title: Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network.
abstract: 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.
authors.affiliation: Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Arturo V
authors.initials: AV
authors.lastname: Orjalo
authors.forename: Dipa
authors.initials: D
authors.lastname: Bhaumik
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Gengler
authors.forename: Gary K
authors.initials: GK
authors.lastname: Scott
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D022782:CCAAT-Enhancer-Binding Protein-beta; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011994:Recombinant Proteins; D001761:Bleomycin; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases