Cigarette smoke extracts decrease basal and lipopolysaccharide-induced expression of macrophage receptor with collagenous structure via degradation of p300

In this study, we investigated the effect of CSE on the expression of MARCO and its regulatory mechanism in RAW264.7 cells. CSE decreased both basal and lipopolysaccharide (LPS)-induced expressions of MARCO mRNA and protein. LPS-induced up-regulation of MARCO is nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent. Knockdown of Nrf2 using siRNAs completely suppressed LPS-induced increase in MARCO transcripts. CSE did not block nuclear translocation of Nrf2 in LPS-treated cells, but rather CSE strongly accumulated Nrf2 in the nucleus via degradation of its cytoplasmic inhibitor, Keap1. Histone acetyltransferase p300/CBP directly acetylates Nrf2 and acetylation of Nrf2 augments promoter specific-DNA binding of Nrf2. Interestingly, We found that CSE induced polyubiquitination and subsequent degradation of p300. Pretreatment with proteasome inhibitors (MG132 and PS-341) completely blocked CSE-induced degradation of p300 and CSE-mediated suppression of MARCO mRNA expression. These findings suggest that CSE decrease MARCO expression via proteasomal degradation of p300 in macrophages, which may be in part responsible for impaired bacterial phagocytosis.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Airway Cell Biology and Immunopathology Source Type: research