Epithelial expression of TLR4 is modulated in COPD and by steroids, salmeterol and cigarette smoke.
The toll-like receptors (TLRs) are a key component of host defense in the respiratory epithelium. Cigarette smoking is associated with increased susceptibility to infection, while COPD is characterised by bacterial colonisation and infective exacerbations. We found reduced TLR4 gene expression in the nasal epithelium of smokers compared with non-smoking controls, while TLR2 expression was unchanged. Severe COPD was associated with reduced TLR4 expression compared to less severe disease, with good correlation between nasal and tracheal expression. We went on to examine the effect of potential modulators of TLR4 expression in respiratory epithelium pertinent to airways disease. Using an airway epithelial cell line, we found a dose-dependent downregulation in TLR4 mRNA and protein expression by stimulation with cigarette smoke extracts. Treatment with the corticosteroids fluticasone and dexamethasone resulted in a dose-dependent reduction in TLR4 mRNA and protein. The functional significance of this effect was demonstrated by impaired IL-8 and HBD2 induction in response to LPS. Stimulation with salmeterol (10-6 M) caused upregulation of TLR4 membrane protein presentation with no upregulation of mRNA, suggesting a post-translational effect. The effect of dexamethasone and salmeterol in combination was additive, with downregulation of TLR4 gene expression, and no change in membrane receptor expression. Modulation of TLR4 in respiratory epithelium may have important implications for airway inflammation and infection in response to inhaled pathogens.
Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland. rmacredmond@mrl.ubc.ca
Ruth E
RE
MacRedmond
Catherine M
CM
Greene
Delbert R
DR
Dorscheid
Noel G
NG
McElvaney
Shane J
SJ
O'Neill
D000305:Adrenal Cortex Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000730:Androstadienes / Q000494:pharmacology; D016022:Case-Control Studies; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D000068298:Fluticasone; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D012720:Severity of Illness Index; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D023083:beta-Defensins / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D000730:Androstadienes; C106641:DEFB4A protein, human; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D012906:Smoke; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D023083:beta-Defensins; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D000068298:Fluticasone; D000420:Albuterol