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PMID: 17618288 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1.

Nature immunology ·Vol. 8 ·No. 8 ·2007-08-00 ·Pages 856-63

Huntington ND, Puthalakath H, Gunn P, Naik E, Michalak EM, Smyth MJ, Tabarias H, Degli-Esposti MA, Dewson G, Willis SN, Motoyama N, Huang DC, Nutt SL, Tarlinton DM, Strasser A

Abstract

Interleukin 15 (IL-15) promotes the survival of natural killer (NK) cells by preventing apoptosis through mechanisms unknown at present. Here we identify Bim, Noxa and Mcl-1 as key regulators of IL-15-dependent survival of NK cells. IL-15 suppressed apoptosis by limiting Bim expression through the kinases Erk1 and Erk2 and mechanisms dependent on the transcription factor Foxo3a, while promoting expression of Mcl-1, which was necessary and sufficient for the survival of NK cells. Withdrawal of IL-15 led to upregulation of Bim and, accordingly, both Bim-deficient and Foxo3a-/- NK cells were resistant to cytokine deprivation. Finally, IL-15-mediated inactivation of Foxo3a and cell survival were dependent on phosphotidylinositol-3-OH kinase. Thus, IL-15 regulates the survival of NK cells at multiple steps, with Bim and Noxa being key antagonists of Mcl-1, the critical survivor factor in this process.

MeSH Terms
Animals Apoptosis/immunology Apoptosis Regulatory Proteins/immunology,metabolism Bcl-2-Like Protein 11 Cell Survival/immunology Flow Cytometry Forkhead Box Protein O3 Forkhead Transcription Factors/immunology,metabolism Immunoblotting Interleukin-15/immunology,metabolism Killer Cells, Natural/immunology,metabolism Membrane Proteins/immunology,metabolism Mice Mitogen-Activated Protein Kinase 3/immunology,metabolism Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Proteins/immunology,metabolism Phosphatidylinositol 3-Kinases/immunology,metabolism Polymerase Chain Reaction Proto-Oncogene Proteins/immunology,metabolism Proto-Oncogene Proteins c-bcl-2/immunology,metabolism
Chemicals
Apoptosis Regulatory Proteins Bcl-2-Like Protein 11 Bcl2l11 protein, mouse Forkhead Box Protein O3 Forkhead Transcription Factors FoxO3 protein, mouse Interleukin-15 Mcl1 protein, mouse Membrane Proteins Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Proteins Pmaip1 protein, mouse Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Phosphatidylinositol 3-Kinases Mitogen-Activated Protein Kinase 3
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Huntington Nicholas D
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia. [email protected]
Puthalakath Hamsa
Gunn Priscilla
Naik Edwina
Michalak Ewa M
Smyth Mark J
Tabarias Hyacinth
Degli-Esposti Mariapia A
Dewson Grant
Willis Simon N
Motoyama Noboru
Huang David C S
Nutt Stephen L
Tarlinton David M
Strasser Andreas
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2908
DOI
10.1038/ni1487
Email
[email protected]
Published
2007-08-00
Epub
2007-00-08
Pages
856-63
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2951739
Subset
IM
Grants
NCI NIH HHS · R01 CA043540 · United States
NCI NIH HHS · R01 CA080188-07 · United States
NCI NIH HHS · CA 43540 · United States
NCI NIH HHS · R01 CA043540-21 · United States
NCI NIH HHS · CA 80188 · United States
NCI NIH HHS · R01 CA080188 · United States
External Links
PubMed source DOI: 10.1038/ni1487 PMC Full Text View journal details
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