Medical College of Wisconsin
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The CDK domain of p21 is a suppressor of IL-1beta-mediated inflammation in activated macrophages. Eur J Immunol 2009 Mar;39(3):820-5

Date

02/04/2009

Pubmed ID

19189309

Pubmed Central ID

PMC2734089

DOI

10.1002/eji.200838683

Scopus ID

2-s2.0-64049113191 (requires institutional sign-in at Scopus site)   65 Citations

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-1beta synthesis in macrophages. Mice deficient in p21 (p21(-/-)) display increased susceptibility to endotoxic shock, which is associated with increased serum levels of IL-1beta. 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-1beta, reveals that deficiency for p21 led to more IL-1beta mRNA and pro-protein synthesis following TLR ligation. The increase in IL-1beta pro-protein is associated with elevated secretion of active IL-1beta by p21(-/-) macrophages. siRNA-mediated knockdown of p21 in human macrophages results in increased IL-1beta 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-1beta 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.

Author List

Scatizzi JC, Mavers M, Hutcheson J, Young B, Shi B, Pope RM, Ruderman EM, Samways DS, Corbett JA, Egan TM, Perlman H

Author

John A. Corbett PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases
Humans
Inflammation
Interleukin-1beta
Lipopolysaccharides
Macrophage Activation
Macrophages, Peritoneal
Mice
Mice, Inbred C57BL
Mice, Knockout
Monocytes