Steroids and histone deacetylase in ventilation-induced gene transcription.
Histone acetylation and deacetylation promote and repress gene transcription, respectively. Recruitment of histone deacetylases (HDAC) to sites of inflammatory gene transcription has been proposed to explain part of the anti-inflammatory activity of steroids. To examine whether this concept extends to other inflammatory conditions, the current authors investigated the role of histone acetylation and the effects of steroids on the ventilation-induced induction of pro-inflammatory genes. Isolated perfused mouse lungs were ventilated for 180 min with low peak inspiratory pressure of 10 cmH(2)O or high peak inspiratory pressure of 22.5 cmH(2)O (overventilation) and treated with the HDAC inhibitor trichostatin A (TSA), the steroid dexamethasone or both. Overventilation increased histone acetylation at H4K12, as well as gene and protein expression of tumour necrosis factor (TNF), macrophage inflammatory protein (MIP)-2alpha and interleukin (IL)-6; these effects were reversed by dexamethasone. In the presence or absence of dexamethasone, TSA enhanced overventilation-induced induction of TNF and MIP-2alpha, but decreased that of IL-6, indicating that the effects of HDAC are gene dependent. Thus, H4K12 acetylation and its regulation by steroids may be relevant for inflammatory gene transcription during overventilation. Histone deacetylases appear to play an important gene-dependent regulatory role in this process, with the caveat that histones are not the only substrates of histone deacetylase isoenzymes.
Dombrowsky
H
H
Division of Pulmonary Pharmacology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
Uhlig
S
S
D000107:Acetylation; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015151:Immunoblotting; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016016:Proportional Hazards Models; D012121:Respiration, Artificial; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D054426:Chemokine CXCL2; D006877:Hydroxamic Acids; D015850:Interleukin-6; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C012589:trichostatin A; D003907:Dexamethasone; D006655:Histone Deacetylases