Interleukin-27: Regulation of Immune Responses and Disease Development by a Pleiotropic Cytokine with Pro- and Anti-inflammatory Properties

Mizoguchi, Itaru; Higuchi, Kaname; Mitobe, Kana; Tsunoda, Ren; Mizuguchi, Junichiro; Yoshimoto, Takayuki

doi:10.1007/978-4-431-54442-5_14

Cited by 6 publications

(11 citation statements)

References 129 publications

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“…The p40 subunit is also covalently bound with an IL‐12 p35‐related protein, p19, to form IL‐23, which plays an important role in developing tissue‐specific autoimmune diseases and inflammatory diseases by enhancing IL‐17 production and maintaining pathogenic Th17 cells . IL‐27 consists of an IL‐12 p35‐related protein, p28, which is also called IL‐30, and an IL‐12 p40‐related protein, Epstein–Barr virus‐induced gene 3 (EBI3) (Fig. ).…”

Section: Interleukin‐12 Cytokine Familymentioning

confidence: 99%

Potential clinical application of interleukin‐27 as an antitumor agent

et al. 2015

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Cancer immunotherapies such as sipuleucel-T and ipilimumab are promising new treatments that harness the power of the immune system to fight cancer and achieve long-lasting remission. Interleukin (IL)-27, a member of the IL-12 heterodimeric cytokine family, has pleiotropic functions in the regulation of immune responses with both pro-inflammatory and anti-inflammatory properties. Evidence obtained using a variety of preclinical mouse models indicates that IL-27 possesses potent antitumor activity against various types of tumors through multiple mechanisms without apparent adverse effects. These mechanisms include those mediated not only by CD8+ T cells, natural killer cells and macrophages, but also by antibody-dependent cell-mediated cytotoxicity, antiangiogenesis, direct antiproliferative effects, inhibition of expression of cyclooxygenase-2 and prostaglandin E2, and suppression of epithelial–mesenchymal transition, depending on the characteristics of individual tumors. However, the endogenous role of IL-27 subunits and one of its receptor subunits, WSX-1, in the susceptibility to tumor development after transplantation of tumor cell lines or endogenously arising tumors seems to be more complicated. IL-27 functions as a double-edged sword: IL-27 increases IL-10 production and the expression of programmed death ligand 1 and T-cell immunoglobulin and mucin domain-3, and promotes the generation of regulatory T cells, and IL-27 receptor α singling enhances transformation; IL-27 may augment protumor effects as well. Here, we review both facets of IL-27, antitumor effects and protumor effects, and discuss the potential clinical application of IL-27 as an antitumor agent.

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Section: Interleukin‐12 Cytokine Familymentioning

confidence: 99%

Potential clinical application of interleukin‐27 as an antitumor agent

et al. 2015

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“…1 Antitumor effect of IL-27 was first demonstrated in 2004 using mouse colon carcinoma Colon 26 transfected with IL-27 expression vector, which greatly reduced tumor growth through mainly CD8 C T cells. 2 Since then accumulating evidence by several groups has revealed that IL-27 possesses potent antitumor activity against a variety of tumor models, ranging from a transplanted mouse tumor genetically engineered to secret IL-27 before transplantation to a human therapeutic model by injection of IL-27 protein into immunodeficient mice after transplantation of human tumor as preclinical tumor models.…”

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confidence: 99%

“…Since several tumors were revealed to express both IL-27R subunits on the cell surface, IL-27 elicited direct antiproliferative effects via WSX-1/ STAT1 signaling, presumably, by its cytostatic effects rather than by cytotoxic effects. 1 Recently, we have further elucidated a novel antitumor mechanism that IL-27 augments the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Toll-like receptor 3 (TLR3) in human melanoma cell lines, SK-MEL-13, 28, and 37, and that IL-27 inhibits the tumor growth in cooperation with a TRL3 agonist, polyinosinic-polycytidylic acid [poly(I:C)], partly in a TRAIL-dependent manner. 7 Moreover, repeated injections of IL-27 protein and poly(I:C) cooperatively suppressed in vivo tumor growth of human melanoma in immunodeficient non-obese diabetic/ severe combined mice.…”

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confidence: 99%

“…4 IL-27 strongly inhibited their tumor growth in vivo mainly due to suppression of pro-angiogenesis-related molecules such as vascular endothelial growth factors, angiopoietins, and matrix metalloproteinases, and also due to inverse augmentation of anti-angiogenesis-related molecules such as tissue inhibitor of metalloproteinase. 5,6 Since IL-27 possesses both pro-inflammatory and anti-inflammatory activities, 1 some of them such as IL-27-mediated augmentation of IL-10 production and up-regulation of programmed deathligand 1 (PD-L1) may function against its antitumor effects, although the role of IL-27 in the induction of Treg cells is still controversial. 8,9 Therefore, it is reasonable to consider that the potent antitumor activity of IL-27 is the sum of these positive and negative effects on the immune responses to tumors.…”

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confidence: 99%

“…10 Moreover, IL-27 was recently shown to induce the expression of PD-L1 in T cells, a major mediator of T-cell exhaustion, which hampers the induction of antitumor immune responses. 1 However, since antibody drugs have currently become very popular as one of the most promising cancer immunotherapies, IL-27 injection could augment antitumor immune responses in synergy with antibodies against immune checkpoints such as PD-L1, whose possibility remains to be clarified. On the other hand, IL-27 was initially demonstrated to inhibit the differentiation of naive CD4…”

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