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

• Published in: The Journal of biological chemistry Vol. 285; no. 8; pp. 5405 - 5416
• Main Authors: Yao, Hongwei, Hwang, Jae-woong, Moscat, Jorge, Diaz-Meco, Maria T., Leitges, Michael, Kishore, Nandini, Li, Xiong, Rahman, Irfan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.02.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation - drug effects; Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; Aldehydes; Aldehydes - adverse effects; Aldehydes - pharmacology; Animals; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Nucleus - pathology; Chromatin; Chromatin Assembly and Disassembly - drug effects; Chromatin Assembly and Disassembly - genetics; Cigarette Smoke; Enzyme Inhibitors - pharmacology; Histone Acetylation; Histone Modification; Histones - genetics; Histones - metabolism; Humans; Inflammation; Inflammation Mediators - physiology; Lipopolysaccharide; Lipopolysaccharides - adverse effects; Lipopolysaccharides - pharmacology; Lung; Macrophages, Alveolar - enzymology; Macrophages, Alveolar - pathology; Mice; Mice, Knockout; NF-κB; Oxidative Stress; Oxygen/Radicals; Phosphorylation - drug effects; Phosphorylation - genetics; Pneumonia - chemically induced; Pneumonia - enzymology; Pneumonia - genetics; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - deficiency; Protein Kinase C - metabolism; Signal Transduction; Smoking - adverse effects; Smoking - metabolism; Smoking - pathology; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; NF-κB; Chromatin; Histone Modification; Oxidative Stress; Lung; Lipopolysaccharide; Inflammation; Oxygen/Radicals; Aldehydes; Histone Acetylation; Cigarette Smoke
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.041418

Atypical protein kinase C (PKC) ζ is an important regulator of inflammation through activation of the nuclear factor-κB (NF-κB) 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 PKCζ is an important regulator of chromatin remodeling, and down-regulation of PKCζ ameliorates lung inflammation by CS and LPS exposures. We determined the role and molecular mechanism of PKCζ in abnormal lung inflammatory response to CS and LPS exposures in PKCζ-deficient (PKCζ−/−) and wild-type mice. Lung inflammatory response was decreased in PKCζ−/− mice compared with WT mice exposed to CS and LPS. Moreover, inhibition of PKCζ by a specific pharmacological PKCζ 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-κB into the nucleus. Furthermore, CS/reactive aldehydes and LPS exposures led to activation and translocation of PKCζ 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 PKCζ 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.