IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist

Nakae, Susumu; Saijo, Shinobu; Horai, Reiko; Sudo, Katsuko; Mori, Shigeki; Iwakura, Yoichiro

doi:10.1073/pnas.1035999100

Cited by 447 publications

(394 citation statements)

References 31 publications

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“…Il17 –/– mice show significantly reduced severity in various inflammatory and autoimmune disease models, such as collagen‐induced arthritis,6 Il1rn −/− mouse arthritis,7 EAE8 and imiquimod (IMQ)‐induced skin inflammation,9, 10 suggesting critical roles of IL‐17 in inflammatory/autoimmune diseases. γδ 17 cells are detected in inflamed tissues of these disease models.…”

Section: The Pathogenic Roles Of γδ17 Cells In Mouse Inflammatory Dismentioning

confidence: 99%

“…As described, the importance of IL‐17 in the development of rheumatoid arthritis (RA) is suggested in mouse models and γδ 17 cells are accumulated in arthritic joints,7, 20, 22, 24 but the importance of γδ 17 cells in patients with RA is controversial. A recent report shows that V δ 2 + γδ T cells accumulate in the synovium of patients with RA and produce high levels of IL‐17 as well as IFN‐ γ 98.…”

Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 99%

“…Mice deficient for IL‐17RA are highly susceptible to Klebsiella pneumoniae 3 and IL‐17‐deficient mice are susceptible to bacterial and fungal infection 4, 5. Interleukin‐17 is also implicated in various inflammatory/autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE), arthritis in IL‐1 receptor antagonist‐deficient (Il1rn –/– ) mice and imiquimod‐induced psoriatic dermatitis in mice 6, 7, 8, 9, 10. Anti‐IL‐17 and anti‐IL‐17RA antibodies are effective to treat patients with psoriasis and psoriatic arthritis 11, 12, 13.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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SummaryInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17.

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Section: The Pathogenic Roles Of γδ17 Cells In Mouse Inflammatory Dismentioning

confidence: 99%

Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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“…Identifying T cells that initiate acute uveitis or mechanisms that allow autoreactive T cells to persist in the retina and mediate recurrent uveitis is a challenge. Interleukin-17-producing T (Th17) cells produce TNF-a, IL-21, IL-22, granzyme B, contribute to host defense against microbial agents and have recently been implicated in the development of chronic inflammation in several mouse models [3][4][5], suggesting that the Th17 subset may also be involved in the pathogenesis of immune-mediated diseases in humans, including uveitis. Several studies have reported that IL-23 and IL-17 are elevated in Behc -et's and VKH patients with active uveitis [6][7][8][9], while elevated serum levels of IL-23 and Th17-induced cytokines were found to correlate with intraocular inflammation after cataract surgery in VKH patients [10].…”

Section: Introductionmentioning

confidence: 99%

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Golestaneh

et al. 2011

Eur J Immunol

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Compared with other T‐helper subsets, Th17 cell numbers are very low in human blood but become elevated in chronic inflammatory diseases. In this study, we investigated mechanisms that may explain the frequent involvement of Th17 cells in autoimmune diseases such as uveitis. We compared Th17 and Th1 subsets and found that Th17 cells expressed lower IL‐2 levels during Ag‐priming and this correlated with their decreased susceptibility to activation‐induced cell death (AICD). However, complete depletion of IL‐2 with IL‐2 neutralizing antibodies rendered Th17 cells as susceptible to apoptosis as Th1 cells, suggesting that the low levels of IL‐2 produced by Th17 cells conferred survival advantages to this subset. We describe here a Th17 subtype that constitutively produces very low levels of IL‐2 (Th17‐DP). The Th17‐DP population increased dramatically in the blood and retina of mice during experimental autoimmune uveitis, indicating their potential involvement in the etiology of uveitis. We further show that the majority of the memory Th17 cells in human blood are Th17‐DP and are targets of daclizumab, an IL‐2R antibody used in treating recalcitrant uveitis. Thus, Th17 cells may persist in tissues and contribute to chronic inflammation by limiting IL‐2 production to levels that cannot provoke IL‐2‐induced AICD yet are sufficient to promote Th17 homeostatic expansion.

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“…Judging from these findings, GPI-induced arthritis is considered a useful murine model for analyzing the role of CD4ϩ T cells in the effector phase of the arthritis. Several studies have examined the roles of Th17 cells, a distinct lineage of CD4ϩ effector T cells, in various arthritis models (14)(15)(16)(17). CIA was shown to be partially suppressed in IL-17-deficient mice (16), whereas it was exacerbated in IFN␥-deficient mice or IFN␥ receptor-deficient mice (18)(19)(20).…”

mentioning

confidence: 99%

Crucial role of the interleukin‐6/interleukin‐17 cytokine axis in the induction of arthritis by glucose‐6‐phosphate isomerase

Iwanami¹,

Matsumoto²,

Tanaka-Watanabe³

et al. 2008

Arthritis & Rheumatism

124

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Objective. To clarify the glucose-6-phosphate isomerase (GPI)-specific CD4؉ T cell lineage involved in GPI-induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease.Methods. DBA/1 mice were immunized with GPI to induce arthritis. CD4؉ T cells and antigen-presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme-linked immunosorbent assay. Anti-interferon-␥ (anti-IFN␥) monoclonal antibody (mAb), anti-interleukin-17 (anti-IL-17) mAb, or the murine IL-6 receptor (IL-6R) mAb MR16-1 was injected at different time points, and arthritis development was monitored visually. After MR16-1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4؉ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester.Results. GPI-specific CD4؉ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti-IL-17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti-IFN␥ mAb exacerbated arthritis.Neither anti-IL-17 mAb nor anti-IFN␥ mAb administration on day 14 ameliorated arthritis. Administration of MR16-1 on day 0 or day 3 protected against arthritis induction, and MR16-1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16-1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4؉ T cell proliferation was also suppressed.Conclusion. IL-6 and Th17 play an essential role in GPI-induced arthritis. Since it has previously been shown that treatment with a humanized anti-IL-6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL-6/IL-17 axis might also be involved in the generation of RA, especially in the early effector phase.

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IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist

Cited by 447 publications

References 31 publications

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Crucial role of the interleukin‐6/interleukin‐17 cytokine axis in the induction of arthritis by glucose‐6‐phosphate isomerase

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