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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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Augmentation of IL-1β, IL-6, TNF-α, COX-2, and IL-1R mRNA expression in the joints of BALB/cA IL-1ra−/− mice. Total RNA was isolated from the joints, and poly (A)+ RNA was purified. Expression of the genes for IL-1ra, IL-1α, IL-1β, IL-6, TNF-α, IL-1RI, IL-1RII, and COX-2 was examined by Northern blot hybridization analysis. (a) Lanes 1 and 2 and 5–8, IL-1ra+/+ mice; lanes 3 and 4 and 9–12, IL-1ra−/− mice. Lanes 1 and 2 and 5–12, nonarthritic mice; lanes 3 and 4, arthritic mice (severity score = 6). Ages of the mice are indicated at top. The results were reproducible in three independent experiments. (b) Densitometric analysis of mRNA expression levels. The radioactivity for a band shown in panel a was measured by a BAS 2000 system and normalized by that of β-actin; the radioactivities of the mutant mice relative to those of age-matched wild-type mice are shown. White bar, wild-type mouse; black bar, arthritic IL-1ra−/− mouse; gray bar, nonarthritic IL-1ra−/− mouse. w, wk.
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Figure 4: Augmentation of IL-1β, IL-6, TNF-α, COX-2, and IL-1R mRNA expression in the joints of BALB/cA IL-1ra−/− mice. Total RNA was isolated from the joints, and poly (A)+ RNA was purified. Expression of the genes for IL-1ra, IL-1α, IL-1β, IL-6, TNF-α, IL-1RI, IL-1RII, and COX-2 was examined by Northern blot hybridization analysis. (a) Lanes 1 and 2 and 5–8, IL-1ra+/+ mice; lanes 3 and 4 and 9–12, IL-1ra−/− mice. Lanes 1 and 2 and 5–12, nonarthritic mice; lanes 3 and 4, arthritic mice (severity score = 6). Ages of the mice are indicated at top. The results were reproducible in three independent experiments. (b) Densitometric analysis of mRNA expression levels. The radioactivity for a band shown in panel a was measured by a BAS 2000 system and normalized by that of β-actin; the radioactivities of the mutant mice relative to those of age-matched wild-type mice are shown. White bar, wild-type mouse; black bar, arthritic IL-1ra−/− mouse; gray bar, nonarthritic IL-1ra−/− mouse. w, wk.

Mentions: We then investigated the pathogenesis of arthritis and autoimmunity. It was conceivable that the deficiency of IL-1ra could exaggerate IL-1 signaling, because IL-1ra is a competitive inhibitor of IL-1α and IL-1β. As IL-1 is known to induce various inflammatory cytokines, we analyzed expression of inflammatory mediators in the joints of IL-1ra−/− mice to examine whether IL-1 signaling is augmented in these mice. As shown in Fig. 4, the IL-1β mRNA level was increased 10-fold in arthritic joints at 16 wk of age (grade = 6) compared with IL-1ra+/+ mice. The expression levels of IL-6 and TNF-α were also augmented in the arthritic joints, although the augmentation of TNF-α was less intensive (IL-6, 10–26-fold; TNF-α, 1.2–1.5-fold). On the other hand, the expression level of IL-1α was rather suppressed (1/3–1/2). The COX-2 mRNA level was elevated 2.5–3.5-fold in 16-wk-old arthritic mice, coinciding with inflammation in the joints. The expression levels of both IL-1RI and IL-1RII were also increased twofold at 16 wk of age.


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)

Augmentation of IL-1β, IL-6, TNF-α, COX-2, and IL-1R mRNA expression in the joints of BALB/cA IL-1ra−/− mice. Total RNA was isolated from the joints, and poly (A)+ RNA was purified. Expression of the genes for IL-1ra, IL-1α, IL-1β, IL-6, TNF-α, IL-1RI, IL-1RII, and COX-2 was examined by Northern blot hybridization analysis. (a) Lanes 1 and 2 and 5–8, IL-1ra+/+ mice; lanes 3 and 4 and 9–12, IL-1ra−/− mice. Lanes 1 and 2 and 5–12, nonarthritic mice; lanes 3 and 4, arthritic mice (severity score = 6). Ages of the mice are indicated at top. The results were reproducible in three independent experiments. (b) Densitometric analysis of mRNA expression levels. The radioactivity for a band shown in panel a was measured by a BAS 2000 system and normalized by that of β-actin; the radioactivities of the mutant mice relative to those of age-matched wild-type mice are shown. White bar, wild-type mouse; black bar, arthritic IL-1ra−/− mouse; gray bar, nonarthritic IL-1ra−/− mouse. w, wk.
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Figure 4: Augmentation of IL-1β, IL-6, TNF-α, COX-2, and IL-1R mRNA expression in the joints of BALB/cA IL-1ra−/− mice. Total RNA was isolated from the joints, and poly (A)+ RNA was purified. Expression of the genes for IL-1ra, IL-1α, IL-1β, IL-6, TNF-α, IL-1RI, IL-1RII, and COX-2 was examined by Northern blot hybridization analysis. (a) Lanes 1 and 2 and 5–8, IL-1ra+/+ mice; lanes 3 and 4 and 9–12, IL-1ra−/− mice. Lanes 1 and 2 and 5–12, nonarthritic mice; lanes 3 and 4, arthritic mice (severity score = 6). Ages of the mice are indicated at top. The results were reproducible in three independent experiments. (b) Densitometric analysis of mRNA expression levels. The radioactivity for a band shown in panel a was measured by a BAS 2000 system and normalized by that of β-actin; the radioactivities of the mutant mice relative to those of age-matched wild-type mice are shown. White bar, wild-type mouse; black bar, arthritic IL-1ra−/− mouse; gray bar, nonarthritic IL-1ra−/− mouse. w, wk.
Mentions: We then investigated the pathogenesis of arthritis and autoimmunity. It was conceivable that the deficiency of IL-1ra could exaggerate IL-1 signaling, because IL-1ra is a competitive inhibitor of IL-1α and IL-1β. As IL-1 is known to induce various inflammatory cytokines, we analyzed expression of inflammatory mediators in the joints of IL-1ra−/− mice to examine whether IL-1 signaling is augmented in these mice. As shown in Fig. 4, the IL-1β mRNA level was increased 10-fold in arthritic joints at 16 wk of age (grade = 6) compared with IL-1ra+/+ mice. The expression levels of IL-6 and TNF-α were also augmented in the arthritic joints, although the augmentation of TNF-α was less intensive (IL-6, 10–26-fold; TNF-α, 1.2–1.5-fold). On the other hand, the expression level of IL-1α was rather suppressed (1/3–1/2). The COX-2 mRNA level was elevated 2.5–3.5-fold in 16-wk-old arthritic mice, coinciding with inflammation in the joints. The expression levels of both IL-1RI and IL-1RII were also increased twofold at 16 wk of age.

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