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

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.

Recombinant mycobacterial HSP65 in combination with incomplete Freund's adjuvant induced rat arthritis comparable with that induced by complete Freund's adjuvant

“…Moreover, TLR2 signaling induced by MHSP65 could lead to an increased IL-17 production from Th17 cells. The speculation could be partially supported by the data that PG, a typical bacterium-derived TLR2 ligand, induced vigorous production of IL-17 from PBMCs isolated from patients with Sjogren's syndrome (Kwok et al, 2012). Administration of rMHSP65 aggravated experimental autoimmune uveitis (EAU) in mice by inducing the expansion of Th17 cells (Marengo et al, 2009).…”

Toll-Like Receptor Pathways in Autoimmune Diseases

“…The TLR expression level showed similar pattern in all types of human salivary gland cells [44]. As mentioned before, peptidoglycans could activate TLR2, which has been indicated to induce the production of interleukins such as IL-17 and IL-23 in the peripheral blood mononuclear cells (PBMCs) of SS patients via IL-6, signal transducer and activator of transcription (STAT) 3 and NF-κB pathways [45].…”

Multiple antigen-presenting system (MAPS) to induce comprehensive B- and T-cell immunity

“…4D), all of which have important roles in the development of Th1-and/or Th17-mediated cellular responses (16,17). To evaluate this further, we designed MAPS constructs that would or would not activate Toll-like receptor (TLR) 2, which enhances Th17 responses (18,19). We did this through the incorporation of a lipidated version of rhavi to the biotinylated PS (Fig.…”