Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts by toll‐like receptor signaling

Abstract

Objective. To test the hypothesis that bacterial products acting as adjuvants, such as CpG oligodeoxynucleotides (ODNs) and peptidoglycans (PGs), are able to activate synoviocytes, and to determine the involvement of Toll-like receptors (TLRs) in this activation process.Methods Conclusion. We demonstrate that bacterial PGs activate synovial fibroblasts, at least partially via TLR-2, to express integrins, MMPs, and proinflammatory cytokines. Inhibition of TLR signaling pathways might therefore have a beneficial effect on both joint inflammation and joint destruction.

Pre–B cell colony‐enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix‐degrading activities

“…Moreover, in our experiments, down-regulation of PBEF in RASFs by siRNA not only decreased basal IL-6, MMP-1, and MMP-3 levels but also significantly inhibited TLR ligand-induced production of cytokines and destructive enzymes. TLRs were shown to be key players in inflammatory and destructive processes in RA (3,4,20,25). TLR ligands of microbial origin as well as endogenous TLR ligands were demonstrated to be present in RA synovial fluid as possible drivers of inflammatory processes (1,26).…”

“…In previous studies, we demonstrated that TLR-2, TLR-3, and TLR-4 ligands induce high amounts of cytokines and matrix-degrading enzymes in RASFs (3,5,20). In order to investigate whether PBEF is involved in the up-regulation of these effector molecules, we treated siPBEF-transfected RASFs with bLP, poly(I-C), and LPS, and analyzed the induction of IL-6, IL-8, MMP-1, and MMP-3, 24 hours after TLR ligand stimulation.…”

“…Activation of cells by microbial components and also by endogenous molecules via pattern recognition receptors, such as Toll-like receptors (TLRs), results in the production of a variety of cytokines, chemokines, and matrix metalloproteinases (MMPs), some of which are characteristically observed in patients with RA (2). We previously reported induction in SFs of the proinflammatory cytokine interleukin-6 (IL-6) and the chemokines IL-8, granulocyte chemotactic protein 2, macrophage chemotactic protein 2, and RANTES by the TLR-2 ligand bacterial peptidoglycan (3,4). In a subsequent study, we demonstrated overexpression of TLR-3 in RA synovial tissue and established that RNA released by necrotic synovial fluid cells can act as endogenous ligand for TLR-3 on cultured RASFs (5).…”

Increased macrophage activation mediated through toll‐like receptors in rheumatoid arthritis

“…In a study utilizing immunohistochemistry, both TLR-2 and TLR-4 were found to be expressed in the synovial tissue of patients with RA (16)(17)(18). Furthermore, in a study using reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization, TLR-2 was found to be expressed in the rheumatoid joint and to be up-regulated in RA synovial fibroblasts by TNF␣ and IL-1␤ (8,19).…”

BAFF synthesis by rheumatoid synoviocytes is positively controlled by α5β1 integrin stimulation and is negatively regulated by tumor necrosis factor α and toll‐like receptor ligands

“…Bacterial products known as pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) or peptidoglycan, are known to activate FLS by interacting with cellular pattern-recognition receptors (PRRs) present on these cells (15,16). A large number of PRRs, such as Toll-like receptor 2 (TLR-2), TLR-4, and TLR-9, as well as numerous integrins are expressed by FLS, and their expression is increased in response to inflammatory stimuli (16,17). We previously showed that LPS, bacterial lipopeptide (BLP), and protein I/II, which are ligands of TLR-4, TLR-2, and ␣5␤1 integrin, respectively, can trigger the release of IL-6 and IL-8 from activated FLS (18,19).…”