Interleukin-4 Induces Up-regulation of Endothelial Cell Claudin-5 through Activation of FoxO1

Dalmasso, Agustin P.; Goldish, Daniel; Benson, Barbara A.; Tsai, Alexander K.; Wasiluk, Karen R.; Vercellotti, Gregory M.

doi:10.1074/jbc.m113.455766

Cited by 23 publications

(33 citation statements)

References 37 publications

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“…The molecular mechanism of this effect is unclear at present, and it does not involve induction of the Serpin inhibitor Spi6. Notably, IL-4-induced phosphorylation of another FoxO family member, FoxO1, has been shown to prevent EC cytolysis by up-regulating claudin-5 expression and junction tightness (31).…”

Section: Discussionmentioning

confidence: 99%

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CD31 signals confer immune privilege to the vascular endothelium

Cheung

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Constitutive resistance to cell death induced by inflammatory stimuli activating the extrinsic pathway of apoptosis is a key feature of vascular endothelial cells (ECs). Although this property is central to the maintenance of the endothelial barrier during inflammation, the molecular mechanisms of EC protection from cell-extrinsic, proapoptotic stimuli have not been investigated. We show that the Ig-family member CD31, which is expressed by endothelial but not epithelial cells, is necessary to prevent EC death induced by TNF-α and cytotoxic T lymphocytes in vitro. Combined quantitative RT-PCR array and biochemical analysis show that, upon the engagement of the TNF receptor with TNF-α on ECs, CD31 becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF-α via activation of the Erk/Akt pathway. Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95/Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar. Both CD31 intracellular immunoreceptor tyrosinebased inhibition motifs are required for its prosurvival function. In vivo, CD31 gene transfer is sufficient to recapitulate the cytoprotective mechanisms in CD31 − pancreatic β cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients.endothelium | immunology | inflammation | lymphocytes | transplantation

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Section: Discussionmentioning

confidence: 99%

“…7G), indicating that perforin-induced osmotic lysis is only partially inhibited by CD31 signals. FoxO3, which has been implicated in osmotic lysis (31), localized to the nucleus only in mock-transduced but not in CD31-expressing MIN6 cells after incubation with CTLs (Fig. 7H).…”

Section: Cd31 Expression Confers Resistance To Cytolysis By Alloreactmentioning

confidence: 99%

CD31 signals confer immune privilege to the vascular endothelium

Cheung

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In our previous studies, we have also found that the protection induced with IL-4 and IL-13 was intrinsic and required activation of fatty acid and phospholipid synthesis, including cardiolipin, and preservation of mitochondrial integrity [3,4]. In addition, we found that IL-4 induced up-regulation of the junction protein claudin-5, which contributed to EC protection from complement injury [5].…”

Section: Introductionmentioning

confidence: 73%

IL‐4 and IL‐13 induce protection from complement and melittin in endothelial cells despite initial loss of cytoplasmic proteins: membrane resealing impairs quantifying cytotoxicity with the lactate dehydrogenase permeability assay

Benson

Vercellotti

Dalmasso

2015

Xenotransplantation

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Background Endothelial cell activation and injury by the terminal pathway of complement is important in various pathobiological processes, including xenograft rejection. Protection against injury by human complement can be induced in porcine endothelial cells (ECs) with IL-4 and IL-13 through metabolic activation. However, despite this resistance, the complement-treated ECs were found to lose membrane permeability control assessed with the small molecule calcein. Therefore to define the apparent discrepancy of permeability changes vis-à-vis the protection from killing we now investigated whether IL-4 and IL-13 influence the release of the large cytoplasmic protein lactate dehydrogenase (LDH) in ECs incubated with complement or the pore-forming protein melittin. Methods Primary cultures of ECs were pretreated with IL-4 or IL-13 and then incubated with human serum as source of antibody and complement or melittin. Cell death was assessed using neutral red. Membrane permeability was quantitated measuring LDH release. Results We found that IL-4/IL-13 induced protection of ECs from killing by complement or melittin despite loss of LDH in amounts similar to control ECs. However, the cytokine-treated ECs that were protected from killing rapidly regained effective control of membrane permeability. Moreover, the viability of the protected ECs was maintained for at least 2 days. Conclusion We conclude that the protection induced by IL-4/IL-13 in ECs against lethal attack by complement or melittin is effective and durable despite severe initial impairment of membrane permeability. The metabolic changes responsible for protection allow the cells to repair the membrane injury caused by complement or melittin.

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“…[167][168][169] New intracellular mechanisms that mediate protection from complement injury include increased expression of claudin-5, and endothelial induction of adenoIL-4; IL-4 is a potent inducer of protection . [170][171][172] Importantly, this protection is associated with maintenance of mitochondrial morphology and membrane potential and is not related to upregulation of complement-regulatory proteins.…”

Section: Survival With Immunosuppressive Therapy (Ref)mentioning

confidence: 98%

The complex functioning of the complement system in xenotransplantation

Zhou

Hara

Cooper

2019

Xenotransplantation

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The role of complement in xenotransplantation is well-known, and is a topic that has been reviewed previously. However, our understanding of the immense complexity of its interaction with other constituents of the innate immune response and of the coagulation, adaptive immune, and inflammatory responses to a xenograft is steadily increasing. In addition, the complement system plays a function in metabolism and homeostasis. New reviews at intervals are therefore clearly warranted. The pathways of complement activation, the function of the complement system, and the interaction between complement and coagulation, inflammation, and the adaptive immune system in relation to xenotransplantation are reviewed. Through several different mechanisms, complement activation is a major factor in contributing to xenograft failure. In the organ-source pig, the detrimental influence of the complement system is seen during organ harvest and preservation, e.g., in ischemia-reperfusion injury. In the recipient, the effect of complement can be seen through its interaction with the immune, coagulation, and inflammatory responses. Genetic-engineering and other therapeutic methods by which the xenograft can be protected from the effects of complement activation are discussed. The review provides an updated source of reference to this increasingly complex subject.

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Interleukin-4 Induces Up-regulation of Endothelial Cell Claudin-5 through Activation of FoxO1

Cited by 23 publications

References 37 publications

CD31 signals confer immune privilege to the vascular endothelium

CD31 signals confer immune privilege to the vascular endothelium

IL‐4 and IL‐13 induce protection from complement and melittin in endothelial cells despite initial loss of cytoplasmic proteins: membrane resealing impairs quantifying cytotoxicity with the lactate dehydrogenase permeability assay

The complex functioning of the complement system in xenotransplantation

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