• Endotoxic shock;
  • IL-1β;
  • Inflammation;
  • Macrophages;
  • p21


Significant morbidity and mortality can be attributed to inflammatory diseases; therefore, a greater understanding of the mechanisms involved in the progression of inflammation is crucial. Here, we demonstrate that p21(WAF1/CIP1), an established suppressor of cell cycle progression, is a inhibitor of IL-1β synthesis in macrophages. Mice deficient in p21 (p21−/−) display increased susceptibility to endotoxic shock, which is associated with increased serum levels of IL-1β. Administration of IL-1 receptor antagonist reduces LPS-induced lethality in p21−/− mice. Analysis of isolated macrophages, which are one of the central producers of IL-1β, reveals that deficiency for p21 led to more IL-1β mRNA and pro-protein synthesis following TLR ligation. The increase in IL-1β pro-protein is associated with elevated secretion of active IL-1β by p21−/− macrophages. siRNA-mediated knockdown of p21 in human macrophages results in increased IL-1β secretion as well. A peptide mapping strategy shows that the cyclin-dependent-kinase (CDK)-binding domain of p21 is sufficient to reduce the secretion of IL-1β by p21−/− macrophages. These data suggest a novel role for p21 and specifically for the CDK-binding domain of p21(WAF1/CIP1) in inhibiting inflammation.