Abstract
The interleukin 17 (IL17) cytokine family and its receptors are essential to normal host immune function, and their dysregulation has been linked to a broad range of human diseases, most notably inflammatory conditions and cancer. Interleukin 17 receptor B (IL17RB), in particular, has emerged as an important contributor to tumorigenesis. Here we identified IL17RB as a target of p53-mediated repression. Nutlin-3a treatment substantially decreased IL17RB expression across several cell lines harboring wild-type p53, but not in mutant-p53 or p53-null lines, and the effect was not reversed by proteasome inhibition. Depletion of either p53 or p21 partially rescued IL17RB expression. Functionally, IL17RB depletion enhanced, whereas IL17RB overexpression attenuated, nutlin-3a-induced inhibition of cell proliferation and migration. In line with this, IL17RB knockdown increased, while IL17RB overexpression reduced, nutlin-3a-induced p21 expression. IL17B treatment attenuated nutlin-3a-mediated p21 induction and Bcl-2 repression. Bioinformatic analysis showed that IL17RB expression was higher in prostate and colon tumors than in their respective matched normal tissue. Interestingly, IL17RB correlated modestly but significantly with Bcl-2 and inversely with p21 in colon tumors. Collectively, these findings indicate that p53-dependent repression of IL17RB reinforces p53 responses, revealing a functional connection between inflammatory signaling and p53-dependent tumor suppression.