IL-19, a novel SASP factor, is upregulated during senescence and in response to DSBs (#169)
ATR is a serine/threonine kinase that activates cell cycle checkpoints in response to stalled replication forks and resected double strand breaks (DSBs). Deletion of ATR causes DSBs to be generated during S phase due to replication fork collapse. Notably, when ATR is deleted in a mosaic manner in p53-/- mice, the ATR-deleted cells persist in the tissues despite high levels of DSBs, and result in widespread inflammation and defects in tissue regeneration. These results suggest that highly-damaged ATR-deleted cells generate extrinsic factors. To characterize the factors involved in this response, we performed a gene expression microarray on p53-/- and p53-/-ATRΔ/- skin epithelial cells and identified several cytokines and growth factors that were selectively upregulated upon ATR deletion. These factors included a few factors previously identified as members of the senescence-associated secretory phenotype (SASP), but more prominently included IL-19, which has not previously been identified as a SASP factor. IL-19 is a member of a distinct grouping of cytokines known as the IL-10 family. In cultured cells, IL-19 is upregulated in response to DSBs or after passage- or oncogene-induced senescence. These treatments also lead in parallel to the induction of classic SASP factors, such as IL-1 and IL-6. Importantly, the degree of induction of IL-19 is far greater than that of IL-6 or IL-8, and in fact IL-19 is required for ionizing radiation-induced SASP factor upregulation. Thus, the mechanism governing the regulation of IL-19 expression and its effects on the regulation of other cytokines will be discussed.