Niklander, Sven E.Crane, Hannah L.Darda, LavLambert, Daniel W.Hunter, Keith D.2022-07-272022-07-272021-02Journal of Cell Science Volume 134, Issue 4 February 2021 Article number jcs2520800021-9533https://repositorio.unab.cl/xmlui/handle/ria/23356Indexación ScopusThere 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.enHead and neck cancerIL-1RAInterleukin 1 receptor antagonistSASPSenescenceArtículoAttribution 4.0 International (CC BY 4.0)10.1242/jcs.252080