Expression and Regulation of Toll-Like Receptor 2 in Rheumatoid Arthritis Synovium

Abstract

Toll-like receptors (TLRs) are involved in mediating cell activation on stimulation with microbial constituents. We investigated the role for TLRs in synovial fibroblast (SF) activation in rheumatoid arthritis (RA). We analyzed whether stimulation with interleukin-1␤ and tumor necrosis factor-␣, cytokines present in RA synovium, influences expression of TLR genes in SFs. The effects were compared with those of treatment with lipopolysaccharide and a synthetic lipopeptide (sBLP). Gene expression was examined using quantitative polymerase chain reaction. TLR2-mediated cell activation was investigated by electromobility shift assay for nuclear factor-B. To localize TLR2 expression in joint tissue sections of RA patients were stained using in situ hybridization. Expression of TLR2 in RA SFs was increased after treatment with interleukin-1␤, tumor necrosis factor-␣, lipopolysaccharide, and sBLP. Nuclear factor-B translocation in SFs was triggered by TLR2-mediated cell stimulation.

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

“…Expression of TLR-2 and TLR-4 is increased and regulated by proinflammatory cytokines that are present in the synovial compartment (33,34) and by the identification of the TLR-4 (Asp 299 Gly) functional variant as a marker for RA disease susceptibility (35). In addition, the link between DNA and TLRs in RA, as recently demonstrated by Leadbetter and colleagues, further substantiated the potential role of TLRs in arthritis (36).…”

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

“…Previous studies demonstrated that TLR-2 and TLR-4 are expressed in RA synovial tissue (8,16,18) and that this expression was increased compared with that in osteoarthritis or normal synovial tissue (18). TLR-2 was detected by in situ hybridization primarily in cells expressing fibroblast markers (8), while 2-color immunohistochemistry showed that TLR-2 colocalized with CD16ϩ macrophages in the lining (17).…”

“…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).…”

“…This activation promotes the development of the adaptive immune response involving T and B lymphocytes, which then contributes to clearance of the pathogenic stimulus and resolution of the inflammatory response. Despite the development of an adaptive immune response, expression of the early responders TNF␣ and IL-1␤ persists and may directly contribute to the pathogenesis of RA (2,(4)(5)(6)(7)(8).…”

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

“…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.…”