Expression of Toll‐like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin‐12 and interleukin‐18 via interferon‐γ

Abstract

Objective. To study the expression of Toll-like receptor 2 (TLR-2) and TLR-4 and its association with proinflammatory cytokines in synovial tissue from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and healthy individuals.Methods. Synovial tissue specimens from 29 RA patients were stained for TLR-2, TLR-4, and proinflammatory cytokines (interleukin-1␤ [IL-1␤], IL-12, IL-17, IL-18, and tumor necrosis factor ␣ [TNF␣]). The expression of TLR-2, TLR-4, and cytokines as well as the degree of inflammation in synovial tissue were compared between patients with RA, patients with OA (n ‫؍‬ 5), and healthy individuals (n ‫؍‬ 3). Peripheral blood mononuclear cells (PBMCs) were incubated with IL-12 and IL-18, and TLR expression was assessed using fluorescence-activated cell sorter analysis. Production of TNF␣ and IL-6 was measured using Luminex bead array technology.Results. In RA synovial tissue, the expression of TLR-2 was slightly higher than that of TLR-4. Interestingly, both TLR-2 and TLR-4 were expressed at higher levels in moderately inflamed synovium, as compared with synovial tissue with no or severe inflammation.

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

“…Recently, the adaptor protein MyD88 and its downstream pathway were shown to play a critical role in both spontaneous and carcinogeninduced tumor development [42,43]. Also, in rheumatoid arthritis and psoriasis, several works support evidence of an important role of endogenous TLR ligands that are involved in the induction of inflammation and initiation of diseases [44][45][46]. cPKC inhibitors that inhibit MyD88-dependent inflammatory signals downstream of TLR and IL-1R can be very promising molecules in the treatment of autoimmune inflammatory diseases, as it has been demonstrated with the AEB071 PKC inhibitor on psoriasis [47].…”

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).…”

“…TLR-2 expression was increased on PB monocytes in response to LPS and IL-1␤ (40,41). Further, treatment of monocytes with interferon-␥ (IFN␥) resulted in increased cell surface expression of both TLR-2 and TLR-4 (18,42), and IFN␥ sensitized the monocytes to respond to LPS (43). Although the levels of IFN␥ detected in SF of patients with established RA were low (44), IFN␥ mRNA was present in synovial tissue lymphocytes (45), and it is possible that IFN␥ contributes to sensitizing macrophages to express increased levels of TLR-2 and TLR-4 in vivo.…”

“…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).…”

“…While the expression of TLR-2 and TLR-4 on synovial tissue macrophages has been documented (16)(17)(18), quantitative studies have not been performed to examine the level of expression of TLR-2 and TLR-4 on synovial macrophages (the principal source of proinflammatory cytokines in RA) and to define the response to TLR ligands. These studies are important, because ligands for TLR-2 and TLR-4 have been identified in the rheumatoid joint.…”