock
I M
IM
D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005821:Genetic Techniques; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D030421:Peroxynitrous Acid / Q000494:pharmacology; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism*
D016207:Cytokines; D006657:Histones; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D009566:Nitrates; D012097:Repressor Proteins; D030421:Peroxynitrous Acid; D014443:Tyrosine; D004247:DNA; D006861:Hydrogen Peroxide; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases