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Carbonylation caused by cigarette smoke extract is associated with defective macrophage immunity.

Abstract：

:Oxidants in cigarette smoke inhibit pathogen recognition receptor function and phagocytosis, but the molecular basis of this inhibition remains obscure. We sought to identify the inhibitory mechanisms that impair alveolar macrophage function. Balb/c mice were acutely exposed to four cigarettes for 4 hours before treatment with intranasal LPS (1 μg). The mice exhibited significantly reduced airway neutrophilia and expression of TNF-α. Balb/c-derived MH-S alveolar macrophage cells exposed to cigarette smoke extract (CSE) displayed a similar inhibitory response to stimulation with LPS. The induction of inflammatory genes by recombinant (r) TNF-α (100 ng/ml) was also impaired by CSE. Because both pathways converge on NF-κB, the degradation of IκBα and the phosphorylation of p65 were assessed and shown to be blunted by CSE. CSE also blocked the activity of activator protein-1 (AP-1) by inhibiting p38 mitogen activated protein kinase (MAPK) in a reduced glutathione (GSH)-reversible manner. The induction of specific Toll-like receptor (TLR)-negative regulators (suppressor of cytokine signaling-1 [SOCS-1], interleukin-1 receptor associated kinase-M [IRAK-M], and IL-10) did not account for the impaired responses of TLRs. As free radical species are abundant in CSE and GSH restored function, a panel of oxidative/nitrosative stress markers was screened using immunocytochemistry. The panel identified protein carbonylation as the major CSE-inducible marker. Oxyblot analysis confirmed that CSE potently introduced carbonyl groups to many proteins in a dose-dependent and time-dependent manner that inversely correlated with the expression of TNF-α. The formation of pseudopodia was not prevented, but these membrane extensions were heavily carbonylated, and primary alveolar macrophages were also targeted for carbonylation. Oxidants in cigarette smoke drive a rapid, persistent, and global protein carbonylation that may represent a common pathway to altered immunity in disease.

journal_name

Am J Respir Cell Mol Biol

journal_title

American journal of respiratory cell and molecular biology

authors

Bozinovski S,Vlahos R,Zhang Y,Lah LC,Seow HJ,Mansell A,Anderson GP

doi

10.1165/rcmb.2010-0272OC

subject

Has Abstract

pub_date

2011-08-01 00:00:00

pages

229-36

issue

eissn

1044-1549

issn

1535-4989

pii

2010-0272OC

journal_volume

pub_type

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Carbonylation caused by cigarette smoke extract is associated with defective macrophage immunity.