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Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice.

Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y - J. Exp. Med. (2000)

Bottom Line: Proinflammatory cytokines such as IL-1beta, IL-6, and tumor necrosis factor alpha 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

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-1beta, IL-6, and tumor necrosis factor alpha 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.

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Antibody production in IL-1ra−/− mice. Serum antibody levels in IL-1ra−/− mice (−/−) and their wild-type littermates (+/+) were determined by ELISA at 16 wk of age. (a) Levels of total IgM, IgG, and IgE in BALB/cA background mice. (b) Levels of IgG subclasses in BALB/cA background mice. (c) Levels of autoantibodies against IgG (RF) of IgG class and IgM class, IIC, and dsDNA in BALB/cA background mice. (d) Autoantibody levels in C57BL/6J background mice. The serum dilution in c and d was 1/25. Autoantibody levels were expressed as the relative absorbance of the ELISA. Average ± SD of each genotype is shown. Open bars: wild-type mice; n = 13 (a), n = 11 (b), n = 9 (c), and n = 8 (d). Shaded bars: IL-1ra−/− mice; n = 14 (a), n = 12 (b), n = 10 (c), and n = 15 (d). Statistical significance was calculated by Student's t test. *P < 0.0001; ‡P < 0.005; §P < 0.05.
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Figure 3: Antibody production in IL-1ra−/− mice. Serum antibody levels in IL-1ra−/− mice (−/−) and their wild-type littermates (+/+) were determined by ELISA at 16 wk of age. (a) Levels of total IgM, IgG, and IgE in BALB/cA background mice. (b) Levels of IgG subclasses in BALB/cA background mice. (c) Levels of autoantibodies against IgG (RF) of IgG class and IgM class, IIC, and dsDNA in BALB/cA background mice. (d) Autoantibody levels in C57BL/6J background mice. The serum dilution in c and d was 1/25. Autoantibody levels were expressed as the relative absorbance of the ELISA. Average ± SD of each genotype is shown. Open bars: wild-type mice; n = 13 (a), n = 11 (b), n = 9 (c), and n = 8 (d). Shaded bars: IL-1ra−/− mice; n = 14 (a), n = 12 (b), n = 10 (c), and n = 15 (d). Statistical significance was calculated by Student's t test. *P < 0.0001; ‡P < 0.005; §P < 0.05.

Mentions: We next investigated Ig levels in the serum. The IgM concentration was not changed in these mice (Fig. 3 a). In contrast, total IgG and IgE levels were elevated two- to threefold at 16 wk of age (Fig. 3 a). Among the IgG subclasses, the level of IgG1, the major component of serum IgG, was significantly elevated, whereas IgG2a and IgG2b levels were not changed and the IgG3 level was slightly reduced compared with IL-1ra+/+ mice (Fig. 3 b).


Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice.

Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y - J. Exp. Med. (2000)

Antibody production in IL-1ra−/− mice. Serum antibody levels in IL-1ra−/− mice (−/−) and their wild-type littermates (+/+) were determined by ELISA at 16 wk of age. (a) Levels of total IgM, IgG, and IgE in BALB/cA background mice. (b) Levels of IgG subclasses in BALB/cA background mice. (c) Levels of autoantibodies against IgG (RF) of IgG class and IgM class, IIC, and dsDNA in BALB/cA background mice. (d) Autoantibody levels in C57BL/6J background mice. The serum dilution in c and d was 1/25. Autoantibody levels were expressed as the relative absorbance of the ELISA. Average ± SD of each genotype is shown. Open bars: wild-type mice; n = 13 (a), n = 11 (b), n = 9 (c), and n = 8 (d). Shaded bars: IL-1ra−/− mice; n = 14 (a), n = 12 (b), n = 10 (c), and n = 15 (d). Statistical significance was calculated by Student's t test. *P < 0.0001; ‡P < 0.005; §P < 0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195765&req=5

Figure 3: Antibody production in IL-1ra−/− mice. Serum antibody levels in IL-1ra−/− mice (−/−) and their wild-type littermates (+/+) were determined by ELISA at 16 wk of age. (a) Levels of total IgM, IgG, and IgE in BALB/cA background mice. (b) Levels of IgG subclasses in BALB/cA background mice. (c) Levels of autoantibodies against IgG (RF) of IgG class and IgM class, IIC, and dsDNA in BALB/cA background mice. (d) Autoantibody levels in C57BL/6J background mice. The serum dilution in c and d was 1/25. Autoantibody levels were expressed as the relative absorbance of the ELISA. Average ± SD of each genotype is shown. Open bars: wild-type mice; n = 13 (a), n = 11 (b), n = 9 (c), and n = 8 (d). Shaded bars: IL-1ra−/− mice; n = 14 (a), n = 12 (b), n = 10 (c), and n = 15 (d). Statistical significance was calculated by Student's t test. *P < 0.0001; ‡P < 0.005; §P < 0.05.
Mentions: We next investigated Ig levels in the serum. The IgM concentration was not changed in these mice (Fig. 3 a). In contrast, total IgG and IgE levels were elevated two- to threefold at 16 wk of age (Fig. 3 a). Among the IgG subclasses, the level of IgG1, the major component of serum IgG, was significantly elevated, whereas IgG2a and IgG2b levels were not changed and the IgG3 level was slightly reduced compared with IL-1ra+/+ mice (Fig. 3 b).

Bottom Line: Proinflammatory cytokines such as IL-1beta, IL-6, and tumor necrosis factor alpha 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

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-1beta, IL-6, and tumor necrosis factor alpha 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.

Show MeSH
Related in: MedlinePlus