title: Dendritic cells provide a potential link between smoking and inflammation in rheumatoid arthritis.
abstract: BACKGROUND
  Smoking increases the risk of developing rheumatoid arthritis (RA) and affects the severity of established RA. Smoking can impact on Th17 lymphocyte differentiation and function through activation of the aryl hydrocarbon receptor (AHR), a process with implications for the pathogenic mechanisms in RA that involve the cytokine, interleukin (IL)-17A. The objective of this study was to establish any effect of smoking on the inflammatory tissue lesions of rheumatoid arthritis via the AHR and IL-17A.
  
  
  METHODS
  Twenty synovial and eighteen subcutaneous nodule tissue samples from 31 patients with RA were studied. Patient smoking status at the time of tissue collection was established. Expression of AHR, CYP1A1, AHRR, IL6, IL17A, IL17F, IL22, IL23, IL23R, IFNG, TBX21, IDO1 and FOXP3 genes were assessed in tissues and cultured cells using real-time PCR. Two-colour immunofluorescence was used to co-localise AHR and CYP1A1 protein in synovial tissues. The response of monocytes and monocyte-derived dendritic cells (mo-DCs) to the AHR agonist, benzo(a)pyrene (BaP) was compared in vitro.
  
  
  RESULTS
  AHR gene expression was demonstrated in rheumatoid synovial tissues and nodules with significantly greater expression in synovia. Expression was not influenced by smoking in either tissue. Evidence of AHR activation, indicated by CYP1A1 and AHRR gene expression, was found only in synovia from patients who smoked. However, IL17A gene expression was lower in synovia from smokers. TBX21 and FOXP3 expression was not affected by smoking. Within the synovial tissues of smokers the principal cell type with evidence of AHR activation was a subset of synovial DCs. This observation was consistent with the sensitivity of human mo-DCs to BaP stimulation demonstrated in vitro. Exposure to BaP affected mo-DC function as demonstrated by decreased IL6 expression induced by PolyI:C, without affecting indoleamine 2,3 dioxygenase (IDO)1 expression.
  
  
  CONCLUSIONS
  Our findings show that one effect of smoking on inflamed rheumatoid synovial tissue involves activation of the AHR pathway. A subset of synovial DCs is important in the response to cigarette smoke. The potential for smoking to affect DC behaviour in joint tissues has relevance to both early and late phases of RA pathogenesis and warrants further investigation.
authors.forename: Marina G
authors.initials: MG
authors.lastname: Kazantseva
authors.forename: John
authors.initials: J
authors.lastname: Highton
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.forename: Paul A
authors.initials: PA
authors.lastname: Hessian
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000494:pharmacology; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology; D012907:Smoking / Q000009:adverse effects*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D020381:Interleukin-17; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human