Regulation of macrophage activation and septic shock susceptibility via p21(WAF1/CIP1). Academic Article uri icon

Overview

abstract

  • p21 is a cell-cycle inhibitor that is also known to suppress autoimmunity. Here, we provide evidence of a novel role for p21 as an inhibitor of macrophage activation. LPS stimulation of p21-deficient peritoneal macrophages induced increased activation compared with controls, with elevated production of proinflammatory mediators such as TNF-alpha and IL-1beta. The enhanced activity of LPS-stimulated p21-deficient macrophages correlated with increased activity of the transcription factor NF-kappaB. LPS stimulation of p21-deficient macrophages led to increased IkappaBalpha kinase activity, and increased IkappaBalpha phosphorylation and degradation, resulting in elevated NF-kappaB activity. The effect of p21 in macrophage activation was independent of its cell-cycle inhibitory role. p21(-/-) mice showed greater sensitivity to LPS-induced septic shock than did WT mice, indicating that p21 contributes to maintenance of a balanced response to inflammatory stimuli and suggesting biological significance for the role of p21 in macrophage activation. Our findings project a role for p21 in the control of NF-kappaB-associated inflammation, and suggest that therapeutic modulation of p21 expression could be beneficial in inflammation-associated diseases.

publication date

  • March 1, 2009

Research

keywords

  • Cyclin-Dependent Kinase Inhibitor p21
  • Macrophage Activation
  • Macrophages, Peritoneal
  • Shock, Septic

Identity

Scopus Document Identifier

  • 64049115134

Digital Object Identifier (DOI)

  • 10.1002/eji.200838676

PubMed ID

  • 19224635

Additional Document Info

volume

  • 39

issue

  • 3