Title | Regulation of macrophage activation and septic shock susceptibility via p21(WAF1/CIP1). |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Trakala M, Arias CF, García MI, M Moreno-Ortiz C, Tsilingiri K, Fernández PJ, Mellado M, Diaz-Meco MT, Moscat J, Serrano M, Martínez-A C, Balomenos D |
Journal | Eur J Immunol |
Volume | 39 |
Issue | 3 |
Pagination | 810-9 |
Date Published | 2009 Mar |
ISSN | 1521-4141 |
Keywords | Animals, Cyclin-Dependent Kinase Inhibitor p21, Disease Susceptibility, Female, I-kappa B Kinase, Interleukin-1beta, Lipopolysaccharides, Macrophage Activation, Macrophages, Peritoneal, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Shock, Septic, Tumor Necrosis Factor-alpha |
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. |
DOI | 10.1002/eji.200838676 |
Alternate Journal | Eur J Immunol |
PubMed ID | 19224635 |
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.