title: Protein kinase C zeta mediates cigarette smoke/aldehyde- and lipopolysaccharide-induced lung inflammation and histone modifications.
abstract: Atypical protein kinase C (PKC) zeta is an important regulator of inflammation through activation of the nuclear factor-kappaB (NF-kappaB) 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 PKCzeta is an important regulator of chromatin remodeling, and down-regulation of PKCzeta ameliorates lung inflammation by CS and LPS exposures. We determined the role and molecular mechanism of PKCzeta in abnormal lung inflammatory response to CS and LPS exposures in PKCzeta-deficient (PKCzeta(-/-)) and wild-type mice. Lung inflammatory response was decreased in PKCzeta(-/-) mice compared with WT mice exposed to CS and LPS. Moreover, inhibition of PKCzeta by a specific pharmacological PKCzeta 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 (Ser(311)) and translocation of the RelA/p65 subunit of NF-kappaB into the nucleus. Furthermore, CS/reactive aldehydes and LPS exposures led to activation and translocation of PKCzeta 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 PKCzeta 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.
authors.affiliation: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Jae-woong
authors.initials: JW
authors.lastname: Hwang
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Nandini
authors.initials: N
authors.lastname: Kishore
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000107:Acetylation / Q000187:drug effects; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000447:Aldehydes / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008070:Lipopolysaccharides / Q000009:adverse effects* / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism / Q000473:pathology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D006657:Histones; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011493:Protein Kinase C; D051996:Transcription Factor RelA; D000099221:Protein Kinase C zeta; C498144:Rela protein, mouse