IL-27p28 inhibits central nervous system autoimmunity by concurrently antagonizing Th1 and Th17 responses

Chong, Wai Po; Horai, Reiko; Mattapallil, Mary J.; Silver, Phyllis B.; Chen, Jun; Zhou, Ru; Sergeev, Yuri V.; Villasmil, Rafael; Chan, Chi‐Chao; Caspi, Rachel R

doi:10.1016/j.jaut.2013.08.003

Cited by 65 publications

(54 citation statements)

References 60 publications

(91 reference statements)

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“…In chronic liver inflammation, IL-30 recruits natural-killer–like T (NKT) cells to the liver to remove activated hepatic stellate cells [4]. Another of its functions is inhibition of central nervous system autoimmunity via antagonizing Th1 and Th17 responses in experimental autoimmune uveitis [1,5]. These limited in vivo studies show that IL-30 has an anti-inflammatory role in inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells

Yan

Mitra

et al. 2016

Journal of Hepatology

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Background & Aims Sepsis is an acute systemic inflammatory response to infection associated with high patient mortality (28-40%). We hypothesized that interleukin (IL)-30, a novel cytokine protecting mice against liver injury resulted from inflammation, would generate a protective effect against systemic inflammation and sepsis-induced death. Methods Sepsis was induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). The inhibitory effects of IL-30 on septic inflammation and associated therapeutic effects were determined in wild-type, IL-30 (p28)−/−, IL10−/−, and CD1d−/− mice. Results Mice treated with pIL30 gene therapy or recombinant IL-30 protein (rIL30) were protected from LPS-induced septic shock or CLP-induced polymicrobial sepsis and showed markedly less liver damage and lymphocyte apoptosis than control septic mice. The resulting reduction in mortality was mediated through attenuation of the systemic pro-inflammatory response and augmentation of bacterial clearance. Mice lacking IL-30 were more sensitive to LPS-induced sepsis. Natural killer–like T cells (NKT) produced much higher levels of IL-10 and lower levels of interferon–gamma and tumor necrosis factor–alpha in IL-30–treated septic mice than in control septic mice. Likewise, deficiency in IL-10 or NKT cells abolished the protective role of IL-30 against sepsis. Furthermore, IL-30 induced IL-10 production in purified and LPS-stimulated NKT cells. Blocking IL-6R or gp130 inhibited IL-30 mediated IL-10 production. Conclusions IL-30 is important in modulating production of NKT cytokines and subsequent NKT cell–mediated immune regulation of other cells. Therefore, IL-30 has a role in prevention and treatment of sepsis via modulation of cytokine production by NKT.

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Section: Introductionmentioning

confidence: 99%

Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells

Yan

Mitra

et al. 2016

Journal of Hepatology

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“…However, in one study, IL-27 failed to inhibit IL-17 production from Th17 in vitro and in vivo, and consequently failed to suppress EAE development, showing the inhibitory effect of IL-27 on T cell differentiation but not on committed Th17 cells [38]. In another study, overexpression of the p28 subunit of IL-27 inhibited the initiation and progression of EAE, thus showing the immunoregulatory effect on IL-27 on CNS autoimmunity [87]. This outcome involved reduced generation and activity of both Th1 and Th17 cells.…”

Section: Involvement Of Il-27 In the Pathogenesis Of Autoimmune DImentioning

confidence: 99%

“…The effect of p28/p40 was superior to that of p28 alone. Similarly, the overexpression of IL-27p28 in mice led to attenuated uveitis following the regimen aimed at prevention versus progression of uveitis [87]. The protective effect of IL-27 was attributed to the inhibitory effect of IL-27 on pathogenic Th1 and Th17 responses.…”

