Abstract
BackgroundHeightened inflammation, including expression of COX-2, is associated with COPD pathogenesis. RelB is an NF-κB family member that attenuates COX-2 in response to cigarette smoke by a mechanism that may involve the miRNA miR-146a. There is no information on the expression of RelB in COPD or if RelB prevents COX-2 expression through miR-146a.MethodsRelB, Cox-2 and miR-146a levels were evaluated in lung fibroblasts and blood samples derived from non-smokers (Normal) and smokers (At Risk) with and without COPD by qRT-PCR. RelB and COX-2 protein levels were evaluated by western blot. Human lung fibroblasts from Normal subjects and smokers with and without COPD, along with RelB knock-down (siRNA) in Normal cells, were exposed to cigarette smoke extract (CSE) in vitro and COX-2 mRNA/protein and miR-146a levels assessed.ResultsBasal expression of RelB mRNA and protein were significantly lower in lung cells derived from smokers with and without COPD, the latter of which expressed more Cox-2 mRNA and protein in response to CSE. Knock-down of RelB in Normal fibroblasts increased Cox-2 mRNA and protein induction by CSE. Basal miR-146a levels were not different between the three groups, and only Normal fibroblasts increased miR-146a expression in response to smoke. There was a positive correlation between systemic RelB and Cox-2 mRNA levels and circulating miR-146a levels were higher only in GOLD stage I subjects.ConclusionsOur data indicate that RelB attenuates COX-2 expression in lung structural cells, such that loss of pulmonary RelB may be an important determinant in the aberrant, heightened inflammation associated with COPD pathogenesis.
Highlights
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with an enhanced, chronic inflammatory response due to exposure to noxious particles or gases
COX-2 catalyzes the transformation of arachidonic acid (AA) into thromboxanes and prostaglandins (PG) such as PGE2, an immunoregulatory PG that is elevated in COPD subjects [5,6]
COX-2 is over-expressed by COPD lung fibroblasts [19] and we have shown that RelB protein is degraded by cigarette smoke [29], rendering it possible that heightened smokeinduced COX-2 expression in COPD is associated with absent/low RelB expression
Summary
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with an enhanced, chronic inflammatory response due to exposure to noxious particles or gases. Cigarette smoke contributes to COPD by inciting inflammation, recruiting T cells, macrophages and neutrophils to the lung in part via the induction of inflammatory mediators, including cyclooxygenase-2 (COX-2) [3,4,5]. Numerous cell types within the lung are capable of producing COX-2 in response to smoke, including lymphocytes, epithelial. Heightened inflammation, including expression of COX-2, is associated with COPD pathogenesis. RelB is an NF-κB family member that attenuates COX-2 in response to cigarette smoke by a mechanism that may involve the miRNA miR-146a. There is no information on the expression of RelB in COPD or if RelB prevents COX-2 expression through miR-146a
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