Interferon-β Counteracts Inflammatory Mediator-Induced Effects on Brain Endothelial Cell Tight Junction Molecules—Implications for Multiple Sclerosis

Kuruganti, Poonam A.; Hinojoza, Julian R.; Eaton, Mary J.; Ehmann, Ursula K.; Sobel, Raymond A.

doi:10.1093/jnen/61.8.710

Cited by 32 publications

(22 citation statements)

References 72 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: 48%

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: 48%

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

et al. 2014

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“…16 Moreover, application of toxic concentrations of H 2 O 2 resulted in an obvious redistribution of ZO-1 and ZO-2 as well as in distinct changes of cell morphology in a human brain endothelial cell line. 41 The authors stated that the changes they observed in vitro were very sim- ilar to changes they found in active MS lesions with an intracellular staining for ZO-1 and ZO-2. These data point toward a functional relevance of the immunolocalization patterns of TJ-associated proteins in BBB endothelium.…”

Section: Fig 4 Dose-dependent Stabilization Of the In Vitro Blood-brmentioning

confidence: 78%

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

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Hamm

et al. 2004

Annals of Neurology

101

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Multiple sclerosis (MS) is accompanied by a breakdown of the blood-brain barrier (BBB) leading to edema formation and aggravation of the disease. Interferon-beta (IFN-beta) has been approved for the treatment of MS and besides its immunomodulatory effects has been demonstrated to lead to a stabilization of BBB integrity in vivo. To investigate whether human recombinant IFN-beta exerts direct effects on the BBB, we used an in vitro BBB model in which brain endothelial cells in coculture with astrocytes form a tight permeability barrier for 3H-inulin and 14C-sucrose. Removal of the astrocytes from the coculture or alternatively addition of histamine resulted in an increased paracellular permeability for small tracers across the brain endothelial cell monolayer. Strikingly, in the presence of IFN-beta, permeability increase under both conditions was inhibited. Permeability changes were accompanied by minor changes in the staining for tight junction-associated proteins in brain endothelial cell monolayers. Taken together, our data demonstrate a direct stabilizing effect of IFN-beta on BBB cerebral endothelial cells in vitro that might significantly contribute to the beneficial effects of IFN-beta treatment in MS in vivo.

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“…IFN-I has been shown to stabilize the permeability of the blood brain barrier and to block disintegration of the endothelial barrier induced by proinflammatory mediators, such as IFNγ, TNFα and histamine [46]–[48]. Also, TLR9-triggered protection against experimental colitis, which reflects bacterial invasion, was IFN-I dependent [49], and poly(I:C), a strong IFN-I inducer, protected mice against inflammatory bowel disease [50].…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon Protects against Pneumococcal Invasive Disease by Inhibiting Bacterial Transmigration across the Lung

et al. 2013

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Streptococcus pneumoniae infection is a leading cause of bacterial pneumonia, sepsis and meningitis and is associated with high morbidity and mortality. Type I interferon (IFN-I), whose contribution to antiviral and intracellular bacterial immunity is well established, is also elicited during pneumococcal infection, yet its functional significance is not well defined. Here, we show that IFN-I plays an important role in the host defense against pneumococci by counteracting the transmigration of bacteria from the lung to the blood. Mice that lack the type I interferon receptor (Ifnar1 −/−) or mice that were treated with a neutralizing antibody against the type I interferon receptor, exhibited enhanced development of bacteremia following intranasal pneumococcal infection, while maintaining comparable bacterial numbers in the lung. In turn, treatment of mice with IFNβ or IFN-I-inducing synthetic double stranded RNA (poly(I:C)), dramatically reduced the development of bacteremia following intranasal infection with S. pneumoniae. IFNβ treatment led to upregulation of tight junction proteins and downregulation of the pneumococcal uptake receptor, platelet activating factor receptor (PAF receptor). In accordance with these findings, IFN-I reduced pneumococcal cell invasion and transmigration across epithelial and endothelial layers, and Ifnar1 −/− mice showed overall enhanced lung permeability. As such, our data identify IFN-I as an important component of the host immune defense that regulates two possible mechanisms involved in pneumococcal invasion, i.e. PAF receptor-mediated transcytosis and tight junction-dependent pericellular migration, ultimately limiting progression from a site-restricted lung infection to invasive, lethal disease.

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Interferon-β Counteracts Inflammatory Mediator-Induced Effects on Brain Endothelial Cell Tight Junction Molecules—Implications for Multiple Sclerosis

Cited by 32 publications

References 72 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

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

Type I Interferon Protects against Pneumococcal Invasive Disease by Inhibiting Bacterial Transmigration across the Lung

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