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

By R. Horai, S. Saijo, H. Tanioka, S. Nakae, K. Sudo, A. Okahara, T. Ikuse, M. Asano, Y. Iwakura. Journal of Experimental Medicine, 2000

781 citations recorded by the source corpus.

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.

Subfields: Hematology, Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/284e2992acb0fe7026fb14a421b6518056833fe4

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Citations in the corpus

The IL-1 family and inflammatory diseases. (2002, background): “In contrast, as described below, mice deficient in IL-1Ra do not exhibit normal reproduction, have stunted growth and in selected strains develop spontaneous diseases such as rheumatoid arthritislike polyarthropathy and a fatal arteritis (9, 10).”
Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade (2005, background): “IL-1b–deficient mice fail to develop chronic, erosive arthritis in response to arthritogenic stimuli (27) and IL-1Ra–deficient mice develop autoimmunity and arthritis spontaneously (28).”
IL‐1, IL‐18, and IL‐33 families of cytokines (2008, background): “The importance of IL-1Ra in maintaining homeostasis and avoiding disease is illustrated by the spontaneous development of a T-cell-dependent chronic inflammatory arthropathy resembling rheumatoid arthritis (RA) in BALB/cA mice rendered genetically deficient in production of all isoforms of IL-1Ra (3”
THE INTERLEUKIN-1 FAMILY: BACK TO THE FUTURE (2013, positive): “Deficiency of IL-1Ra in mice results in spontaneous and lethal arteritis, destructive arthritis, and psoriatic-like skin lesions, as well as increased susceptibility to carcinogenesis (Horai et al., 2000; Nicklin et al., 2000).”
Anti-inflammatory Agents: Present and Future (2010, positive): “, 1994), and mice deficient in IL-1Ra develop diseases such as destructive arthritis (Horai et al., 2000), arteritis (Nicklin et al.”
Cytokines in the pathogenesis of rheumatoid arthritis (2007, background): “, and mice deficient in IL-1 Receptor antagonist (IL-1RA; also known as IL1RN) develop spontaneous erosive arthritis associated with the induction of T H 17 cell”
The balance between IL-1 and IL-1Ra in disease. (2002, background): “Furthermore, an inflammatory arthritis resembling rheumatoid arthritis developed spontaneously in IL-1Ra knockout mice bred on the BALB/cA background [79].”
The P2X7 Receptor: A Key Player in IL-1 Processing and Release1 (2006, background): “The IL-1Ra knockout mouse spontaneously develops diseases similar to human rheumatoid arthritis and arteritis (24, 25).”