Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis

Abstract

Objective. To examine the ability of fibroblast-like synoviocytes in rheumatoid arthritis (RA) to produce interleukin-7 (IL-7) and IL-15, and the ability of these cytokines to induce the proliferation of synoviuminfiltrating T cells.Methods. Messenger RNA (mRNA) and protein levels of IL-7 and IL-15 in synovial tissue cells and fibroblast cell lines were determined by reverse transcriptase-polymerase chain reaction and enzymelinked immunosorbent assay, respectively. T cellenriched populations from RA synovial tissues were isolated by deleting adherent cells after a 14-hour incubation in plastic dishes or by expanding T cells during a 14-day incubation of tissue cells with IL-2 alone, and their proliferative responses to IL-7, IL-15, and IL-2 were measured by 3 H-thymidine incorporation. Results. Freshly isolated cells from RA synovial tissues more strongly expressed mRNA for both IL-7 and IL-15 compared with the cells from osteoarthritis tissues, and could spontaneously release greater amounts of these cytokine proteins in culture. Fibroblast cell lines prepared from RA patients were able to produce large amounts of IL-15 and small amounts of IL-7 at both the transcriptional and protein levels, and their cytokine production was significantly elevated when stimulated with IL-1 and tumor necrosis factor ␣. Purified synovial tissue macrophages spontaneously released IL-15 but not IL-7, and synovial T cells did not produce either cytokine. IL-7 and IL-15, similar to IL-2, stimulated the proliferation of synovial tissue T cells from RA patients; IL-7 was less potent than IL-15 or IL-2.Conclusion. These results indicated that fibroblast-like synoviocytes are an important source of the cytokines with IL-2-like activity, IL-15 and IL-7, in RA joints, and that IL-15 may be mainly responsible for local T cell activation and expansion in the presence of deficient IL-2 production by T cells.

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4+ T cell response to produce IL‐17

“…IL-15 is known to stimulate activation, proliferation, survival, and effector functions of a variety of immune cells [15][16][17][18][19][20][21][22][23][24][25]. Increased expression of IL-15 in RA patients suggests that IL-15 is involved in the pathogenesis of RA [25,26].…”

“…Expression of IL-15 was demonstrated not only in macrophages but also in endothelial cells and fibroblastlike synoviocytes, and the concentration of IL-15 in synovial fluids was shown to be elevated in RA patients [22][23][24][25][26]. It was also shown that IL-15 induced TNF-a production from macrophages through activation of synovial T cells in RA patients [27].…”

“…IL-15, a member of the four-helix bundle cytokine family, stimulates macrophages/dendritic cells, natural killer (NK) cells, NKT cells, mucosal cd T cells, and memory CD8 + T cells to proliferate and/or exhibit cytokine production or cytotoxic activity [15][16][17][18][19][20][21]. Expression of IL-15 was demonstrated not only in macrophages but also in endothelial cells and fibroblastlike synoviocytes, and the concentration of IL-15 in synovial fluids was shown to be elevated in RA patients [22][23][24][25][26]. It was also shown that IL-15 induced TNF-a production from macrophages through activation of synovial T cells in RA patients [27].…”

Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients Express Functional IL-15 Receptor Complex: Endogenous IL-15 in Autocrine Fashion Enhances Cell Proliferation and Expression of Bcl-xL and Bcl-2

“…Moreover, FLS are important sources of IL-15 in RA joints. Indeed, IL-15 expressed by RA FLS may be responsible for intraarticular T cell activation and expansion (34). The aim of this study was to test the hypothesis that IL-15 is critical to FLS activation and survival.…”

Regulation of fibronectin and metalloproteinase expression by Wnt signaling in rheumatoid arthritis synoviocytes

“…They produce chemotactic and proinflammatory cytokines that promote leukocyte infiltration in the joints (4)(5)(6)(7)(8)(9)(10). In addition, the FLS synthesize extracellular matrix proteins, such as fibronectin, that facilitate cell attachment to the articular surface and promote cell survival (1,2,11).…”