MK2/p38/p53 negatively regulate basal IL-1β and non-canonical NF-κB signaling

Interleukin (IL)-1β is a pro-inflammatory cytokine implicated in sterile inflammation and tumor development. Investigating the role of MAPKAP kinase 2 (MK2) in IL-1β processing, we found that Il1b mRNA and IL-1β protein levels were elevated in resting MK2-knockout (KO) macrophages and in the serum of MK2/3-double-KO mice. This was linked to activation of the non-canonical NF-κB pathway in the absence of MK2 or its activator, p38α. Rescue by MK2, its kinase-inactive mutant MK2K79R, or p38α suppressed this pathway and reduced Il1b expression. We also observed decreased basal protein levels of tumor suppressor p53 in MK2- or p38α-deficient cells. Mechanistically, p53 interacts with mitochondrial caspase-3, promoting cleavage of RelB, thereby inhibiting non-canonical NF-κB signaling and subsequent Il1b and TP53 expression. These findings explain elevated basal IL-1β levels in MK2-KO macrophages and uncover a new autoregulatory mechanism of TP53 expression. Additionally, they reveal a new mechanism that contributes to the long-discussed link between cancer and inflammation, wherein the tumor suppressor p53 inhibits cytokine production in parallel.