The CDK domain of p21 is a suppressor of IL‐1β‐mediated inflammation in activated macrophages |
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| Authors: | John C Scatizzi Melissa Mavers Jack Hutcheson Brittany Young Bo Shi Richard M Pope Eric M Ruderman Damien S K Samways John A Corbett Terrance M Egan Harris Perlman |
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| Institution: | 1. Department of Molecular Microbiology and Immunology, School of Medicine, Saint Louis University, Saint Louis, MO, USA;2. These authors contributed equally to the work.;3. Department of Medicine, Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;4. Department of Pharmacology and Physiological Science, School of Medicine, Saint Louis University, Saint Louis, MO, USA;5. Department of Medicine, The Comprehensive Diabetes Center, Division of Endocrinology, University of Alabama at Birmingham, Birmingham, AL, USA |
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| Abstract: | 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. |
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| Keywords: | Endotoxic shock IL‐1β Inflammation Macrophages p21 |
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