Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network

AV Orjalo, D Bhaumik, BK Gengler… - Proceedings of the …, 2009 - National Acad Sciences
AV Orjalo, D Bhaumik, BK Gengler, GK Scott, J Campisi
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
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-1α is …
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-1α 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-1α mRNA, intracellular protein, and cell surface-associated protein, but secreted very little protein. An IL-1 receptor (IL1R) antagonist, neutralizing IL-1α antibodies, and IL-1α 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-1α neutralizing antibodies prevented IRAK1 degradation, indicating engagement of the IL-1R signaling pathway. Furthermore, IL-1α depletion reduced the DNA binding activity of NF-κB and C/EBPβ, which stimulate IL-6/IL-8 transcription. IL-1α was a general regulator of senescence-associated IL-6/IL-8 secretion because IL-1α 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-1α-depleted senescent cells markedly reduced the IL-6/IL-8-dependent invasiveness of metastatic cancer cells, indicating that IL-1α regulates the biological effects of these cytokines. Thus, cell surface IL-1α is an essential cell-autonomous regulator of the senescence-associated IL-6/IL-8 cytokine network.
National Acad Sciences