Interferon‐β stabilizes barrier characteristics of brain endothelial cells in vitro

Kraus, Jörg; Ling, Anne K.; Hamm, Stefan; Voigt, K.; Oschmann, Patrick; Engelhardt, Britta

doi:10.1002/ana.20161

Cited by 102 publications

(89 citation statements)

References 49 publications

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“…Adenosine is a known anti-inflammatory agent, which promotes endothelial integrity and has neuroprotective properties [17,[22][23][24]. IFN-b directly or indirectly stabilizes the BBB in RRMS patients, as suggested by a number of in vitro studies [25,26]. Moreover, gadolinium enhancement of magnetic resonance imagins lesions is indicative of BBB damage, and treating MSpatients with IFN-b in vivo leads to an early reduction in the appearance of gadolinium-enhancing lesions [2,8].…”

Section: Discussionmentioning

confidence: 99%

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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IFN-b treatment reduces the relapse rate in MS but its mechanism of action remains incompletely understood. Our aim was to clarify the beneficial effect of IFN-b in the treatment of MS. We assessed the influence of IFN-b treatment on (i) CD73 expression on the surface of primary cultures of human blood-brain barrier endothelial cells (BBB-EC) and human astrocytes using immunofluorescence staining and flow cytometry, (ii) transmigration of CD4 1 T lymphocytes using an in vitro model of BBB and (iii) CD73 enzyme activity, i.e. ecto-5 0 -nucleotidase activity in the serum of MS patients using a radiochemical assay. IFN-b increases the expression of ecto-5 0 -nucleotidase both on BBB-EC and astrocytes. As a consequence, lymphocyte transmigration through BBB-EC is reduced. Importantly, this reduction can be reversed using a,b-methyleneadenosine-5 0 -diphosphate, a specific inhibitor of ecto-5 0 -nucleotidase. CD73 is strongly expressed in microvasculature in samples of postmortem MS brain and, moreover, in the majority of MS patients there was a clear upregulation both in the soluble serum ecto-5 0 -nucleotidase activity and skin microvascular CD73 expression after IFN-b treatment. Upregulation of ecto-5 0 -nucleotidase and a subsequent increase in adenosine production might contribute to the beneficial effects of IFN-b on MS via enhancing the endothelial barrier function.Key words: Adenosine . Blood-brain barrier . CD73 . IFN-b . MS Introduction MS is a demyelinating disease characterized by perivascular inflammatory cell infiltrates in the white matter of the CNS. MS is generally thought to be an autoimmune disease in which the immune system attack against self-antigens results in inflammation and neurological symptoms [1]. First line treatment of MS is subcutaneous or intramuscular administration of IFN-b, which leads to a reduced number of relapses and a slower disease progression [2][3][4]. The proposed beneficial effects of IFN-b include a decrease in antigen presentation, MHC class II expression, T-cell proliferation, IFN-b production, ECM degradation, and the expression of adhesion molecules [5]. Moreover, recent reports describe IFN-b as a suppressor of both myeloid [6] and Th17-cells [7]. IFN-b also reduces the number of gadolinium enhancing lesions in brain magnetic resonance imaging of MS patients [2,3,8], which is thought to reflect its ability to regulate the blood-brain barrier (BBB) function [9]. Ecto-5 0 -nucleotidase (CD73; EC 3.1.3.5) is a 70 kDa GPI-anchored glycoprotein. It is abundantly expressed on vascular endothelium and subpopulations of lymphocytes, but not on granulocytes or monocytes [10] and it also circulates in blood in a soluble 2718form [11]. Ecto-5 0 -nucleotidase activity is found on many CNS cell types such as astrocytes, oligodendrocytes, microglial cells and brain EC in many species including human, rat, mouse and bovine [12][13][14][15]. CD73 modulates the extent of immune and inflammatory responses in vitro and in vivo. These effects are mediated via its enzymatic capability ...

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Section: Discussionmentioning

confidence: 99%

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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“…7,36,[56][57][58][59][60] Consequently, IFN-b is thought to exert part of its beneficial effect by limiting the transmigration of activated pro-inflammatory T cells across the blood-brain barrier into the CNS. 61,62 Another possible mechanism underlying the therapeutic effect of IFN-b is the inhibition of CD4 + and CD8 + T-cell activation and proliferation. [8][9][10] Based on the difficulties they had in establishing MOG-reactive T-cell clones from IFN-b-treated MS patients, Koehler et al concluded that therapy with IFN-b might reduce the number of antigenspecific CD4 + T cells in the periphery.…”

