Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease characterized by insensitivity to glucocorticoids (GCs). Reactive oxygen species (ROS) are an etiologic factor in the pathogenesis of COPD and contribute to the reduced GC action. Insensitivity to GCs has been associated with impaired catalytic activity of HDAC2 in the lungs of COPD patients. GSK3beta is a constitutively active kinase that regulates cell cycle and gene expression. Phosphorylation of Ser9 on GSK3beta leads to its inactivation and elevated levels of the phospho-GSK3beta have been documented in the peripheral lung of COPD patients.
Monocytes from healthy volunteers were treated with H2O2 which induced GSK3beta Ser9 phosphorylation in a concentration- and time-dependant manner. Use of selective inhibitors showed that the ERK pathway mediates the ROS induced GSK3beta phosphorylation. To examine how inactivation of GSK3beta regulates GC function, we assessed the effect of a selective inhibitor (CT99021) on GC-mediated inhibition of GM-CSF release. The data showed that inhibition of GSK3beta alone had no significant effect on LPS induced GM-CSF release but it attenuated the ability of dexamethasone to suppress GM-CSF release by up to 50%. Selective inhibition of GSK3beta also significantly decreased HDAC2 activity suggesting that HDAC2 is an important mediator in this pathway.
Our results indicate that ROS induces inhibition of GSK3beta via the ERK pathway leading to decreased HDAC2 activity and GC insensitivity. This pathway should be considered in evaluating the therapeutic potentials of GSK3beta activators in restoring GC sensitivity in COPD.
- © 2011 ERS