Innate immunity

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The CDK domain of p21 is a suppressor of IL-1β-mediated inflammation in activated macrophages

  1. John C. Scatizzi1,†,
  2. Melissa Mavers1,†,
  3. Jack Hutcheson1,
  4. Brittany Young1,
  5. Bo Shi2,
  6. Richard M. Pope2,
  7. Eric M. Ruderman2,
  8. Damien S. K. Samways3,
  9. John A. Corbett4,
  10. Terrance M. Egan3,
  11. Harris Perlman1,2,*

Article first published online: 2 FEB 2009

DOI: 10.1002/eji.200838683

Issue

European Journal of Immunology

European Journal of Immunology

Volume 39, Issue 3, pages 820–825, March 2009

Additional Information

How to Cite

Scatizzi, J. C., Mavers, M., Hutcheson, J., Young, B., Shi, B., Pope, R. M., Ruderman, E. M., Samways, D. S. K., Corbett, J. A., Egan, T. M. and Perlman, H. (2009), The CDK domain of p21 is a suppressor of IL-1β-mediated inflammation in activated macrophages. Eur. J. Immunol., 39: 820–825. doi: 10.1002/eji.200838683

Author Information

  1. 1

    Department of Molecular Microbiology and Immunology, School of Medicine, Saint Louis University, Saint Louis, MO, USA

  2. 2

    Department of Medicine, Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

  3. 3

    Department of Pharmacology and Physiological Science, School of Medicine, Saint Louis University, Saint Louis, MO, USA

  4. 4

    Department of Medicine, The Comprehensive Diabetes Center, Division of Endocrinology, University of Alabama at Birmingham, Birmingham, AL, USA

  1. †

    These authors contributed equally to the work.

*Department of Medicine/Rheumatology, Feinberg School of Medicine, Northwestern University, 240 E Huron Street, McGaw Pavilion M307, Chicago, IL 60611, USA. Fax: +1-312-503-0994

  1. †

    These authors contributed equally to the work.

Publication History

  1. Issue published online: 12 MAR 2009
  2. Article first published online: 2 FEB 2009
  3. Manuscript Accepted: 16 DEC 2008
  4. Manuscript Revised: 10 NOV 2008
  5. Manuscript Received: 8 JUL 2008

Funded by

  • predoctoral American Heart Association. Grant Numbers: 0515499Z, 0710060Z
  • ACR REF/Abbott Medical Student Research
  • National Institutes of Health. Grant Numbers: AI44458, GM070925, HL056236, AR048269, AR049217, AR050250, AR054796, AI067590

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Keywords:

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

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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