| Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. | |
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MedLine Citation:
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PMID: 19805069 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Inflammation underlies most age-related diseases, including cancer, but the etiology is poorly understood. One proposed factor is the presence of senescent cells, which increase with age. The senescence response arrests the proliferation of potentially oncogenic cells, and most senescent cells secrete high levels of proinflammatory cytokines and other proteins. The complex senescence-associated secretory phenotype is likely regulated at multiple levels, most of which are unknown. We show that cell surface-bound IL-1alpha is essential for signaling the senescence-associated secretion of IL-6 and IL-8, 2 proinflammatory cytokines that also reinforce the senescence growth arrest. Senescent human fibroblasts expressed high levels of IL-1alpha mRNA, intracellular protein, and cell surface-associated protein, but secreted very little protein. An IL-1 receptor (IL1R) antagonist, neutralizing IL-1alpha antibodies, and IL-1alpha depletion by RNA interference all markedly reduced senescence-associated IL-6/IL-8 secretion. Depletion of the key IL-1R signaling component IRAK1 also suppressed this secretion, and IL-1alpha neutralizing antibodies prevented IRAK1 degradation, indicating engagement of the IL-1R signaling pathway. Furthermore, IL-1alpha depletion reduced the DNA binding activity of NF-kappaB and C/EBPbeta, which stimulate IL-6/IL-8 transcription. IL-1alpha was a general regulator of senescence-associated IL-6/IL-8 secretion because IL-1alpha blockade reduced IL-6/IL-8 secretion whether cells senesced owing to DNA damage, replicative exhaustion, oncogenic RAS, or chromatin relaxation. Furthermore, conditioned medium from IL-1alpha-depleted senescent cells markedly reduced the IL-6/IL-8-dependent invasiveness of metastatic cancer cells, indicating that IL-1alpha regulates the biological effects of these cytokines. Thus, cell surface IL-1alpha is an essential cell-autonomous regulator of the senescence-associated IL-6/IL-8 cytokine network. |
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Authors:
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Arturo V Orjalo; Dipa Bhaumik; Bridget K Gengler; Gary K Scott; Judith Campisi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-09-28 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 106 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-10-09 Completed Date: 2010-01-15 Revised Date: 2010-09-27 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 17031-6 Citation Subset: IM |
Affiliation:
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Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antibiotics, Antineoplastic
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pharmacology Antibodies / pharmacology Bleomycin / pharmacology Blotting, Western CCAAT-Enhancer-Binding Protein-beta / metabolism Cell Aging* Cell Line Cell Line, Tumor Cell Membrane / metabolism Cells, Cultured Dose-Response Relationship, Drug Fibroblasts / cytology, drug effects, metabolism Humans Interleukin-1 Receptor-Associated Kinases / genetics, metabolism Interleukin-1alpha / genetics, immunology, metabolism* Interleukin-1beta / genetics, metabolism, pharmacology Interleukin-6 / metabolism* Interleukin-8 / metabolism* Male NF-kappa B / metabolism RNA Interference Recombinant Proteins / pharmacology Reverse Transcriptase Polymerase Chain Reaction Signal Transduction |
| Grant Support | |
ID/Acronym/Agency:
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P01-AG025901/AG/NIA NIH HHS; P30-AG025708/AG/NIA NIH HHS; R37-AG09909/AG/NIA NIH HHS; T32-AG000266/AG/NIA NIH HHS; U54-CA12654/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Antibodies; 0/CCAAT-Enhancer-Binding Protein-beta; 0/Interleukin-1alpha; 0/Interleukin-1beta; 0/Interleukin-6; 0/Interleukin-8; 0/NF-kappa B; 0/Recombinant Proteins; 11056-06-7/Bleomycin; EC 2.7.1.37/IRAK1 protein, human; EC 2.7.11.1/Interleukin-1 Receptor-Associated Kinases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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