Protein Kinase Cζ Mediates Cigarette Smoke/Aldehyde- and Lipopolysaccharide-induced Lung Inflammation and Histone Modifications

Atypical protein kinase C (PKC) zeta is an important regulator of inflammation through activation of the nuclear factor-kappa B (NF-kappa B) pathway. Chromatin remodeling on pro-inflammatory genes plays a pivotal role in cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced abnormal lung inflammation. However, the signaling mechanism whereby chromatin remodeling occurs in CS-and LPS-induced lung inflammation is not known. We hypothesized that PKC zeta is an important regulator of chromatin remodeling, and down-regulation of PKC zeta ameliorates lung inflammation by CS and LPS exposures. We determined the role and molecular mechanism of PKC zeta in abnormal lung inflammatory response to CS and LPS exposures in PKC zeta-deficient (PKC zeta(-/-)) and wild-type mice. Lung inflammatory response was decreased in PKC zeta(-/-) mice compared with WT mice exposed to CS and LPS. Moreover, inhibition of PKC zeta by a specific pharmacological PKC zeta inhibitor attenuated CS extract-, reactive aldehydes (present in CS)-, and LPS-mediated pro-inflammatory mediator release from macrophages. The mechanism underlying these findings is associated with decreased RelA/p65 phosphorylation (Ser311) and translocation of the RelA/p65 subunit of NF-kappa B into the nucleus. Furthermore, CS/reactive aldehydes and LPS exposures led to activation and translocation of PKC zeta into the nucleus where it forms a complex with CREB-binding protein (CBP) and acetylated RelA/p65 causing histone phosphorylation and acetylation on promoters of pro-inflammatory genes. Taken together, these data suggest that PKC zeta plays an important role in CS/aldehyde-and LPS-induced lung inflammation through acetylation of RelA/p65 and histone modifications via CBP. These data provide new insights into the molecular mechanisms underlying the pathogenesis of chronic inflammatory lung diseases.