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

Sven E. Niklander, Hannah L. Crane, Lav Darda, Daniel W. Lambert, Keith D. Hunter

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numberjcs252080
JournalJournal of Cell Science
Volume134
Issue number4
DOIs
Publication statusPublished - Feb 2021

Keywords

  • Head and neck cancer
  • IL-1RA
  • Interleukin 1 receptor antagonist
  • SASP
  • Senescence

ASJC Scopus subject areas

  • Cell Biology

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