Cigarette smoke extract-induced downregulation of p300 is responsible for the impaired inflammatory cytokine response of macrophages

Patients with chronic obstructive pulmonary disease (COPD) are susceptible to infection owing to the impaired immune function of alveolar macrophages. This is presumed to be caused, at least partially, by cigarette smoke (CS), which is a major risk factor for COPD. Although CS has been reported to inhibit Toll-like receptor (TLR) function and phagocytosis in macrophages, the molecular mechanism of CS-mediated impairment of macrophage immune function has not been completely elucidated. We investigated the effects of CS extracts (CSE) on macrophage immune function and its molecular mechanism. We assessed lipopolysaccharide (LPS, TLR4 ligand)-, Pam3CSK4 (TLR2 ligand)-, or CpG-oligodeoxynucleotide (TLR9 ligand)-induced IL-6, TNF-a, and IL-1I3 pro-duction in macrophages. Upregulation of IL-6, TNF-a, and IL-1I3 mRNA and protein by TLR ligands was sup -pressed on treatment with CSE. However, LPS-induced MAP kinase activation, IKBa degradation, and nuclear translocation of NF-KB were not impeded by CSE. In contrast, CSE significantly suppressed NF-KB transcriptional activity in the nucleus. We found that p300, which acetylates RelA/p65 at lysine 310, and acetyl-p65 (K310) were downregulated upon CSE treatment. Knock-down of p300 suppressed LPS-induced acetylation of NF-KB p65 and production of inflammatory cytokine. To summarize, these results suggest that CSE impair cytokine response by decreasing the expression levels of p300.

Automated summary

The study found that CSE may impair cytokine response by decreasing the expression levels of p300. While CS has been shown to affect macrophage immune function, its molecular mechanism is not fully understood.