Inflammation in the Central Nervous System and Th17 Responses Are Inhibited by IFN-γ–Induced IL-18 Binding Protein

Millward, Jason M.; Løbner, Morten; Wheeler, Robert W.; Owens, Trevor

doi:10.4049/jimmunol.0902153

Cited by 38 publications

(34 citation statements)

References 47 publications

(54 reference statements)

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“…However, our data shown in Fig 6, as well as that reported by others (15,17), suggest that IL-18 or IL-18R may also have a key role in promoting IL-17 production and autoimmunity. One explanation for this is that IL-18 may function at least in part through induction of IL-1.…”

Section: Il-18 With Il-23 Promotes Il-17 Production By Cd4 T Cells contrasting

confidence: 40%

“…It has also been shown that overexpression of IL-18bp, an endogenous inhibitor of IL-18, reduced Th17 responses and the severity of EAE in mice, independently of IFN-g (15). Furthermore, it was demonstrated that IL-18-deficient mice are unable to mount autoreactive Th1 responses and are resistant to the development of EAE (16).…”

Section: Foxp3mentioning

confidence: 93%

“…Our findings suggest that IL-18 promotes innate IL-17 production from gd T cells, which may be more important in initiating EAE but also promotes IL-17 production from CD4 T cells during development of disease. There is conflicting evidence in the literature on the role of IL-18 in the development of autoimmune diseases, with some studies failing to demonstrate a significant role in autoimmune pathology and others showing that the absence of IL-18 in knockout mice or blocking its function by overexpression of the IL-18bp reduces the severity of EAE (14)(15)(16)(17)19). The present study provides indirect and direct evidence of a pathogenic role for IL-18 in autoimmunity and may explain some of the previous inconsistencies in the literature.…”

Section: Discussionmentioning

confidence: 99%

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Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

Lalor

Dungan

Sutton

et al. 2011

The Journal of Immunology

317

260

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IL-1β plays a critical role in promoting IL-17 production by γδ and CD4 T cells. However, IL-1–targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1β and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1–processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1β and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1β or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and γδ T cells in vivo and attenuated the clinical signs of EAE. γδ T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1β and IL-23, stimulated IL-17 production by γδ T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1–processed cytokines IL-1β and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1β and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases.

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Section: Il-18 With Il-23 Promotes Il-17 Production By Cd4 T Cells contrasting

confidence: 40%

Section: Foxp3mentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

Lalor

Dungan

Sutton

et al. 2011

The Journal of Immunology

317

260

View full text Add to dashboard Cite

show abstract

“…While detection of live B. burgdorferi microorganisms in patients is difficult, chronic Lyme disease displays clinical similarities with autoimmune disorders such as rheumatoid arthritis (RA) and multiple sclerosis (MS), in which T cells are known to play important roles. Pathogenic Th17 cells (CD4 ϩ T cells) play a prominent role in the pathogenesis of these diseases (8,21,23).…”

Section: Interleukin-23 (Il-mentioning

confidence: 99%

Role of Interleukin-23 (IL-23) Receptor Signaling for IL-17 Responses in Human Lyme Disease

et al. 2011

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“…It was first described as interferon-␥ (IFN-␥)-inducing factor, because of its ability to induce IFN-␥ production from T cells in synergy with IL-12 (37) and as such is an important promoter of Th1-type immune responses and an enhancer of T cell cytotoxicity (16,57). Additionally IL-18 has a role in Th2 (8)-and Th17-driven processes (30,44).…”

mentioning

confidence: 99%

Interleukin-18 binding protein therapy is protective in adriamycin nephropathy

Wyburn

Chadban

Kwan

et al. 2013

American Journal of Physiology-Renal Physiology

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Adriamycin nephropathy (AN) is an experimental model of focal segmental glomerulosclerosis (FSGS) in which macrophages are considered to play a pathogenic role. We hypothesize that interleukin-18 (IL-18), largely derived from macrophages, is a key contributor to kidney injury in AN and a potential therapeutic target. In this study, BALB/c mice received adriamycin (9.6 mg/kg) via tail vein injection and subsequently were treated with either neutralizing IL-18 binding protein (IL-18BP; 250 μg) or normal saline (control). At 5 wk, IL-18 was upregulated in AN, and IL-18BP therapy afforded significant protection against the development of AN, resulting in less proteinuria ( P < 0.01), kidney dysfunction ( P < 0.01), glomerulosclerosis ( P < 0.001), and interstitial accumulation of macrophages and T cells ( P < 0.001). Gene expression of IL-18 downstream inflammatory molecules, including inducible nitric oxide synthase ( P < 0.001), TNF-α ( P < 0.001), and IFN-γ ( P < 0.01); IL-17 ( P < 0.001) and the chemokines CCL2 ( P < 0.01) and CCL5 ( P < 0.005), was reduced. We demonstrate that IL-18 plays a significant role in the pathogenesis of AN. The protective effect of IL-18BP therapy illustrates the importance of immune mediators in chronic proteinuric kidney disease and highlights the potential of IL-18BP therapy.

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Inflammation in the Central Nervous System and Th17 Responses Are Inhibited by IFN-γ–Induced IL-18 Binding Protein

Abstract: Material

Cited by 38 publications

References 47 publications

Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

Role of Interleukin-23 (IL-23) Receptor Signaling for IL-17 Responses in Human Lyme Disease

Interleukin-18 binding protein therapy is protective in adriamycin nephropathy

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