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

Sénécal, Vincent; Deblois, Gabrielle; Beauseigle, Diane; Schneider, Raphaël; Brandenburg, Jonas; Newcombe, Jia; Moore, Craig S.; Prat, Alexandre; Antel, Jack P.; Arbour, Nathalie

doi:10.1002/glia.22948

Cited by 58 publications

(60 citation statements)

References 103 publications

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“…Also, murine B16F10 melanoma cells transfected with WSX-1 receptor chain up-regulate MHC class I expression [43]. In addition, also human keratinocytes [44], astrocytes [45], and hepatocytes or hepatoma cells [38] or THP-1 monocytic cells [46] display increased HLA class I expression in response to IL-27. On the contrary, IL-27 has been reported to impair HLA class I antigen presentation in human immature DCs [47].…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

et al. 2016

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IL-27, a member of the IL-12-family of cytokines, has shown anti-tumor activity in several pre-clinical models due to anti-proliferative, anti-angiogenic and immune-enhancing effects. On the other hand, IL-27 demonstrated immune regulatory activities and inhibition of auto-immunity in mouse models. Also, we reported that IL-27, similar to IFN-γ, induces the expression of IL-18BP, IDO and PD-L1 immune regulatory molecules in human cancer cells. Here, a proteomic analysis reveals that IL-27 and IFN-γ display a broad overlap of functions on human ovarian cancer cells. Indeed, among 990 proteins modulated by either cytokine treatment in SKOV3 cells, 814 showed a concordant modulation by both cytokines, while a smaller number (176) were differentially modulated. The most up-regulated proteins were common to both IFN-γ and IL-27. In addition, functional analysis of IL-27-regulated protein networks highlighted pathways of interferon signaling and regulation, antigen presentation, protection from natural killer cell-mediated cytotoxicity, regulation of protein polyubiquitination and proteasome, aminoacid catabolism and regulation of viral protein levels.Importantly, we found that IL-27 induced HLA class I molecule expression in human cancer cells of different histotypes, including tumor cells showing very low expression. IL-27 failed only in a cancer cell line bearing a homozygous deletion in the B2M gene. Altogether, these data point out to a broad set of activities shared by IL-27 and IFN-γ, which are dependent on the common activation of the STAT1 pathway. These data add further explanation to the anti-tumor activity of IL-27 and also to its dual role in immune regulation.

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Section: Discussionmentioning

confidence: 99%

Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

et al. 2016

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“…Furthermore, IL-27 can be secreted by resident cells of the CNS such as astrocytes or microglia cultured in vitro [10, 11]. IL-27 was shown to be expressed in astrocytes and microglia in MS brains [12]. However, it is not known if IL-27 could be detected directly in the CSF of RRMS patients.…”

Section: Introductionmentioning

confidence: 99%

Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients

Lalive

Kreutzfeldt

Devergne

et al. 2017

J Neuroinflammation

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BackgroundMultiple sclerosis (MS) is an autoimmune disorder characterized by chronic inflammation, demyelination, and neuronal damage. During autoimmunity, cytokines are important mediators of the inflammation. In this line, interleukin-27 (IL-27) modulates inflammation and can be produced directly at inflammatory sites such as in the joints during rheumatoid arthritis or in the central nervous system (CNS) during MS. While in animal models of MS, treatment with IL-27 decreases the disease severity, its role in humans is not clearly established and it is not known if IL-27 could be detected in the cerebrospinal fluid (CSF) of MS patients.MethodsIn this study, we measured IL-27 levels using a quantitative enzyme-linked immunosorbent assay in CSF of patients with relapsing remitting multiple sclerosis (RRMS), isolated optic neuritis (ON) and non-inflammatory neurological disease (NIND) as well as in the sera of healthy donors (HD) and RRMS patients undergoing different disease modifying treatments. We further confirmed by immunohistology of patient biopsies the identity of IL-27 producing cells in the brain of active MS lesions.ResultsWe observed that IL-27 levels are increased in the CSF but not in the sera of RRMS compared to HD. We confirmed that IL-27 is expressed in active MS plaques by astrocytes of MS patients.ConclusionsOur results point toward a local secretion of IL-27 in the CNS that is increased during autoimmune processes. We propose that local production of IL-27 could sign the induction of a regulatory response that promotes inflammation’s resolution. The effect of new immunomodulatory therapies on cerebral IL-27 production could be used to understand the biology of IL-27 in MS disease.

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“…Astrocytes, as well as microglia and macrophages, were important sources of IL-27 in the human disease, multiple sclerosis (MS). IL-27 triggered the phosphorylation of the transcription regulator STAT1, and can modulate immune properties of astrocytes and infiltrating immune cells in an MS patient’s brain [40]. …”

Section: Introductionmentioning

confidence: 99%

Neuroimmunological Implications of AQP4 in Astrocytes

Ikeshima-Kataoka

2016

IJMS

116

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The brain has high-order functions and is composed of several kinds of cells, such as neurons and glial cells. It is becoming clear that many kinds of neurodegenerative diseases are more-or-less influenced by astrocytes, which are a type of glial cell. Aquaporin-4 (AQP4), a membrane-bound protein that regulates water permeability is a member of the aquaporin family of water channel proteins that is expressed in the endfeet of astrocytes in the central nervous system (CNS). Recently, AQP4 has been shown to function, not only as a water channel protein, but also as an adhesion molecule that is involved in cell migration and neuroexcitation, synaptic plasticity, and learning/memory through mechanisms involved in long-term potentiation or long-term depression. The most extensively examined role of AQP4 is its ability to act as a neuroimmunological inducer. Previously, we showed that AQP4 plays an important role in neuroimmunological functions in injured mouse brain in concert with the proinflammatory inducer osteopontin (OPN). The aim of this review is to summarize the functional implication of AQP4, focusing especially on its neuroimmunological roles. This review is a good opportunity to compile recent knowledge and could contribute to the therapeutic treatment of autoimmune diseases through strategies targeting AQP4. Finally, the author would like to hypothesize on AQP4’s role in interaction between reactive astrocytes and reactive microglial cells, which might occur in neurodegenerative diseases. Furthermore, a therapeutic strategy for AQP4-related neurodegenerative diseases is proposed.

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

Cited by 58 publications

References 103 publications

Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients

Neuroimmunological Implications of AQP4 in Astrocytes

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