The role of cytokines in the pathogenesis of rheumatoid arthritis

Lipsky, Peter E.; Davis, Laurie S.; Cush, John J.; Oppenheimer‐Marks, Nancy

doi:10.1007/bf00197186

Cited by 135 publications

(82 citation statements)

References 172 publications

(282 reference statements)

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“…The persistence of class I1 MHC antigen expression in CRL 1445 cells correlates well with the continued expression of class I1 MHC genes in synovial fibroblasts (10) and in murine bone marrow-derived macrophages (32) in the absence of lFNy after initial exposure. This implies that in vivo, human synovial fibroblasts may require only transient exposure to IFNy to up-regulate both class I and class I1 MHC gene expression, which further amplifies the chronic destructive inflammatory events in the RA joint.…”

Section: Discussionmentioning

confidence: 61%

Role of cytokines in inflammatory synovitis

Chin

Winterrowd

Krzesicki

et al. 1990

Arthritis & Rheumatism

118

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This study was undertaken in an effort to understand the role of cytokines in T lymphocyte trafficking into inflamed synovium and in the potential enhancement of antigen presentation by human synovial fibroblasts. We found that interleukin-lp (IL-lp), tumor necrosis factor a (TNFa), and interferon-y (IFNy) each increased the cell surface expression of intercellular adhesion molecule I (ICAM-I) on human synovial fibroblasts in a dose-and time-dependent manner. Maximal ICAM-1 expression occurred within 8 hours of induction, with the following order of efficacy: IFNy > TNFa > IL-1p. The number of cells bearing the ICAM-1 antigen also increased, from a basal level of -30% to more than 83% after cytokine induction (for all 3 cytokines). ICAM-1 expression rapidly decreased fdlowing cytokine removal. The expression of lymphocyte function-associated antigen 3 was also examined, but it was not changed by any of the 3 cytokines. Class I major histocompatibility complex antigen expression was increased modestly by all 3 cytokines, and expression was maximal by 24 hours after treatment. Only IFNy induced HLA class I1 antigen expression, and this expression persisted for up to 6 days following removal of the lymphokine. IL-6 and granulocyte-macrophage colony- stimulating factor had no effect on any of the parameters examined. Our data support an interactive role for inflammatory cytokines and the expression of adhesion ligands and HLA antigens by human synovial fibroblasts in the pathogenesis of synovial inflammation in rheumatoid arthritis.Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized in part by the proliferation of pannus tissue in diseased joints, which leads to eventual degradation of the articular cartilage and the subchondral bone (1)(2)(3). It has been demonstrated that the RA synovium contains cells that express HLA-DR antigens (4-7). There is also evidence that indicates that cells populating the inflamed tissue lining the RA joint have adhesion molecules as ligands for homing receptors on circulating T lymphocytes (8,9). It is hypothesized that the increased adhesiveness of the inflamed synovial tissue may play a central role in lymphocyte homing and retention in the diseased joint. The current study was initiated in an effort to elucidate cellular mechanisms that may be involved in chronic inflammatory synovitis. We examined the time and dose effects of various cytokines present in the inflammatory microenvironment in RA (10) on the expression of adhesion ligands intercellular adhesion molecule I (ICAM-1) and lymphocyte function-associated antigen 3 (LFA-3), and the expression of class I and class I1 major histocompatibility complex (MHC) antigens, 4 fibroblast cell surface molecules whose regulation may play critical roles in synovial inflammation.In previous studies, interferon-y (IFNy) has been shown to induce the expression of class I1 MHC antigens on synovial fibroblasts (1 l), and ICAM-1 has MATERIALS AND METHODSRecombinant cytokines and antibodies. Recombinant human i...

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Section: Discussionmentioning

confidence: 61%

Role of cytokines in inflammatory synovitis

Chin

Winterrowd

Krzesicki

et al. 1990

Arthritis & Rheumatism

118

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“…The follow-d ing events, which take place in rheumatoid but not in normal synovium, are most likely required for plasma cell accumulation. (a) An initial immune response to a presently unknown antigen; (b) the infiltration of RA synovium by B cell-containing mononuclear cells; (c) the local production of IL-10 by infiltrating monocytes and T cells (33); (d) the local production of ILi 2 by infiltrating T cells (34); and (e) the intense proliferation of synoviocytes which may increase their interaction with B cells. Previous electron microscopic studies of rheumatoid synovium had demonstrated the close contact between plasma cells, macrophage-like cells, blastic T cells, and synoviocytes (11,35), which suggest cell surface molecule or cytokine interactions between all these cell types.…”

Section: Methodsmentioning

confidence: 99%

The ability of synoviocytes to support terminal differentiation of activated B cells may explain plasma cell accumulation in rheumatoid synovium.

Déchanet¹,

Merville²,

Durand³

et al. 1995

J. Clin. Invest.

124

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“…Synovial tissue macrophages are important in mediating RA joint destruction, mainly due to their ability to process antigen stimulating factor-I and granulocyte-macrophage colony-stimulating factor (GM-CSF) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In addition, macrophages mediate the fibroproliferative phase ofRA by producing angiogenic activity (16,17).…”

Section: Introductionmentioning

confidence: 99%

Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis.

Koch¹,

Kunkel²,

Harlow³

et al. 1992

J. Clin. Invest.

587

400

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Cells within the synovial tissue may recruit mononuclear phagocytes into the synovial fluid and tissues of arthritic patients. We investigated the production of the chemotactic cytokine monocyte chemoattractant protein-i (MCP-1) using sera, synovial fluid, synovial tissue, as well as macrophages and fibroblasts isolated from synovial tissues from 80 arthritic patients. MCP-1 levels were significantly higher (P < 0.05) in synovial fluid from RA patients (mean 25.5±8.1 ng/ml ISEI) compared to synovial fluid from osteoarthritis (OA) patients (0.92±0.08), or from patients with other arthritides (2.9±1.5). MCP-1 levels in RA sera (8.44±2.33) were significantly greater than MCP-1 in normal sera (0.16±0.06). The quantities ofRA synovial fluid IL-8, which is chemotactic for neutrophils and lymphocytes, and MCP-1 were strongly positively correlated (P < 0.05). To examine the cellular source of MCP-1, RA synovial tissue macrophages and fibroblasts were isolated. Synovial tissue fibroblasts did not express MCP-1 mRNA, but could be induced to produce MCP-1 by stimulation with either IL-1#, tumor necrosis factor-alpha (TNF-a), or LPS. In contrast, unlike normal peripheral blood monocytes or alveolar macrophages, RA synovial tissue macrophages constitutively expressed MCP-1 mRNA and antigen. Immunohistochemical analysis of synovial tissue showed that a significantly greater percentage of RA macrophages (50±8%) as compared to either OA macrophages (5±2) or normal macrophages (1±0.3) reacted with anti-MCP-1 antibodies. In addition, the synovial lining layer reacted with MCP-1 in both RA and OA synovial tissues. In contrast, only a minority of synovial fibroblasts (18±8%) from RA synovium were positive for immunolocalization of MCP-1. These results suggest that synovial production of MCP-1 may play an important role in the recruitment of mononuclear phagocytes during inflammation associated with RA and that synovial tissue macrophages are the dominant source of this cytokine. (J. Clin. Invest. 1992. 90:772-779.)

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The role of cytokines in the pathogenesis of rheumatoid arthritis

Cited by 135 publications

References 172 publications

Role of cytokines in inflammatory synovitis

Role of cytokines in inflammatory synovitis

The ability of synoviocytes to support terminal differentiation of activated B cells may explain plasma cell accumulation in rheumatoid synovium.

Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis.

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