Interleukin-2 alters distribution of CD144 (VE-cadherin) in endothelial cells

Kim, Dae Won; Zloza, Andrew; Broucek, Joseph; Schenkel, Jason M.; Ruby, Carl E.; Samaha, Georges; Kaufman, Howard L.

doi:10.1186/1479-5876-12-113

Cited by 16 publications

(12 citation statements)

References 12 publications

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“…Consistent with our study, expression of the IL2 receptor complex has been previously documented in pulmonary endothelial cells studied in a lung edema model (29,41). Signaling through the IL2 receptor complex expressed on BMECs induces activation of the NFB pathway similarly to the previously reported action of IL15, another member of the IL2 family.…”

Section: Discussionsupporting

confidence: 92%

“…IL2-induced Disruption of the Adherens Junction-Disruption of the AJ protein complex is accompanied by changes in cell morphology and resulted in the opening of gaps between neighboring cells. These changes in endothelial monolayer integrity are coupled to cytoskeletal reorganization (25,41,42). Indeed, an increase in F-actin fiber bundles was prominently displayed in IL2-activated murine bEnd.3 cells (Fig.…”

Section: Characterization Of Bmecs and Their Expression Of The Il2mentioning

confidence: 87%

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Interleukin 2 Activates Brain Microvascular Endothelial Cells Resulting in Destabilization of Adherens Junctions

Wylezinski

Hawiger

2016

Journal of Biological Chemistry

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The pleiotropic cytokine interleukin 2 (IL2) disrupts the blood-brain barrier and alters brain microcirculation, underlying vascular leak syndrome that complicates cancer immunotherapy with IL2. The microvascular effects of IL2 also play a role in the development of multiple sclerosis and other chronic neurological disorders. The mechanism of IL2-induced disruption of brain microcirculation has not been determined previously. We found that both human and murine brain microvascular endothelial cells express constituents of the IL2 receptor complex. Then we established that signaling through this receptor complex leads to activation of the transcription factor, nuclear factor κB, resulting in expression of proinflammatory interleukin 6 and monocyte chemoattractant protein 1. We also discovered that IL2 induces disruption of adherens junctions, concomitant with cytoskeletal reorganization, ultimately leading to increased endothelial cell permeability. IL2-induced phosphorylation of vascular endothelial cadherin (VE-cadherin), a constituent of adherens junctions, leads to dissociation of its stabilizing adaptor partners, p120-catenin and β-catenin. Increased phosphorylation of VE-cadherin was also accompanied by a reduction of Src homology 2 domain-containing protein-tyrosine phosphatase 2, known to maintain vascular barrier function. These results unravel the mechanism of deleterious effects induced by IL2 on brain microvascular endothelial cells and may inform the development of new measures to improve IL2 cancer immunotherapy, as well as treatments for autoimmune diseases affecting the central nervous system.

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Section: Discussionsupporting

confidence: 92%

Section: Characterization Of Bmecs and Their Expression Of The Il2mentioning

confidence: 87%

Interleukin 2 Activates Brain Microvascular Endothelial Cells Resulting in Destabilization of Adherens Junctions

Wylezinski

Hawiger

2016

Journal of Biological Chemistry

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“…When administered locally in the tumor, IL-2 induces the release of pro-inflammatory mediators, increasing sensitivity to further immune attack. This observation strengthens interest in the use of IL-2 in EOC, in particular of IL-2 immunocytokines such as L19-IL2 that should avoid or at least reduce the VLS (vascular leak syndrome) in healthy organs [38,40,51,52]. Moreover, an increased therapeutic potential was reported by combining radiotherapy with L19-IL2 in ED-B-positive tumors [42].…”

Section: Discussionsupporting

confidence: 61%

L19-IL2 Immunocytokine in Combination with the Anti-Syndecan-1 46F2SIP Antibody Format: A New Targeted Treatment Approach in an Ovarian Carcinoma Model

