Disease protection and interleukin‐10 induction by endogenous interferon‐β in multiple sclerosis?

Hesse, Dan; Krakauer, Martin; Lund, Henrik Hautop; Søndergaard, Helle Bach; Limborg, Signe; Sørensen, Per Soelberg; Sellebjerg, Finn

doi:10.1111/j.1468-1331.2010.03116.x

Cited by 45 publications

(54 citation statements)

References 31 publications

(43 reference statements)

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“…Experimental studies indicate that IFNgamma, at least when expressed by CD4 + T-cells, has important effects along with IL17 in the development of RRMS [8]. Our findings of increased IFNG in WB and CSF-cells in RRMS patients are in accordance with We have previously demonstrated negative correlation between expression of the immunoregulatory cytokine IL10 and the number of active magnetic resonance imaging lesions [21], and IL10 has been suggested to have beneficial effects in MS in numerous studies [22,23]. IL10 is present in perivascular macrophages in MS lesions [24] and is increased in CSF from MS patients [25].…”

Section: Discussionsupporting

confidence: 91%

Relapsing-Remitting Multiple Sclerosis

SpringerReference

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Background: Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce. Methods: We studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4 + , CD8 + T -cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and noninflammatory neurological controls (NIND).Results: RRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T-and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression. Conclusions: Using a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T-and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.

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Section: Discussionsupporting

confidence: 91%

Relapsing-Remitting Multiple Sclerosis

SpringerReference

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“…To our knowledge there are no data available concerning the effect of IFN-β on Tr1 cells, whereas the effect of IFN-β on IL-10 production has been extensively studied in mice and humans. It is evident that in normal conditions IFN-βtreatment of mouse splenocytes or human PBMCs increased the levels of IL-10 mRNA and protein [28,40,80,81]. However, this action was not directly exerted on T cells, but rather on bystander monocytes and APCs [28,38].…”

Section: Regulatory T Cells (Tregs)mentioning

confidence: 89%

“…Regarding the human disease, in vitro treatment of PBMCs from MS patients with IFN-β enhanced the expression of IL-10mRNA and protein [40,82]. Moreover, IFN-β administered to MS patients augmented IL-10 mRNA and protein levels in serum and CSF [67,80]. A very important finding was that, although previous studies did not identify whether the effect of IFN-β was direct on T cells or mediated via modulation of bystander cells, Ramgolam et al detected a direct increase of IL-10 production by CD4 + T cells, isolated from MS patients and treated with IFN-βin vitro [65].…”

Section: Regulatory T Cells (Tregs)mentioning

confidence: 92%

“…Not only in health, but also in CNS autoimmunity IFN-βis shown to enhance IL-10 release. Interestingly, a proportion of untreated MS patients demonstrate increased spontaneous expression of IFN-β inducible genes and this expression was correlated with increased expression levels of IL-10and Foxp3 mRNA, indicating that endogenous IFN-β may induce the expression of immunoregulatoryIL-10 in vivo [80].In addition, stimulation of PLP-specific T cells with IFN-β in vitro led to elevated levels of IL-10 mRNA and protein [40], while IFN-β administration in EAE mice increased IL-10 production by total splenocytes [28]. Regarding the human disease, in vitro treatment of PBMCs from MS patients with IFN-β enhanced the expression of IL-10mRNA and protein [40,82].…”

Section: Regulatory T Cells (Tregs)mentioning

confidence: 95%

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IFN-β differentially regulates the function of T cell subsets in MS and EAE

Kavrochorianou

Markogiannaki

Haralambous

2016

Cytokine & Growth Factor Reviews

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“…Treatment with IFN−β has been shown to reduce virus expression of the latent proteins EBNA-1 and LMP2A. IFN therapy decreases the percentage of circulating memory B cells, likely by inducing FAS-mediated apoptosis [159]. Further investigations into IFN subtypes and ISG sets may enable identification of IFN response signatures for patients with different stages of MS and tailor targeted therapy.…”

Section: Ifns In Human Therapymentioning

confidence: 99%

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

2012

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Interferons (IFNs) comprise type I, II and III families with multiple subtypes. Via transcription of IFNstimulated genes (ISGs), IFNs can exert multiple biological effects on the cell. In infectious and chronic inflammatory diseases, the IFNs and their ISG sets can be potentially utilized as biomarkers of disease outcome. Animal models allow investigations into disease pathogenesis and gene knockout models have proved cause and effect relationships of molecules related to the IFN response. Sets of IFN subtypes and their ISG products provide immunological signature patterns for different viral and other diseases. In this article, we give an overview of IFNs in several virus infection models and autoimmune diseases of medical relevance. Lessons learned from animal models inform us of IFN system parameters as indicators of disease outcome and whether clinical research is warranted. Moreover, validated IFN biomarkers for prognosis enhance our understanding of therapeutic and vaccine development.

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Disease protection and interleukin‐10 induction by endogenous interferon‐β in multiple sclerosis?

Abstract: Our findings suggest that endogenous IFN-β may induce the expression of immunoregulatory IL10 in MS and that this might be associated with dampening of inflammatory disease activity.

Cited by 45 publications

References 31 publications

Relapsing-Remitting Multiple Sclerosis

Relapsing-Remitting Multiple Sclerosis

IFN-β differentially regulates the function of T cell subsets in MS and EAE

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

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