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

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.

• Authors: Marianna Trakala, Cristina F Arias, María I García, M Carmen Moreno-Ortiz, Katerina Tsilingiri, Pablo J Fernández, Mario Mellado, María T Díaz-Meco, Jorge Moscat, Manuel Serrano, Carlos Martínez-A, Dimitrios Balomenos
• Journal: European journal of immunology (Eur J Immunol) Vol. 39 Issue 3 Pg. 810-9 (Mar 2009) ISSN: 1521-4141 [Electronic] Germany
• PMID: 19224635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• Interleukin-1beta
• Lipopolysaccharides
• NF-kappa B
• Tumor Necrosis Factor-alpha
• I-kappa B Kinase

Topics

• Animals
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, immunology, metabolism)
• Disease Susceptibility (immunology, metabolism)
• Female
• I-kappa B Kinase (immunology, metabolism)
• Interleukin-1beta (immunology, metabolism)
• Lipopolysaccharides (pharmacology)
• Macrophage Activation (drug effects, immunology)
• Macrophages, Peritoneal (drug effects, immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (immunology, metabolism)
• Shock, Septic (immunology, metabolism)
• Tumor Necrosis Factor-alpha (immunology, metabolism)