Section: Discussionmentioning

confidence: 99%

Interferon‐β therapy reduces CD4⁺ and CD8⁺ T‐cell reactivity in multiple sclerosis

et al. 2006

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Summary Therapy with interferon‐β (IFN‐β) has well‐established clinical effects in multiple sclerosis (MS), albeit the immunomodulatory mechanisms are not fully understood. We assessed the prevalence and functional capacity of CD4+ and CD8+ T cells in healthy donors, and in untreated and IFN‐β‐treated MS patients, in response to myelin oligodendrocyte glycoprotein (MOG). The proportion of CD45RO+ memory T cells was higher in MS patients than in healthy donors, but returned to normal values upon therapy with IFN‐β. While CD45RO+ CD4+ T cells from all three groups responded to MOG in vitro, untreated patients showed augmented proliferative responses compared to healthy individuals and IFN‐β treatment reduced this elevated reactivity back to the values observed in healthy donors. Similarly, the response of CD45RO+ CD8+ T cells to MOG was strongest in untreated patients and decreased to normal values upon immunotherapy. Overall, the frequency of peripheral CD45RO+ memory T cells ex vivo correlated with the strength of the cellular in vitro response to MOG in untreated patients but not in healthy donors or IFN‐β‐treated patients. Compared with healthy individuals, responding CD4+ and CD8+ cells were skewed towards a type 1 cytokine phenotype in untreated patients, but towards a type 2 phenotype under IFN‐β therapy. Our data suggest that the beneficial effect of IFN‐β in MS might be the result of the suppression or depletion of autoreactive, pro‐inflammatory memory T cells in the periphery. Assessment of T‐cell subsets and their reactivity to MOG may represent an important diagnostic tool for monitoring successful immunotherapy in MS.

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“…1,2 BBB damage commonly associated to inflammatory events has been reported in several central nervous system (CNS) infections and neurodegenerative diseases. [3][4][5] Although BBB permeability disturbances seem to be critical steps as they lead to brain damage, neither the cause of these phenomena nor the effective participation of BBB in such diseases are established.The cerebral vascular wall was formally considered as a barrier that isolates brain from immunecontrol. However, the presence of immune cells in the brain parenchyma in healthy animals, and their increased cerebral residence in pathogenic conditions, demonstrate that the recruitment of inflammatory cells into the CNS, through the BBB, takes place.…”

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Mouse syngenic in vitro blood–brain barrier model: a new tool to examine inflammatory events in cerebral endothelium

Coisne

Dehouck

Faveeuw

et al. 2005

Laboratory Investigation

169

173

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Although cerebral endothelium disturbance is commonly observed in central nervous system (CNS) inflammatory pathologies, neither the cause of this phenomenon nor the effective participation of bloodbrain barrier (BBB) in such diseases are well established. Observations were mostly made in vivo using mouse models of chronic inflammation. This paper presents a new mouse in vitro model suitable for the study of underlying mechanistic events touching BBB functions during CNS inflammatory disturbances. This model consists of a coculture with both primary cell types isolated from mice. Mouse brain capillary endothelial cell (MBCEC)s coming from brain capillaries are in culture with their in vivo partners and form differentiated monolayers that retain endothelial markers and numerous phenotypic properties of in vivo cerebral endothelium, such as: (1) Keywords: BBB; in vitro model; coculture; tight junction; P-glycoprotein; cell adhesion moleculeThe maintenance of brain interstitial fluid homeostasis is established by the presence of the bloodbrain barrier (BBB) which can be considered as the main interface between blood and brain parenchymal cells. This endothelium can be distinguished from the other vascular beds by the presence of continuous tight junctions and the absence of fenestration or channel. Both of these characteristics reduce the unspecific transport of molecules across the BBB. The blood/brain exchanges involve specific carrier-mediated transport systems that facilitate the uptake of nutrients. 1,2 BBB damage commonly associated to inflammatory events has been reported in several central nervous system (CNS) infections and neurodegenerative diseases. [3][4][5] Although BBB permeability disturbances seem to be critical steps as they lead to brain damage, neither the cause of these phenomena nor the effective participation of BBB in such diseases are established.The cerebral vascular wall was formally considered as a barrier that isolates brain from immunecontrol. However, the presence of immune cells in the brain parenchyma in healthy animals, and their increased cerebral residence in pathogenic conditions, demonstrate that the recruitment of inflammatory cells into the CNS, through the BBB, takes place. 6,7 In fact, the presence of cell adhesion molecules (CAMs) on the BBB suggests a direct and selective interaction between blood cells and the cerebral endothelium. These molecules, first described in peripheral capillaries, may mediate leukocyte transmigration across the BBB in a multistep process. 8,9 BBB damages and leukocyte infiltration in brain parenchyma were mostly examined using in vivo mouse models of chronic inflammation, which are

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Interferon‐β stabilizes barrier characteristics of brain endothelial cells in vitro

Cited by 102 publications

References 49 publications

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Interferon‐β therapy reduces CD4⁺ and CD8⁺ T‐cell reactivity in multiple sclerosis

Mouse syngenic in vitro blood–brain barrier model: a new tool to examine inflammatory events in cerebral endothelium

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Interferon‐β stabilizes barrier characteristics of brain endothelial cells in vitro

Cited by 102 publications

References 49 publications

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Interferon‐β therapy reduces CD4+ and CD8+ T‐cell reactivity in multiple sclerosis

Mouse syngenic in vitro blood–brain barrier model: a new tool to examine inflammatory events in cerebral endothelium

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Interferon‐β therapy reduces CD4⁺ and CD8⁺ T‐cell reactivity in multiple sclerosis