Small, Sara
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Publication Il-10 Family Members as Novel Responders to Genotoxic Stress(2015-01-01) Small, SaraAging and cancer are inexorably linked. As the average life expectancy increases, so does the incidence of cancer. Senescence, the irreversible growth arrest that occurs in response to prolonged cellular stress, is one cellular state that affects both cancer and aging. Senescence acts as an anti-tumor mechanism that protects cells from undergoing oncogenic transformation, but senescent cells also secrete factors as part of the senescence-associated secretory phenotype (SASP) that can affect their environment in both positive and negative ways. The SASP is known to be regulated by interleukin (IL)-1α, which initiates a feed-forward mechanism involving NF-κB and C/EBPβ. Non-senescent cells also secrete factors in response to different types of stress. Using an RNA microarray to analyze the secreted factors upregulated by cells with high levels of DNA damage, we identified two interleukin IL-10 family members, IL-19 and IL-24, that were upregulated with DNA damage. Using an in vitro approach, we validated the upregulation of these factors in the context of different types of damage. IL-19 was upregulated in response to ionizing radiation (IR) in multiple cell lines, reaching a peak in mRNA levels 3-4 days after IR treatment. This induction was independent of classical SASP signaling, including IL-1 and ataxia telangiectasia mutated (ATM). Instead, IL-19 induction was dependent on reactive oxygen species (ROS) and c-Jun N-terminal kinase (JNK) signaling. Importantly, we showed that known SASP factors, including IL-1, IL-6, and IL-8, are regulated by IL-19 induction. IL-24, on the other hand, is induced in response to S-phase-specific DNA damage, in a temporally restricted manner; in multiple cell lines examined, maximal IL-24 mRNA induction occurred within 24 hours of stress treatment, and quickly returned to baseline levels. Like IL-19 induction, IL-24 induction was independent of DNA damage response proteins such as ATM, but unlike IL-19, was dependent on p38MAPK activation. We also found that in a mouse pancreatic intraepithelial neoplasia cell line, apoptosis caused by fork collapse was attributable to IL-24 induction, as IL-24 shRNAs prevented cell death induced by ATR inhibitor plus aphidicolin. These studies demonstrate an important role for IL-19 and IL-24 in the regulation and effects of DNA damage-induced cytokine signaling, and open up the possibility of manipulating these factors in the treatment of cancer and age-related diseases.