Orecchia

Balza

Pietra

et al. 2019

Cancers

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Epithelial ovarian cancer (EOC) is the fifth most common cancer affecting the female population. At present, different targeted treatment approaches may improve currently employed therapies leading either to the delay of tumor recurrence or to disease stabilization. In this study we show that syndecan-1 (SDC1) and tumor angiogenic-associated B-fibronectin isoform (B-FN) are involved in EOC progression and we describe the prominent role of SDC1 in the vasculogenic mimicry (VM) process. We also investigate a possible employment of L19-IL2, an immunocytokine specific for B-FN, and anti-SDC1 46F2SIP (small immuno protein) antibody in combination therapy in a human ovarian carcinoma model. A tumor growth reduction of 78% was obtained in the 46F2SIP/L19-IL2-treated group compared to the control group. We observed that combined treatment was effective in modulation of epithelial-mesenchymal transition (EMT) markers, loss of stemness properties of tumor cells, and in alleviating hypoxia. These effects correlated with reduction of VM structures in tumors from treated mice. Interestingly, the improved pericyte coverage in vascular structures suggested that combined therapy could be efficacious in induction of vessel normalization. These data could pave the way for a possible use of L19-IL2 combined with 46F2SIP antibody as a novel therapeutic strategy in EOC.

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“…Moreover, IL-2 interacts on BMEC with intermediate affinity IL-2Rβγ complex inducing destabilization of adherent junctions through an increase in VE-cadherin phosphorylation and internalization accompanied by NF-kB activation; this results in the release of pro-inflammatory mediators, such as CCL2 and IL-6 (Figure 1D) (91, 92). Thus, it is essential that the targeted therapy with IL-2 immunocytokines should avoid, or at least reduce, the VLS in healthy organs.…”

Section: Could Il-2 Be Directly Involved In the Tumor Vessels Destrucmentioning

confidence: 99%

Anti-cancer Therapies Employing IL-2 Cytokine Tumor Targeting: Contribution of Innate, Adaptive and Immunosuppressive Cells in the Anti-tumor Efficacy

et al. 2018

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Antibody-cytokine fusion proteins (immunocytokine) exert a potent anti-cancer effect; indeed, they target the immunosuppressive tumor microenvironment (TME) due to a specific anti-tumor antibody linked to immune activating cytokines. Once bound to the target tumor, the interleukin-2 (IL-2) immunocytokines composed of either full antibody or single chain Fv conjugated to IL-2 can promote the in situ recruitment and activation of natural killer (NK) cells and cytotoxic CD8+ T lymphocytes (CTL). This recruitment induces a TME switch toward a classical T helper 1 (Th1) anti-tumor immune response, supported by the cross-talk between NK and dendritic cells (DC). Furthermore, some IL-2 immunocytokines have been largely shown to trigger tumor cell killing by antibody dependent cellular cytotoxicity (ADCC), through Fcγ receptors engagement. The modulation of the TME can be also achieved with immunocytokines conjugated with a mutated form of IL-2 that impairs regulatory T (Treg) cell proliferation and activity. Preclinical animal models and more recently phase I/II clinical trials have shown that IL-2 immunocytokines can avoid the severe toxicities of the systemic administration of high doses of soluble IL-2 maintaining the potent anti-tumor effect of this cytokine. Also, very promising results have been reported using IL-2 immunocytokines delivered in combination with other immunocytokines, chemo-, radio-, anti-angiogenic therapies, and blockade of immune checkpoints. Here, we summarize and discuss the most relevant reported studies with a focus on: (a) the effects of IL-2 immunocytokines on innate and adaptive anti-tumor immune cell responses as well as immunosuppressive Treg cells and (b) the approaches to circumvent IL-2-mediated severe toxic side effects.

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Interleukin-2 alters distribution of CD144 (VE-cadherin) in endothelial cells

Cited by 16 publications

References 12 publications

Interleukin 2 Activates Brain Microvascular Endothelial Cells Resulting in Destabilization of Adherens Junctions

Interleukin 2 Activates Brain Microvascular Endothelial Cells Resulting in Destabilization of Adherens Junctions

L19-IL2 Immunocytokine in Combination with the Anti-Syndecan-1 46F2SIP Antibody Format: A New Targeted Treatment Approach in an Ovarian Carcinoma Model

Anti-cancer Therapies Employing IL-2 Cytokine Tumor Targeting: Contribution of Innate, Adaptive and Immunosuppressive Cells in the Anti-tumor Efficacy

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