Cigarette Smoke Exposure Alters mSin3a and Mi-2α/β Expression; implications in the control of pro-inflammatory gene transcription and glucocorticoid function

BACKGROUND: The 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. METHODS: Wild type, PI3Kγ knock-out (PI3Kγ(-/-)) and PI3K kinase dead knock-in (PI3Kδ(D910/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. RESULTS: Cigarette smoke exposure impaired glucocorticoid function and reduced HDAC-2 activity which was protected in the PI3Kδ(D910/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 PI3Kδ(D910/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. CONCLUSIONS: Cigarette 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.