Interferon (IFN)-ß1a and IFN-ß1b Block IFN-?-Induced Disintegration of Endothelial Junction Integrity and Barrier

Minagar, Alireza; Long, Alan; Ma, Taha; Jackson, T. H.; Kelley, Roger E.; Ostanin, Dmitry V.; Sasaki, Makoto; Warren, A.; Jawahar, Ajay; Cappell, B; Alexander, J. Steven

doi:10.1080/10623320390272299

Cited by 79 publications

(50 citation statements)

References 38 publications

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“…Enhanced barrier properties induced by IFN activity could potentially protect the endothelium from external permeabilizing factors through resistance to their down regulation (38,45). In the present study, TNF-a-mediated permeability was partially inhibited at the early DENV infection phase (Fig.…”

Section: Discussionsupporting

confidence: 54%

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Dengue Virus neither Directly Mediates Hyperpermeability nor Enhances Tumor Necrosis Factor-^|^alpha;-Induced Permeability In Vitro

et al. 2014

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SUMMARY:The mechanisms of endothelial barrier dysfunction in dengue disease remain poorly understood. Endothelial cell (EC) death due to virus infection or in combination with an infection-induced cytokine storm is deemed as one of the major causes of plasma leakage. Using an in vitro model of human endothelia and several dengue virus (DENV) strains (including a clinical isolate), the direct consequence of infection on endothelial permeability was investigated throughout the course of the infection. All employed DENV-2 strains were able to infect and replicate in ECs. Rather than increase endothelial permeability, DENV infection alone enhanced cell barrier integrity up to 7 days postinfection. Improved cell barrier function was mediated by type I interferon activation at the early phase of infection and by the survival advantage of the infected cells at the late phase of infection. Consistent with this phenomenon, DENV infection did not augment tumor necrosis factor-a-induced permeability. Our results prove that DENV infection does not directly account for vascular permeability; DENV neither induces hyperpermeability nor exacerbates the permeabilizing effect of cytokines. The contributory role of other factors on plasma leakage during dengue disease warrants further investigation.

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Section: Discussionsupporting

confidence: 54%

“…5B and 5C). Indeed, type-I IFNs enhance barrier properties using both in vitro (24,25,38) and in vivo models of the endothelium (39,40). This effect appears to be mediated by up-regulation of junctional adhesion molecules (41), directly resulting in the increased integrity of intracellular junctions.…”

Section: Discussionmentioning

confidence: 99%

Dengue Virus neither Directly Mediates Hyperpermeability nor Enhances Tumor Necrosis Factor-^|^alpha;-Induced Permeability In Vitro

et al. 2014

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“…Interleukin-10 is thought to inhibit the production of Th1 cytokines 22 via an effect on costimulatory molecules on antigen-presenting cells, 34,35 and to protect against disruption of the blood-brain barrier. 17 Interferon-c stimulates a variety of cells of the immune system, including T cells and dendritic cells, 36 and may be detrimental in MS by enhancing endothelial permeability 17,37 and by being toxic for oligodendrocytes. 1 The detrimental effect of IFN-c in MS has clearly been demonstrated in a clinical trial.…”

Section: Cd4mentioning

confidence: 99%

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

et al. 2008

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SummaryAutoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex-matched and age-matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose-dependent release of interferon-c (IFN-c), tumour necrosis factor-a (TNF-a) and interleukin-10 (IL-10) by patient-derived MNCs. The patients' cells produced higher amounts of IFN-c and TNF-a, and lower amounts of IL-10, than cells from healthy controls (P < 0Á03 to P < 0Á04). Five patients with MS and no controls, displayed MBP-induced CD4 + T-cell proliferation. These high-responders exhibited enhanced production of IL-17, IFN-c, IL-5 and IL-4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P < 0Á002 to P < 0Á01). A strong correlation was found between the MBP-induced CD4 + T-cell proliferation and production of IL-17, IFN-c, IL-5 and IL-4 (P < 0Á0001 to P < 0Á01) within the patient group, and the production of IL-17 and IL-5 correlated with the number of active plaques on magnetic resonance images (P = 0Á04 and P = 0Á007). These data suggest that autoantigendriven CD4 + T-cell proliferation and release of IL-17 and IL-5 may be associated with disease activity. Larger studies are needed to confirm this.

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“…Although it is not possible to demonstrate this molecular mechanism at the patient level, treatment of multiple sclerosis patients with IFN-β, which effectively reduces symptoms of disease, resulted in a significant decrease in circulating cells that produce IFN-γ [20] and prevented the IFN-γ-induced disintegration of the endothelial junction integrity and barrier function [21]. These are but a few examples taken from a wider literature to support the view that the inhibition of IFN-γ gene expression, induced by IFN-γ mRNA-mediated activation of PKR resulting in translational attenuation of IFN-γ production, as described here, is enhanced by IFN-β treatment and thus may underlie its beneficial therapeutic effect.…”

Section: Multiple Sclerosis Treatment With Ifn-β: Blocking Overexpresmentioning

confidence: 99%

Interferon- mRNA attenuates its own translation by activating PKR: A molecular basis for the therapeutic effect of interferon- in multiple sclerosis

Kaempfer

2006

Cell Res

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PKR, the interferon (IFN)-inducible protein kinase activated by double-stranded RNA, inhibits translation by phosphorylating the initiation factor eIF2a chain. Uniquely, human IFN-γ mRNA uses local activation of PKR in the cell to control its own translation yield. IFN-γ mRNA activates PKR through a structure in its 5'-region harboring a pseudoknot which is critical for PKR activation. Mutations that impair pseudoknot stability reduce the ability of IFN-γ mRNA to activate PKR and strongly increase its translation efficiency. The cis-acting RNA element in IFN-γ mRNA functions as a biological sensor of intracellular PKR levels. During an immune response, as IFN-γ and other inflammatory cytokines build up in the cell's microenvironment, they act to induce higher levels of PKR in the cell, resulting in a more extensive activation of PKR by IFN-γ mRNA. With the resulting phosphorylation of eIF2a, a negative feedback loop is created and the production of IFN-γ is progressively attenuated. We propose that the therapeutic effect of IFN-β in multiple sclerosis may rest, at least in part, on its exquisite ability to induce high levels of PKR in the cell and thereby to limit IFN-γ mRNA translation through this negative feedback loop, blocking the excessive IFN-γ gene expression that precedes clinical attacks.

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Interferon (IFN)-ß1a and IFN-ß1b Block IFN-?-Induced Disintegration of Endothelial Junction Integrity and Barrier

Cited by 79 publications

References 38 publications

Dengue Virus neither Directly Mediates Hyperpermeability nor Enhances Tumor Necrosis Factor-^|^alpha;-Induced Permeability In Vitro

Dengue Virus neither Directly Mediates Hyperpermeability nor Enhances Tumor Necrosis Factor-^|^alpha;-Induced Permeability In Vitro

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

Interferon- mRNA attenuates its own translation by activating PKR: A molecular basis for the therapeutic effect of interferon- in multiple sclerosis

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