Death deflected: IL‐15 inhibits TNF‐α‐mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL‐15Rα chain

Bulfone–Paus∥, Silvia; Bulanova, Elena; Pohl, Thomas; Budagian, Vadim; Dürkop, Horst; Rückert, Ralph I.; Kunzendorf, Ulrich; Paus, Ralf; Krause, Hans

doi:10.1096/fasebj.13.12.1575

Cited by 138 publications

(107 citation statements)

References 52 publications

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“…Thus, in these cells, the use of anti IL-15 blocking MaB inhibits Ik-Ba phosphorylation and NF-kB nuclear localization, but these events cannot be restored by the addition of TNF-a, since TRAF2 is not`de¯ected' from IL-15Ra to TNFRI chain. It has been proposed that, after binding of the respective cytokines TNFRI and IL-15Ra, acquire high a nity binding for TRAF2 and the IL-15 receptor would display a much more higher a nity (Bulfone-Paus et al, 1999). Our data partially agree with this model but also reveal the existence of a much more complex interplay.…”

Section: Discussionsupporting

confidence: 86%

“…In macrophages, IL-15 displays an autocrine activity through the IL-15Ra chain, suppressing the release of pro-in¯ammatory cytokines (Alleva et al, 1997). In L929 ®brosarcoma cells, exogenous IL-15 inhibits binding of TRAF2 to TNFRI, causes its de¯ection to the IL-15Ra and triggers activation of the transcription factor NF-kB (Bulfone-Paus et al, 1999). Our data in melanoma cells strongly support the involvement of endogenous IL-15 and of IL-15Ra in the control of NF-kB.…”

Section: Discussionsupporting

confidence: 76%

“…Recent data in murine models demonstrate that IL-15Ra is competent for signal transduction, contrary to what was previously reported (Bulfone-Paus et al, 1999;Anderson et al, 1995). In macrophages, IL-15 displays an autocrine activity through the IL-15Ra chain, suppressing the release of pro-in¯ammatory cytokines (Alleva et al, 1997).…”

Section: Discussionmentioning

confidence: 96%

“…It has been recently suggested that, in murine cells, IL-15 could antagonize TNF acting as anti-apoptotic factor. In this context, IL-15 would inhibit the binding of TRAF2 (activator of the transcription factor NFkB) to TNFRI and would cause its de¯ection to an intra-cytoplasmic region of the IL-15Ra which shares high sequence homology with the TNFRI region competent for TRAF2 binding (Bulfone-Paus et al, 1999).…”

Section: Il-15/il-15ra Complex Formation In Melp and Melreo Cellsmentioning

confidence: 99%

“…This subunit could trigger a speci®c signal transduction (Bulfone-Paus et al, 1999) but it could also function as a decoy molecule able to trap circulating IL-15 (Anderson et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα

et al. 2000

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There are two IL-15 isoforms and eight isoforms for the IL-15Ra chain whose biological role is poorly understood. Here, we have analysed the intracellular tra cking of IL-15 and IL-15Ra and tried to shed some light on their function(s). In IL-15/GFP CHO transfectants both IL-15 isoforms show nuclear localization. Two melanoma cell lines (MELP and MELREO) spontaneously expressing the IL-15 isoforms, display di erent intracellular tra cking of the IL-15/IL-15Ra complex. In MELP cells only IL-15Ra is detected inside the nucleus, whereas IL-15 and IL-15Ra assemble at the cell surface and are internalized. Moreover, the transducing molecule TRAF2 co-immunoprecipitates with IL-15Ra and may be de¯ected to TNFRI using anti-IL-15 blocking mAbs and TNF-a. By contrast, MELREO cells display IL15Ra and IL-15 nuclear localization but only a partial co-localization of these molecules on the cell surface. In these cells, TRAF2 is strongly associated with IL-15Ra and cannot be de¯ected by any treatment. Since TRAF2 activates the transcription factor NF-kB, IL-15 through IL-15Ra, could have a role in the control of this pathway. Indeed, anti-IL-15 MaB inhibit the constitutive nuclear localization of NFkB and the phosphorylation of its inhibitor Ik-Ba. Thus, IL-15Ra controls NF-kB activation, however di erences in the intracellular tra cking of the IL-15 and/or IL-15Ra suggest a di erent biological role for this complex in MELP versus MELREO cells. Oncogene (2000) 19, 5153 ± 5162.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 96%

Section: Il-15/il-15ra Complex Formation In Melp and Melreo Cellsmentioning

confidence: 99%

“…This subunit could trigger a speci®c signal transduction (Bulfone-Paus et al, 1999) but it could also function as a decoy molecule able to trap circulating IL-15 (Anderson et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα

et al. 2000

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Differential effect of IL‐15 and IL‐2 on survival of phytohemagglutinin‐activated umbilical cord blood T cells

et al. 2005

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Cytokine immunotherapy using interleukin (IL)-2 and IL-15 may be beneficial for patients receiving umbilical cord blood (CB) transplantation by ameliorating post-transplant T-cell apoptosis. The present study compares the differential effect of IL-15 and IL-2 on survival of phytohemagglutinin (PHA)-activated CB and adult peripheral blood (APB) T lymphocytes. In comparison with IL-2, IL-15 preferentially enhanced the survival of CB PHA-activated T cells by decreasing the caspase-3 + population and by increasing the Bcl-2 + population. Activated CB T cells were more susceptible to TNF-a-induced apoptosis compared to their adult counterparts. However, the susceptibility could be abrogated by IL-15 but not by IL-2. IL-15 but not IL-2 down-regulated CD28 expression on both activated CB and APB CD8 + T cells, with a much greater effect seen with CB. Westernblot analysis shows that IL-15 Ra is deficient in CB compared to APB immediately after PHA stimulation, while culturing with IL-15 significantly enhanced CB IL-15 Ra expression to levels comparable to that of adults. Thus, IL-15 may provide a better therapeutic choice for immune reconstitution than IL-2 post-CB transplantation due to its preferential survival enhancing effect on CB T cells. Am.

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The interleukin‐15/interleukin‐15 receptor system as a model for juxtacrine and reverse signaling

Bulfone–Paus∥¹,

Bulanova²,

Budagian³

et al. 2006

BioEssays

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Interleukin-15 (IL-15) is a pleiotropic cytokine of the 4 alpha-helix bundle family, which binds to a receptor complex that displays common elements with the IL-2 receptor and a unique high-affinity alpha chain. This review focuses on juxtacrine and reverse signaling levels in the IL-15/IL-15R system. Specifically, we discuss how agonistic stimulation of membrane-bound IL-15 induces phosphorylation of members of the MAP kinase family and of focal adhesion kinase (FAK), thereby upregulating processes including cytokine secretion, cell adhesion and migration. In addition, we explore IL-15 trans-presentation and intracellular signaling, and define promising molecular targets for future pharmacological intervention in infectious diseases and immunological disorders. These frontiers in IL-15/IL-15Ralpha research serve as highly instructive examples for key concepts, unsolved problems and therapeutic opportunities in juxtacrine and reverse signaling in general.

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Death deflected: IL‐15 inhibits TNF‐α‐mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL‐15Rα chain

Cited by 138 publications

References 52 publications

IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα

IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα

Differential effect of IL‐15 and IL‐2 on survival of phytohemagglutinin‐activated umbilical cord blood T cells

The interleukin‐15/interleukin‐15 receptor system as a model for juxtacrine and reverse signaling

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