Development of Chronic Inflammatory Arthropathy Resembling Rheumatoid Arthritis in Interleukin 1 Receptor Antagonist–Deficient Mice

Abstract

Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL-1 activity. However, its pathophysiological roles in a body remain largely unknown. To elucidate the roles of IL-1ra, IL-1ra–deficient mice were produced by gene targeting, and pathology was analyzed on different genetic backgrounds. We found that all of the mice on a BALB/cA background, but not those on a C57BL/6J background, spontaneously developed chronic inflammatory polyarthropathy. Histopathology showed marked synovial and periarticular inflammation, with articular erosion caused by invasion of granulation tissues closely resembling that of rheumatoid arthritis in humans. Moreover, elevated levels of antibodies against immunoglobulins, type II collagen, and double-stranded DNA were detected in these mice, suggesting development of autoimmunity. Proinflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor α were overexpressed in the joints, indicating regulatory roles of IL-1ra in the cytokine network. We thus show that IL-1ra gene deficiency causes autoimmunity and joint-specific inflammation and suggest that IL-1ra is important in maintaining homeostasis of the immune system. Possible involvement of IL-1ra gene deficiency in RA will be discussed.

Induction of cartilage damage by overexpression of T cell interleukin‐17A in experimental arthritis in mice deficient in interleukin‐1

“…Local intraarticular expression of human IL-1 following gene transfer has been shown to result in all major pathologic changes of human RA, with severe joint inflammation and erosions of articular cartilage and periarticular bone (43). Recently, it was shown that deficiency of the IL-1Ra gene causes autoimmunity and chronic inflammatory arthropathy that resembles RA (44). Those studies indicate that under certain circumstances, IL-1 might be an appropriate therapeutic target in the protection of cartilage damage during RA.…”

Suppression of autoimmune arthritis in interleukin‐1‐deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells

“…Recently, we found that IL-1Ra-deficient mice spontaneously develop autoimmune arthritis (9). Furthermore, it has been reported that IL-1␣ causes arthritis when it is injected into rabbit joints (10), and treatment with anti-IL-1␣/␤ as well as with anti-IL-␤ antibody alone, but not with anti-IL-1␣ antibody alone, has been shown to ameliorate experimental collageninduced arthritis (CIA) in mice (11).…”

Mice deficient in hepatocyte‐specific IL‐1Ra show delayed resolution of concanavalin A‐induced hepatitis

“…IL-1Ra binds to IL-1 receptors without inducing intracellular signals and acts as a natural competitive IL-1 inhibitor [2]. Genetic IL-1Ra deficiency leads to excessive IL-1 signaling and exaggerated inflammatory responses in several animal models and in humans [1,[3][4][5][6][7][8][9].…”

“…IL-1Ra binds to IL-1 receptors without inducing intracellular signals and acts as a natural competitive IL-1 inhibitor [2]. Genetic IL-1Ra deficiency leads to excessive IL-1 signaling and exaggerated inflammatory responses in several animal models and in humans [1,[3][4][5][6][7][8][9].IL-1β has been proposed as an important mediator in the pathophysiology of hepatic diseases. Indeed, a significant increase of circulating IL-1β levels has been reported in patients with fulminant hepatic failure and chronic liver diseases [10][11][12][13].…”