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.
Highlights
Cigarette smoke (CS)2 is the major etiological factor in the pathogenesis of chronic obstructive pulmonary diseases (COPD), which is characterized by chronic lung inflammation and accelerated decline in lung function
We found that the levels of phosphorylated protein kinase C (PKC) (Thr410), which is shown to be required for activation of PKC [37], were significantly increased in lungs and Bronchoalveolar Lavage (BAL) cells of WT mice exposed to CS and LPS
Treatment with Cigarette Smoke Extract (CSE), the reactive aldehydes, and LPS significantly induced KC release and PKC phosphorylation (Thr410) in mouse alveolar macrophages, which was decreased by the PKC inhibitor (Fig. 4, A and B). These results suggest that CS- and LPS-induced pro-inflammatory mediator release is mediated by activation of PKC, and aldehyde components are crucial for CS-induced PKC activation and inflammatory response in monocytes/macrophages
Summary
Cigarette smoke (CS)2 is the major etiological factor in the pathogenesis of chronic obstructive pulmonary diseases (COPD), which is characterized by chronic lung inflammation and accelerated decline in lung function. We found that the levels of phosphorylated PKC (Thr410), which is shown to be required for activation of PKC [37], were significantly increased in lungs and BAL cells of WT mice exposed to CS and LPS
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