IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells

Sweeney, Cheryl; Lonergan, Roisin; Basdeo, Sharee A.; Kinsella, Katie; Dungan, Lara S.; Higgins, Sarah C.; Kelly, Patrick J.; Costelloe, Lisa; Tubridy, Niall; Mills, Kingston H. G.; Fletcher, Jean M.

doi:10.1016/j.bbi.2011.03.007

Cited by 121 publications

(132 citation statements)

References 46 publications

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“…Interestingly, these finding mirror changes as predicted by detailed in vitro mechanistic studies of IL-17 (9)(10)(11)(12)14) and . Another main finding of our study was the potential difference between responders and non-responders in IL-17A levels before and after treatment.…”

Section: Discussionsupporting

confidence: 54%

“…Also, Th17 cells showed a higher expression of type-1-interferon receptors as compared with Th1 cells, suggesting Th17 cells to be selectively targeted by IFN-β (12). The detailed mechanisms involved in IFN-β actions were recently reported including the ability of IFN-β to inhibit human Th17 cell differentiation (13), to inhibit IL-17-as well as osteopontin production in human CD4+ cells (11), and to inhibit IL-17 production by dendritic cells in MS patients, the latter mechanism probably mediated through IL-27 induction (14). We here report the longitudinal effects on IL-17A during INF-β treatment.…”

Section: Th17-mediated Immunity Has Come Into Focus In Ms Because Of mentioning

confidence: 87%

“…Thus, IFN-β was shown to reduce IL-17 production directly or indirectly by reduction of osteopontin and induction of IL-27 (10). Consequently, studies have demonstrated that IFN-β may exert its effect in MS by reduction of IL-17-associated immunity (11)(12)(13)(14). In contrast, it has been…”

Section: Inflammatory Effects Diminished Trafficking Of T Cells Intomentioning

confidence: 91%

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Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

Kvarnström

Ydrefors

Ekerfelt

et al. 2013

Journal of the Neurological Sciences

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Section: Discussionsupporting

confidence: 54%

Section: Th17-mediated Immunity Has Come Into Focus In Ms Because Of mentioning

confidence: 87%

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Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

Kvarnström

Ydrefors

Ekerfelt

et al. 2013

Journal of the Neurological Sciences

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“…In both single and DKO mice, IL-17F was less increased than in wild-type control mice. Although type I IFNs have been reported in some models to inhibit IL-17A/F through the induction of IL-10 or IL-27 (53,54), we show in the present study reduced IL-17F in the absence of IFNAR1 signaling. Similarly, TNFR1 deficiency resulted in decreased IL-17F blood levels.…”

Section: Discussionsupporting

confidence: 52%

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Grine

Dejager

Libert

et al. 2015

The Journal of Immunology

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Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1-deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis.

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“…In the context of MS, previous in vitro studies have reported that IFN-b inhibited IL-1b and IL-23, but induced IL-27 production in DCs (13,14) and IL-10 production in B cells (15). In addition, direct inhibition of Th17 cell differentiation and IL-17A secretion by IFN-b (16) may contribute to the regulation of the Th17-mediated autoimmune responses in MS.…”

mentioning

confidence: 99%

The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

Tao

Zhang

Chopra

et al. 2014

The Journal of Immunology

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IFN-β has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-β in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-β inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-β secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFN-β from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-β signaling in the CD4+ cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-β signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-β suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-β–1a treatment induced IFNAR1 and its downstream signaling molecules’ gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-β regulation of the CD4+ T cells’ pathogenic cytokine production in patients with MS.

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IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells

Cited by 121 publications

References 46 publications

Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

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