Sven E., Niklander,Hannah L, Crane,Lav, Darda,Lambert, Daniel W.Hunter, Keith D2022-05-132022-05-132021-02Journal of Cell ScienceOpen AccessVolume 134, Issue 4February 2021 Article number jcs25208000219533https://repositorio.unab.cl/xmlui/handle/ria/22512There 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. © 2021 Company of Biologists Ltd. All rights reserved.enHead and neck cancer; IL-1RA; Interleukin 1 receptor antagonist; SASP; SenescenceArtículo