Interleukin‐21 Induces T‐cell Activation and Proinflammatory Cytokine Secretion in Rheumatoid Arthritis

Abstract

Interleukin (IL)‐21 is a CD4+ T‐cell‐derived cytokine, which is involved in innate and adaptive immune response. In this study, we analysed IL‐21 receptor (IL‐21R) expression in peripheral blood and synovial fluid mononuclear cells, and investigated the role of IL‐21 in the induction of proinflammatory cytokine production by peripheral blood T cells (PB‐T) and synovial fluid T cells (SF‐T) from patients with rheumatoid arthritis (RA). Immunohistochemical staining demonstrated that IL‐21R‐positive cells were significantly increased in inflamed synovial tissues of RA patients compared with osteoarthritis (OA) and healthy controls. Flow cytometric analysis confirmed that IL‐21R was mainly expressed in freshly isolated CD4, CD8, B and NK cells from peripheral blood and synovial fluid, but decreased gradually in T cells 24 h after anti‐CD3 stimulation. PB‐ and SF‐T cells from RA patients were more responsive to IL‐21 when compared with controls. Importantly, isolated PB‐ or SF‐T cells from RA patients, when stimulated with IL‐21 and anti‐CD3 MoAb, secreted markedly higher levels of TNF‐α and IFN‐γ than controls. These data indicate that IL‐21R is overexpressed in the inflamed synovial membrane and in peripheral blood or synovial fluid leukocytes of RA patients, and that IL‐21 enhances local T‐cell activation, proliferation and proinflammatory cytokine secretion. Thus, blockade of IL‐21R signalling pathway may have a therapeutic potential in acute RA patients.

Interleukin‐21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen‐induced arthritis

“…Regarding the role of IL-21 in inflammatory forms of arthritis such as RA, studies in both mice and humans suggest that IL-21 might be involved in disease progression (29)(30)(31). Young et al demonstrated that blockade of IL-21 with the IL-21R-Fc fusion protein ameliorated clinical disease activity in animal models of inflammatory arthritis, suggesting that IL-21 contributes to the pathologic process of RA (30).…”

“…Li et al reported that blood and synovial fluid T cells from patients with RA produced higher levels of TNF␣ and interferon-␥ after stimulation with anti-CD3 and IL-21 than did T cells from patients with OA and healthy controls, suggesting that IL-21 contributes to the progression of RA by up-regulating the expression of proinflammatory cytokines (29). Therefore, it is conceivable that the IL-21-induced RANKL expression of CD4ϩ T cells might be partially mediated by the TNF␣ induced by IL-21.…”

“…Several studies have shown that IL-21 production is associated with the development of certain autoimmune diseases such as systemic lupus erythematosus (26)(27)(28), RA (29)(30)(31), and primary Sjögren's syndrome (32). Regarding the role of IL-21 in inflammatory forms of arthritis such as RA, studies in both mice and humans suggest that IL-21 might be involved in disease progression (29)(30)(31).…”

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

“…RA peripheral blood and synovial T cells stimulated with anti-CD3 and IL-21 produce more TNF-a and interferon-g than T-cells from healthy controls. 37 Furthermore, inhibition of IL-21 results in reduced TNF-a production. 34 Taken together with evidence that IL-21 acts in an autocrine fashion upon human Th 17 cells in RA, 38 these data suggest that IL-21 makes a substantial contribution to the systemic inflammatory process in RA through upregulation of T-cell cytokines.…”

In vitro potency, pharmacokinetic profiles and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus

“…[8][9][10] The IL-21R can be upregulated on non-lymphoid tissues as well, suggesting a significant role for this cytokine in orchestrating many aspects of the inflammatory response. Increased expression of IL-21 and IL-21R have been associated with human rheumatoid arthritis, [11][12][13] lupus 14 and…”