Interferon β‐1b decreases the migration of T lymphocytes in vitro: Effects on matrix metalloproteinase‐9

Stüve, Olaf; Dooley, Nora P.; Uhm, Joon H.; Antel, Jack P.; Francis, Gordon; Williams, Gary J.; Yong, V. Wee

doi:10.1002/ana.410400607

Cited by 354 publications

(200 citation statements)

References 50 publications

(23 reference statements)

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“…This suggests a role for CD73 in mediating the inhibitory effect of IFN-b on lymphocyte transmigration through EC and is in line with exacerbated inflammation observed in CD73 deficient mice [28][29][30][31]. It is important to note that in our migration model we targeted IFN-b treatment on EC monolayer and left the lymphocytes untreated, which excludes the possibility that IFN-b treatment affected lymphocyte MMP modulation as reported earlier [27].Within the CNS adenosine is part of the endogenous antiinflammatory and neuroprotective systems. It plays a direct protective role via regulation of neuronal survival [32].…”

supporting

confidence: 83%

“…Thus far, the mechanism of action on the barrier stabilizing effect of IFN-b is not well understood although some mechanisms have been discovered. For example, trafficking of activated T-cells through fibronectin is reduced after IFN-b-treatment by a mechanism which decreases the MMP-9 activity of T cells [27]. We show in this work that transmigration of CD4 + T lymphocytes through IFN-b-treated EC is decreased.…”

Section: Discussionmentioning

confidence: 51%

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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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supporting

confidence: 83%

Section: Discussionmentioning

confidence: 51%

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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“…Moreover, EAE is reduced in mice that are genetically deficient for MMP-2, -7, -8, and -9 (Dubois et al, 1999;Agrawal et al, 2006;Folgueras et al, 2008;Buhler et al, 2009). As well, a first-line therapy used in MS, interferon-␤, reduces the expression of several MMPs in leukocytes of MS patients (Stuve et al, 1996;Bernal et al, 2009). Despite these results, it has not been clear why there is the extensive upregulation of the multiple MMPs in MS and EAE.…”

Section: Discussionmentioning

confidence: 99%

EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Agrawal¹,

Silva²,

Tourtellotte³

et al. 2011

J. Neurosci.

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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the Ig superfamily, with various physiological roles including the induction of matrix metalloproteinases (MMPs), leukocyte activation, and tumor progression. In this study, we illustrate a novel involvement of EMMPRIN in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We found EMMPRIN levels to be upregulated on peripheral leukocytes before onset of EAE clinical signs and on infiltrating leukocytes and resident cells within the CNS in symptomatic mice. In EAE brain sections, EMMPRIN expression was localized with MMP-9 protein and activity. The increased EMMPRIN level was also characteristic of brain samples from MS subjects, particularly in plaque-containing areas. To evaluate the implications of elevated EMMPRIN levels, we treated EAE mice with an EMMPRIN function-blocking antibody and found reduced EAE clinical severity accompanied by decreased CNS parenchymal infiltration of leukocytes. Amelioration of EAE clinical signs by the anti-EMMPRIN antibody was critically dependent on its administration around the period of onset of clinical signs, which is typically associated with significant influx of leukocytes into the CNS. Moreover, the reduction in disease severity in anti-EMMPRINtreated mice was associated with diminished MMP proteolytic activity at the glia limitans, the final barrier before parenchymal infiltration of leukocytes. Together, our results are the first to emphasize a role for EMMPRIN in MS and EAE, whereby EMMPRIN regulates leukocyte trafficking through increasing MMP activity. These results identify EMMPRIN as a novel therapeutic target in MS.

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“…64 Although compounds developed primarily for their MMP inhibitory activity (Table 1) have not been used in clinical neurology or beyond phase I trials, except for brain tumors, [65][66][67] medications with incidental MMP inhibitory activity have given clues to the utility of targeting MMPs for therapeutic benefits. Interferon-␤, an immunomodulator used in MS, inhibits the production of MMPs by T lymphocytes 68,69 although it may also directly inhibit MMP enzymatic activity. 70 These MMP actions of interferon-␤ may account for the reduced ability of lymphocytes to traverse the blood-brain barrier into the CNS to promote MS disease activity.…”

Section: When the Good Guys Go Badmentioning

confidence: 99%

Targeting MMPs in Acute and Chronic Neurological Conditions

2007

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Summary:The matrix metalloproteinases (MMPs) are important enzymes that regulate developmental processes, maintain normal physiology in adulthood and have reparative roles at specific stages after an insult to the nervous system. Conversely, the concordant presence and significant upregulation of several MMP members in virtually all neurological conditions result in pathology. Thus, the MMPs have diverse functions, capable of mediating repair and recovery on the one hand and being involved in producing injury on the other. Therefore, targeting MMPs in neurological conditions has become a complicated challenge. This article highlights the beneficial roles of MMPs in normal and reparative processes within the nervous system and discusses the detriments of MMPs encountered in pathology. We review the availability of MMP inhibitors for clinical use and propose that an important consideration for these inhibitors is timing and duration of their use. With acute injuries where a massive upregulation of several MMPs are observed in the early periods after the insult, early and short-term use of broad spectrum MMP inhibitors would seem logical. In chronic conditions where recurrent insults to the CNS are accompanied by prolonged upregulation of MMPs, thereby necessitating the chronic use of medications, the beneficial effects of MMPs in repair may be compromised by the long-term application of MMP inhibitors. In this review we have used spinal cord injury and multiple sclerosis as examples of acute and chronic neurological conditions, respectively, and we consider the use of MMP inhibitors in these states.

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Interferon β‐1b decreases the migration of T lymphocytes in vitro: Effects on matrix metalloproteinase‐9

Cited by 354 publications

References 50 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

EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Targeting MMPs in Acute and Chronic Neurological Conditions

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