Epstein–Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin

Devergne, Odile; Birkenbach, Mark; Kieff, Elliott

doi:10.1073/pnas.94.22.12041

Cited by 282 publications

(246 citation statements)

References 22 publications

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“…Together, these findings suggest that the different IL-27R components mediate different functional activities (i.e., proliferation vs acquisition of effector functions) or that additional ligands for WSX-1 are involved in the differential regulation of these activities. For example, previous studies have reported that EBI3 and IL-12p35 can dimerize, but no function has been ascribed to this potential cytokine (46). It will be critical to understand how IL-27, or related cytokines, interact with WSX-1 and gp130 to differentially regulate multiple immune cell types in the context of type 2 immunity.…”

Section: Discussionmentioning

confidence: 99%

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

Artis¹,

Villarino²,

Silverman

et al. 2004

The Journal of Immunology

221

210

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Although previous studies have investigated the role of IL-27/WSX-1 interactions in the regulation of Th1 responses, little is known about their role in regulating Th2-type responses. Studies presented in this work identify a direct role for IL-27/WSX-1 interactions in the negative regulation of type 2 responses independent of effects on type 1 cytokines. WSX-1−/− mice infected with the gastrointestinal helminth Trichuris muris displayed accelerated expulsion of parasites and the development of exaggerated goblet cell hyperplasia and mastocytosis in the gut due to increased production of Th2 cytokines. Enhanced mast cell activity in the absence of WSX-1 was consistent with the ability of wild-type mast cells to express this receptor. In addition, IL-27 directly suppressed CD4+ T cell proliferation and Th2 cytokine production. Together, these studies identify a novel role for IL-27/WSX-1 in limiting innate and adaptive components of type 2 immunity at mucosal sites.

show abstract

Section: Discussionmentioning

confidence: 99%

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

Artis¹,

Villarino²,

Silverman

et al. 2004

The Journal of Immunology

221

210

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“…It has been recently shown that a protein encoded by the Epstein-Barr-induced gene 3 (EBI3), sharing 27% of the amino acid sequence identity with the p40 component of IL-12, can form a heterodimer with the p35 subunit. This new heterodimer might function as an IL-12 antagonist and favour the down-regulation of Th1 cytokines [36]. Interestingly, enhanced EBI3 expression has been detected in inflamed mucosa of UC patients but not in active CD [37], suggesting that defective production of counterbalancing molecules may be contributory to the development of Th1 type lymphocytes in CD.…”

Section: Il-12 May Be the Cytokine Responsible For Driving Th1 Responmentioning

confidence: 97%

Recent Developments in the Immunology of Inflammatory Bowel Disease

2000

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Crohn's disease and ulcerative colitis are caused by excessive immune reactivity in the gut wall. Analysis of the type of immune responses ongoing in diseased gut has revealed important features which suggest that these conditions are different. In Crohn's disease tissue there is considerable evidence for an ongoing T helper cell type 1 response, with excess interleukin‐12, interferon‐γ and TNF‐α. There is circumstantial evidence in patients that this response is directed against the normal bacterial flora and definitive evidence in mouse models that T cell responses to the flora cause gut disease. In ulcerative colitis, the role of tissue damaging T cell responses in the gut mucosa is much less clear and there is more evidence that the lesion is owing to antibody‐mediated hypersensitivity. Although different types of immune reactions initiate tissue injury in both Crohn's disease and ulcerative colitis, the downstream events which actually damage the tissue are the same in each condition. Elevated cytokine concentrations in the mucosa lead to the production of excess matrix degrading enzymes by gut fibroblasts, loss of mucosal integrity and ulceration. The same process also leads to an increased production of epithelial growth factors such as KGF Keratinocyte Growth Factor by gut fibroblasts and produces the crypt cell hyperplasia characteristic of all gut inflammatory conditions.

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“…As observed in IL-12R (IL-12R␤1 plus -␤2 on Th1 effecter cells) vs IL-23R (IL-12R␤1 plus unique IL-23R on Th1 memory cells) (33), it is very likely that distinct subunits are used in distinct cell populations, i.e., CD4 ϩ cells and NKT cells, to exert different functions. Similarly, it is also possible that distinct ligands, such as IL-27 (p28 plus EBI-3) vs EBI-3 plus p35 of IL-12 (24,34), bind to the WSX-1 receptor complex in various settings (see Ref. 35 for review).…”

Section: Discussionmentioning

confidence: 99%

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

Yamanaka

Hamano

Miyazaki

et al. 2004

The Journal of Immunology

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Administration of Con A induces liver injury that is considered to be an experimental model for human autoimmune or viral hepatitis, where immunopathology plays roles mediated by activated lymphocytes, especially NK1.1+ CD3+ NKT cells, and inflammatory cytokines, including IFN-γ and IL-4. In the present study we investigated the role of WSX-1, a component of IL-27R, in Con A-induced hepatitis by taking advantage of WSX-1 knockout mice. WSX-1-deficient mice were more susceptible to Con A treatment than wild-type mice, showing serum alanine aminotransferase elevation and massive necrosis in the liver. Although the development of NKT cells appeared normal in WSX-1 knockout mice, purified NKT cells from the knockout mice produced more IFN-γ and IL-4 than those from wild-type mice in response to stimulation with Con A both in vitro and in vivo. In addition, hyperproduction of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, was observed in the knockout mice after Con A administration. These data revealed a novel role for WSX-1 as an inhibitory regulator of cytokine production and inflammation in Con A-induced hepatitis.

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Epstein–Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin

Cited by 282 publications

References 22 publications

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

Recent Developments in the Immunology of Inflammatory Bowel Disease

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

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