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-α and IL-1β. The enhanced activity of LPS-stimulated p21-deficient macrophages correlated with increased activity of the transcription factor NF-κB. LPS stimulation of p21-deficient macrophages led to increased IκBα kinase activity, and increased IκBα phosphorylation and degradation, resulting in elevated NF-κB 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-κB-associated inflammation, and suggest that therapeutic modulation of p21 expression could be beneficial in inflammation-associated diseases.