Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis

McInnes, Iain B.; Leung, Bernard P.; Sturrock, R. D.; Field, Max; Liew, Foo Y.

doi:10.1038/nm0297-189

Cited by 475 publications

(395 citation statements)

References 36 publications

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“…Expression of IL-15 was demonstrated not only in macrophages but also in endothelial cells and fibroblastlike synoviocytes, and the concentration of IL-15 in synovial fluids was shown to be elevated in RA patients [22][23][24][25][26]. It was also shown that IL-15 induced TNF-a production from macrophages through activation of synovial T cells in RA patients [27]. These findings suggest an involvement of IL-15 in the pathogenesis of RA.…”

Section: Introductionmentioning

confidence: 79%

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17

et al. 2007

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IL-15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL-15 plays an important role in the development of murine collagen-induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL-15 KO mice but were increased in IL-15 Tg mice compared with wild-type (WT) mice. The levels of type II collagen (CII)-specific IL-17 production were significantly increased in IL-15 Tg mice compared with WT mice with CIA. Expression of IL-23R was up-regulated in CD4 + T cells in IL-15 Tg mice but down-regulated in IL-15 KO mice compared with WT mice. In correlation with the expression levels of IL-23R, IL-17 production by CD4 + T cells in response to exogenous IL-23 was increased in IL-15 Tg mice compared with WT mice. Furthermore, exogenous IL-15 synergized with IL-23 to induce CII-specific IL-17 production by CD4 + T cells in vitro. Taken together, these results indicate that IL-15 plays an important role in the progression of CIA through increasing antigen-specific IL-17 production by CD4 + T cells. IntroductionRheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial tissues in multiple joints, which results in destruction of bone and cartilage. Pro-inflammatory cytokines play important roles in this process, as evidenced by the clinical success of cytokine blockade therapies [1,2]. Similar to human RA, various pro-inflammatory cytokines including TNF-a and IL-1b are involved in the pathogenesis of collagen-induced arthritis (CIA), a rodent model of human RA [3][4][5]. The development of CIA depends on both cellular and humoral immune responses to type II collagen (CII) that activate inflammatory cytokine cascades [3,6]. The Th1 response was believed to be essential for the development of the disease [3]. However, recent studies have indicated a critical role of IL-17 in the pathogenesis of autoimmune disease models such as CIA [7,8].IL-17 is a pro-inflammatory cytokine produced mainly by memory CD4 + T cells that stimulates synoviocytes or macrophages to induce various cytokines such as TNF-a and IL-1 [9][10][11]. Lubberts et al. [7] have demonstrated that treatment of DBA1 mice with neutralizing anti-IL-17 Ab shortly after the onset suppressed the development of the CIA, suggesting a critical role of IL-17 at the effector phase. In addition, Nakae et al. [8] have reported, using IL-17-deficient mice with C57BL/6 Â 129 background, that IL-17 was also involved in CIA at the induction phase. IL-17 expression is strongly induced in memory T cells by IL-23, a member of the IL-12 family of cytokines, via signaling through its receptor composed of . Recently, it was demonstrated that IL-23 but not IL-12 is indispensable for the development of CIA, indicating that an IL-17-producing CD4 + T cell response, but not the "classical" Th1 response, is essential for the disease [13,14]. IL-15, a member of the four-helix bundle cytokine family, stimulates macrophages/dendritic cells, natural killer (NK) cells, NKT cells, mucosal...

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Section: Introductionmentioning

confidence: 79%

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17

et al. 2007

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“…38 This cytokine induced TNF-a production by synovial fluid T cells. 39 IL-15 is also a potent activator of NK cell function, stimulating proliferation, cytokine secretion and cytotoxicity. 40 In addition, recent data suggest that the action of certain drugs effective in the treatment of RA (antimalarials and cyclosporin A) could be attributable to effects on NK cell activation.…”

Section: Fccriiia Allelic Polymorphisms In Ramentioning

confidence: 99%

FcγR expression on NK cells influences disease severity in rheumatoid arthritis

et al. 2004

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“…Thus, IL-15 may influence both Th1 and Th2 cells. Aberrant IL-15 expression was observed in patients with inflammatory autoimmune disease, such as rheumatoid arthritis (18,19) and inflammatory bowel diseases (20,21), suggesting that IL-15 is involved in the pathogenesis of inflammatory disease. However, the potential role of IL-15 in allergic responses in vivo remains to be elucidated.…”

Section: Overexpression Of Il-15 In Vivo Enhancesmentioning

confidence: 99%

Overexpression of IL-15 In Vivo Enhances Tc1 Response, Which Inhibits Allergic Inflammation in a Murine Model of Asthma

Ishimitsu

Nishimura

Yajima

et al. 2001

The Journal of Immunology

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IL-15, a pleiotropic cytokine, is involved in the inflammatory responses in various infectious and autoimmune diseases. We have recently constructed IL-15-transgenic (Tg) mice, which have an increased number of memory-type CD8+ T cells in the peripheral lymphoid tissues. In the present study, we found that eosinophilia and Th2-type cytokine production in the airway were severely attenuated in OVA-sensitized IL-15-Tg mice following OVA inhalation. IL-15-Tg mice preferentially developed Tc1 responses mediated by CD8+ T cells after OVA sensitization, and in vivo depletion of CD8+ T cells by anti-CD8 mAb aggravated the allergic airway inflammation in IL-15-Tg mice following OVA inhalation. Adoptive transfer of CD8+ T cells from OVA-sensitized IL-15-Tg mice into normal mice before OVA sensitization suppressed Th2 response to OVA in the normal mice. These results suggest that overexpression of IL-15 in vivo suppresses Th2-mediated-allergic airway response via induction of CD8+ T cell-mediated Tc1 response.

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Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis

Cited by 475 publications

References 36 publications

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17

FcγR expression on NK cells influences disease severity in rheumatoid arthritis

Overexpression of IL-15 In Vivo Enhances Tc1 Response, Which Inhibits Allergic Inflammation in a Murine Model of Asthma

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Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis

Cited by 475 publications

References 36 publications

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4+ T cell response to produce IL‐17

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4+ T cell response to produce IL‐17

FcγR expression on NK cells influences disease severity in rheumatoid arthritis

Overexpression of IL-15 In Vivo Enhances Tc1 Response, Which Inhibits Allergic Inflammation in a Murine Model of Asthma

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IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17

IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4⁺ T cell response to produce IL‐17