Steroids and histone deacetylase in ventilation-induced gene transcription

¹ Division of Pulmonary Pharmacology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany
² Division of Pulmonary Pharmacology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany; and Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany.

^* To whom correspondence should be addressed. E-mail: suhlig{at}ukaachen.de.

	Abstract

Histone acetylation promotes and deacetylation represses gene transcription. 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, we investigated the role of histone acetylation and the effects of steroids on the venti-la-tion-induced induction of pro-inflammatory genes.

Isolated perfused mouse lungs were ventilated for 180 min with low peak inspiratory pressure of 10 cm H₂O or high peak inspiratory pressure of 25 cm H₂O (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 TNF, MIP-2 and IL-6; these effects were reversed by dexamethasone. With or without dexamethasone, TSA enhanced overventilation-induced induction of TNF and MIP-2, 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. HDACs appear to play an important gene-dependent regulatory role in this process, with the caveat that histones are not the only substrates of HDAC isoenzymes.

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