title: TLR2 ligation induces the production of IL-23/IL-17 via IL-6, STAT3 and NF-kB pathway in patients with primary Sjogren's syndrome.
abstract: BACKGROUND
  The study was undertaken to investigate the interrelation of toll-like receptor (TLR) and interleukin (IL)-17 in the salivary glands of patients with primary Sjogren's syndrome (pSS) and to determine the role of TLR and IL-17 in the pathophysiology of pSS.
  
  
  METHODS
  The expressions of various TLRs, IL-17 and the cytokines involved in Th17 cell differentiation including IL-6, IL-23, tumor necrosis factor-alpha (TNF-α) and IL-1β were examined by immunohistochemistry in salivary glands of pSS patients. The IL-17 producing CD4+ T cells (Th17 cells) were examined by flow cytometry and confocal staining in peripheral mononuclear blood cells (PMBCs) and salivary glands of pSS patients. After PBMCs were treated with TLR specific ligands, the induction of IL-17 and IL-23 was determined using real-time PCR and ELISA. The signaling pathway that mediates the TLR2 stimulated production of IL-17 and IL-23 was investigated by using treatment with specific signaling inhibitors.
  
  
  RESULTS
  We showed that TLR2, TLR4, TLR6, IL-17 and the cytokines associated with Th17 cells were highly expressed in salivary glands of pSS patients but not in controls. The expressions of TLR2, TLR4 and TLR6 were observed in the infiltrating mononuclear cells and ductal epithelial cells, whereas IL-17 was mainly observed in infiltrating CD4+ T cells. The number of IL-17 producing CD4+ T cells was significantly higher in pSS patients both in PBMCs and minor salivary glands. The stimulation of TLR2, TLR4 and TLR6 additively induced the production of IL-17 and IL-23 from the PBMCs of pSS patients especially in the presence of TLR2 stimulation. IL-6, signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappaB (NF-kB) pathways were implicated in the TLR2 stimulated IL-17 and IL-23.
  
  
  CONCLUSIONS
  Our data demonstrate that TLR2 ligation induces the production of IL-23/IL-17 via IL-6, STAT3 and NF-kB pathway in pSS. Therefore, therapeutic strategies that target TLR/IL-17 pathway might be strong candidates for treatment modalities of pSS.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea,505 Banpo-dong, Seocho-gu, Seoul 137-701, Korea.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Yang-Mi
authors.initials: YM
authors.lastname: Her
authors.forename: Hye-Joa
authors.initials: HJ
authors.lastname: Oh
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Seon-Yeong
authors.initials: SY
authors.lastname: Lee
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Woo
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Kyung-Su
authors.initials: KS
authors.lastname: Park
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000502:physiology*; D008024:Ligands; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D012469:Salivary Glands / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012859:Sjogren's Syndrome / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: C508600:IL6 protein, human; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D008024:Ligands; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2