Regulation of macrophage activation and septic shock susceptibility via p21(WAF1/CIP1).
Eur J Immunol
; 39(3): 810-9, 2009 Mar.
Article
em En
| MEDLINE
| ID: mdl-19224635
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Choque Séptico
/
Macrófagos Peritoneais
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Inibidor de Quinase Dependente de Ciclina p21
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Ativação de Macrófagos
Limite:
Animals
Idioma:
En
Revista:
Eur J Immunol
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Espanha