Cigarette smoke extracts inhibit TLR ligand-induced inflammation via inactivation of NF-κB and activation of histone deacetylase in macrophages (INM7P.353)

Abstract

Abstract Cigarette smoke (CS) is the major risk factor of chronic obstructive pulmonary disease (COPD). CS has been reported to inhibit Toll-like receptor (TLR) function and phagocytosis in macrophages. Moreover, alveolar macrophages in COPD have impaired responsiveness to TLR stimulation. However, the molecular mechanism of CS-mediated impairments of macrophage immunity is not fully defined. We investigated the inhibitory mechanism of cigarette smoke extracts (CSE) in macrophages. Lipopolysaccharide (LPS, TLR4 ligand), Pam3CSK4 (TLR2 ligand), and CpG-oligodeoxynucleotides (TLR9 ligand) induced IL-6, TNF-α, and IL-1β production in RAW264.7 macrophage cells, which was significantly suppressed by CSE co-treatment. CSE did not block LPS-induced IκBα degradation, MAP kinase activation, and nuclear translocation of NF-κB subunit. However, it markedly suppressed mRNA expression of IL-6, TNF-α, and IL-1β, which implies that CSE regulate inflammatory cytokine production at the transcriptional level. Therefore, we next investigated the activity and modification of transcription factor, NF-κB, and histone deacetylase (HDAC). CSE significantly suppressed basal and LPS-induced NF-κB activity and reduced the level of acetyl-NF-κB p65. CSE increased HDAC activity and decreased the level of acetyl- and phospho-Histone H3 (Lys9/Ser10) expression. Together, these results suggest that CSE-mediated impairments of macrophage immunity are mediated by inhibition of NF-κB activation and activation of HDAC.