A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis

S. Kobayashi, H. Okamoto, T. Iwamoto, Y. Toyama, T. Tomatsu, H. Yamanaka, S. Momohara

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)

Abstract

Objective. Environmental factors are involved in RA pathogenesis and epidemiological studies have suggested that smoking is an environmental risk factor for RA. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the major toxic components in cigarettes. To clarify the biological effects of smoking in RA, we investigated the role of TCDD in RA pathogenesis. Methods. Human synovial tissue was obtained from RA and OA patients and aryl hydrocarbon receptor (AhR) expression in these tissues was evaluated using immunohistochemistry and real-time PCR. Expression of various cytokines was measured by real-time PCR following stimulation of RA synoviocytes with different concentrations of TCDD. To study the role of AhR, we treated RA synoviocytes with α-naphthoflavone, a known AhR antagonist. To evaluate which signal transduction pathways were stimulated by the TCDD-AhR interaction, we used inhibitors of nuclear factor-κB (NF-κB) and extra-cellular stimulus-activated kinase (ERK). Results. Higher AhR mRNA and protein levels were observed in RA synovial tissue than in OA tissue. TCDD up-regulated the expression of IL-1β, IL-6 and IL-8 through binding to AhR, and this effect was transmitted via the NF-κB and ERK signalling cascades. AhR expression in synovial cells was up-regulated by TNF-α. Conclusion. TNF-α activates AhR expression in RA synovial tissue, and that cigarette smoking and exposure to TCDD enhances RA inflammatory processes. TCDD induces inflammatory cytokines via its association with AhR, resulting in stimulation of the NF-κB and ERK signalling cascades. Thus TCDD exposure, such as smoking exacerbates RA pathophysiology.

Original languageEnglish
Pages (from-to)1317-1322
Number of pages6
JournalRheumatology
Volume47
Issue number9
DOIs
Publication statusPublished - 2008

Keywords

  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin
  • Aryl hydrocarbon receptor
  • Extra-cellular stimulus-activated kinase
  • Interleukin-1
  • Interleukin-6
  • Interleukin-8
  • Nuclear factor-kB
  • Rheumatoid arthritis
  • Smoking

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

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