The role of icIL-1RA in keratinocyte senescence and development of the senescence-associated secretory phenotype

• Published in: Journal of cell science Vol. 134; no. 4
• Main Authors: Niklander, Sven E., Crane, Hannah L., Darda, Lav, Lambert, Daniel W., Hunter, Keith D.
• Format: Journal Article
• Language: English
• Published: England 22.02.2021
• Subjects: Head and neck cancer; Senescence; IL-1RA; Interleukin 1 receptor antagonist; SASP
• ISSN: 0021-9533; 1477-9137; 1477-9137
• DOI: 10.1242/jcs.252080

There is compelling evidence that senescent cells, through the senescence-associated secretory phenotype (SASP), can promote malignant transformation and invasion. Interleukin-1 (IL-1) is a key mediator of this cytokine network, but the control of its activity in the senescence programme has not been elucidated. IL-1 signalling is regulated by IL-1RA, which has four variants. Here, we show that expression of intracellular IL-1RA type 1 (icIL-1RA1), which competitively inhibits binding of IL-1 to its receptor, is progressively lost during oral carcinogenesis ex vivo and that the pattern of expression is associated with keratinocyte replicative fate in vitro. We demonstrate that icIL-1RA1 is an important regulator of the SASP in mortal cells, as CRISPR/Cas9-mediated icIL-1RA1 knockdown in normal and mortal dysplastic oral keratinocytes is followed by increased IL-6 and IL-8 secretion, and rapid senescence following release from RhoA-activated kinase inhibition. Thus, we suggest that downregulation of icIL-1RA1 in early stages of the carcinogenesis process can enable the development of a premature and deregulated SASP, creating a pro-inflammatory state in which cancer is more likely to arise.