Abstract
IntroductionThe 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.MethodsThe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
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 and to determine the role of TLR and IL-17 in the pathophysiology of pSS
TLR2, TLR4, TLR6, IL-17, and IL-23 are highly expressed in patients with SS To determine the roles of TLRs and the Th17-associated cytokines in the pathogenesis of SS, we first examined the in situ expression of various TLRs (TLR2, TLR4, and TLR6) and Th17-associated cytokines such as IL-17 and IL-23 by immunohistochemistry in the minor salivary glands of 16 patients with SS and five disease controls
Our immunohistochemical analysis showed that intense staining of TLR2, TLR4, and TLR6 was evident in infiltrating mononuclear cells and ductal epithelial cells
Summary
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. Sjögren’s syndrome (SS) is a relatively common autoimmune exocrinopathy that is associated with infiltration of lymphocytes and is characterized by gradually progressive lachrymal and salivary dysfunction [1,2]. The Toll-like receptor (TLR) family is the prototype of pattern recognition receptors that sense diverse pathogen-associated molecular patterns (PAMPs), including lipids, lipoproteins, proteins, and nucleic acids [3,4]. Recognition of PAMPs by TLRs activates intracellular signaling pathways and this culminates in the induction of inflammatory cytokines, chemokines, and interferons and upregulation of co-stimulatory molecules. The pathogenic role of TLRs in SS remains to be determined
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