Section: Involvement Of Il-27 In the Pathogenesis Of Autoimmune DImentioning

confidence: 99%

IL-27-induced modulation of autoimmunity and its therapeutic potential

Meka

Venkatesha

Dudics

et al. 2015

Autoimmunity Reviews

147

130

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Interleukin-27 (IL-27) is a new member of the IL-12 family. It is produced by activated antigen-presenting cells and plays an important role in the regulation of CD4+ T cell differentiation and immune response. IL-27 activates multiple signaling cascades, including the JAK-STAT and p38 MAPK pathways. Several studies have revealed that IL-27 promotes the differentiation of Th1 and Tr1, but inhibits Th2, Th17, and Treg cells. However, a few studies have shown an opposite effect on certain T cell subsets, such as Treg. IL-27 displays both pro- and anti- inflammatory activities in different autoimmune diseases. Here, we have discussed the role of IL-27 in rheumatoid arthritis, multiple sclerosis, colitis, lupus, psoriasis, type 1 diabetes, and uveitis. Most of this information is derived from experimental models of these autoimmune diseases. The mechanistic basis of the dual role of IL-27 in inflammation and autoimmunity is still not fully defined. In general, the pro-/ anti- inflammatory activity of IL-27 is influenced by the underlying immune effector pathways, the phase of the disease, the presence or absence of counter-regulatory cytokines/T cell subsets, and the tissue/cell type under study. Despite a spectrum of outcomes in various autoimmune diseases, mostly anti-inflammatory and immunomodulatory effects of IL-27 have been observed in this category of diseases. Accordingly, IL-27 represents a novel, promising target/agent for the treatment of autoimmune diseases.

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“…IL‐27 can inhibit the development of experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS (Batten et al, ; Fitzgerald et al, ; Goldberg et al, ; Stumhofer et al, ). Interestingly, the p28 subunit of IL‐27 diminishes autoimmune responses in EAE and experimental autoimmune uveitis (Chong et al, ). The mechanisms involved include impaired Th17 cell development, increased differentiation of IL‐10‐producing regulatory T cells, and induction of CD39 on dendritic cells leading to their diminished capacity to promote Th1 and Th17 differentiation (Batten et al, ; Fitzgerald et al, ; Mascanfroni et al, ; Stumhofer et al, ).…”

Section: Introductionmentioning

confidence: 99%

Production of IL‐27 in multiple sclerosis lesions by astrocytes and myeloid cells: Modulation of local immune responses

Sénécal

Deblois

Beauseigle

et al. 2015

Glia

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The mechanisms whereby human glial cells modulate local immune responses are not fully understood. Interleukin-27 (IL-27), a pleiotropic cytokine, has been shown to dampen the severity of experimental autoimmune encephalomyelitis, but it is still unresolved whether IL-27 plays a role in the human disease multiple sclerosis (MS). IL-27 contribution to local modulation of immune responses in the brain of MS patients was investigated. The expression of IL-27 subunits (EBI3 and p28) and its cognate receptor IL-27R (the gp130 and TCCR chains) was elevated within post-mortem MS brain lesions compared with normal control brains. Moreover, astrocytes (GFAP(+) cells) as well as microglia and macrophages (Iba1(+) cells) were important sources of IL-27. Brain-infiltrating CD4 and CD8 T lymphocytes expressed the IL-27R specific chain (TCCR) implying that these cells could respond to local IL-27 sources. In primary cultures of human astrocytes inflammatory cytokines increased IL-27 production, whereas myeloid cell inflammatory M1 polarization and inflammatory cytokines enhanced IL-27 expression in microglia and macrophages. Astrocytes in postmortem tissues and in vitro expressed IL-27R. Moreover, IL-27 triggered the phosphorylation of the transcription regulator STAT1, but not STAT3 in human astrocytes; indeed IL-27 up-regulated MHC class I expression on astrocytes in a STAT1-dependent manner. These findings demonstrated that IL-27 and its receptor were elevated in MS lesions and that local IL-27 can modulate immune properties of astrocytes and infiltrating immune cells. Thus, therapeutic strategies targeting IL-27 may influence not only peripheral but also local inflammatory responses within the brain of MS patients.

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IL-27p28 inhibits central nervous system autoimmunity by concurrently antagonizing Th1 and Th17 responses

Cited by 65 publications

References 60 publications

Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells

Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells

IL-27-induced modulation of autoimmunity and its therapeutic potential

Production of IL‐27 in multiple sclerosis lesions by astrocytes and myeloid cells: Modulation of local immune responses

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