Our results show that CS activates MSK1, leading to phospho-acetylation of RelA/p65 at Ser276 and Lys310, respectively, in epithelial cells. Similar observations were found when the cells were treated with a component of CS, the aldehyde acrolein . Other studies have shown the control of phosphorylation of RelA/p65 at multiple serine residues regulates transcriptional activity of NF-kB RelA/p65 by TNF-a, IL-1b, UV, farnesol, respiratory BAY-60-7550 syncytial virus in various cell types . Hence, it is possible that MSK1 activation regulates RelA/p65 phosphorylation in lung epithelial cells in response to CS. This is shown by the evidence that CS causes a significant increase in the levels of phosphorylated MSK1 and phospho-acetylation of RelA/p65 in control vector and wild-type MSK1 transfected H292 cells. There was a modest but significant reduction of MSK1 activation and RelA/p65 phosphorylation without any change in acetylation of RelA/p65 in MSK1 N- and C-terminal kinase-dead mutant transfected H292 cells suggest the role of both N- and C- terminal domains of MSK1 are crucial for it activation. Based on previous report , we speculated that the kinase activity will be affected in cells transfected with MSK1 N- and C-terminal kinase-dead mutants without any appreciable effects on MSK1 levels. Nevertheless, CS-induced activation of MSK1 and RelA/p65 was modest, but a significant reduction was seen in MSK1 siRNA transfected H292 cells compared to non-targeted control siRNA transfected cells. This suggests that the activation of RelA/p65 is MSK1-dependent in epithelial cells. MSK1 contains two catalytic active kinase domains , which are required for proper function . Earlier reports show that nAG-013736 either of the kinase-dead mutants of MSK1 possessed detectable activity nor showed any change in the total levels of MSK1 either before or after stimulation of cells with TPA or exposure to UV . Therefore, both the N- and C-terminal kinase domains play an essential role in activity of MSKs . MSK1 also acts as a regulator of inflammation . However, the signaling mechanism by which CS activates MSK1 is not known. It has been shown that IKKa translocated into the nucleus and is required for optimal NF-kB-mediated transcription and phosphorylation of histone H3 at Ser10 of NF-kB target genes , as well as EGF-induced transcriptional regulation of immediate early genes . Hence, we proposed that CS activates MSK1 via IKKa, leading to chromatin modifications in human lung epithelial cells. In support of this, we found that CS increases the levels of phosphorylated MSK1 and phospho-acetylated RelA/p65 in H292 cells overexpressing IKKa compared both to cells expressing a dominant-negative IKKa and to non-transfected control cells. These data suggest that IKKa plays an important role in CSE-induced activation of MSK1 and histone modifications in epithelial cells.