Cigarette Smoke Exposure Alters mSin3a and Mi-2alpha/beta Expression; implications in the control of pro-inflammatory gene transcription and glucocorticoid function.
BACKGROUND
The key co-repressor complex components HDAC-2, Mi-2alpha/beta and mSin3a are all critical to the regulation of gene transcription. HDAC-2 function is impaired by oxidative stress in a PI3Kdelta 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 Mi2alpha/beta and their role in glucocorticoid responsiveness is unknown.


METHODS
Wild type, PI3Kgamma knock-out (PI3Kgamma-/-) and PI3K kinase dead knock-in (PI3KdeltaD910/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-2alpha and Mi-2beta 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 PI3KdeltaD910/A910 mice. Both mSin3a and Mi-2alpha protein expression was reduced in smoke-exposed mice. Budesonide alone protected mSin3a protein expression with no additional effect seen with abrogation of PI3Kgamma/delta activity, however Mi-2alpha, but not Mi-2beta, expression was protected in both PI3KdeltaD910/A910 and PI3Kgamma-/- budesonide-treated smoke-exposed mice. The restoration of glucocorticoid function coincided with the protection of both HDAC activity and mSin3a and Mi-2alpha 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 PI3Kdelta signalling in combination with glucocorticoid treatment may therefore provide a therapeutic strategy for restoring oxidant-induced glucocortiocid unresponsiveness.
Marwick
John A
JA
Section of Airways Disease, National Heart & Lung Institute, Imperial College London, UK. john.Marwick@ed.ac.uk.
Stevenson
Christopher S
CS
Chung
Kian Fan
KF
Adcock
Ian M
IM
Kirkham
Paul A
PA