Abstract
BackgroundThe key co-repressor complex components HDAC-2, Mi-2α/β and mSin3a are all critical to the regulation of gene transcription. HDAC-2 function is impaired by oxidative stress in a PI3Kδ dependant manner which may be involved in the chronic glucocorticoid insensitive inflammation in the lungs of COPD patients. However, the impact of cigarette smoke exposure on the expression of mSin3a and Mi2α/β and their role in glucocorticoid responsiveness is unknown.MethodsWild type, PI3Kγ knock-out (PI3Kγ-/-) and PI3K kinase dead knock-in (PI3KδD910/A910) transgenic mice were exposed to cigarette smoke for 3 days and the expression levels of the co-repressor complex components HDAC-2, mSin3a, Mi-2α and Mi-2β and HDAC-2 activity in the lungs were assessed.ResultsCigarette smoke exposure impaired glucocorticoid function and reduced HDAC-2 activity which was protected in the PI3KδD910/A910 mice. Both mSin3a and Mi-2α protein expression was reduced in smoke-exposed mice. Budesonide alone protected mSin3a protein expression with no additional effect seen with abrogation of PI3Kγ/δ activity, however Mi-2α, but not Mi-2β, expression was protected in both PI3KδD910/A910 and PI3Kγ-/- budesonide-treated smoke-exposed mice. The restoration of glucocorticoid function coincided with the protection of both HDAC activity and mSin3a and Mi-2α protein expression.ConclusionsCigarette smoke exposure induced glucocorticoid insensitivity and alters co-repressor activity and expression which is prevented by blockade of PI3K signaling with glucocorticoid treatment. Inhibition of PI3Kδ signalling in combination with glucocorticoid treatment may therefore provide a therapeutic strategy for restoring oxidant-induced glucocortiocid unresponsiveness.
Highlights
Gene transcription is tightly regulated by a highly complex and dynamic set of processes central to which is the recruitment of co-repressors to promoter bound sequence specific transcription factors [1,2,3]
In this study we look at the impact of cigarette smoke exposure on the expression of HDAC-2, mammalian Sin3a (mSin3a) and Mi2α/β in the lungs of mice
Cigarette smoke-mediated reduction in HDAC-2 activity but not expression is associated with relative glucocorticoid insensitive inflammation in the lungs
Summary
Gene transcription is tightly regulated by a highly complex and dynamic set of processes central to which is the recruitment of co-repressors to promoter bound sequence specific transcription factors [1,2,3]. Two of the major co-repressor complexes in mammalian cells are the mammalian Sin3a (mSin3a) and Mi-2/nucleosome remodelling and deacetylase (NuRD) complex, both of. Both the mSin3a and Mi-2/NuRD co-repressor complexes are large multi-component complexes in which not all of the components and their functions have been identified [2,6]. HDACs function by deacetylating of key components of the transcriptional machinery including the core histone proteins resulting in their in re-association with the DNA, presenting a transcriptionally closed conformation [1,16]. The key co-repressor complex components HDAC-2, Mi-2α/β and mSin3a are all critical to the regulation of gene transcription. The impact of cigarette smoke exposure on the expression of mSin3a and Mi2α/β and their role in glucocorticoid responsiveness is unknown
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