Response to Endotoxin Endothelial Junction Protein p120-Catenin in Innate Immune Function of the Adherens

Sepsis-induced acute lung injury is a common clinical disorder in critically ill patients that is associated with high mortality. In this study, we investigated the role of p120-catenin (p120), a constituent of endothelial adherens junctions, in regulating the innate immune function of lungs. In mice in which acute lung injury was induced by i.p. administration of LPS, we observed a rapid decrease in the expression of p120 in lungs. The p120 protein expression was correlated inversely with severity of inflammation. Suppression of p120 expression in lung endothelial cells in mice using small interfering RNA resulted in high sensitivity to endotoxin and greatly increased the mortality compared with controls. Knockdown of p120 also increased the expression of ICAM-1, neu-trophil recruitment, production of cytokines TNF-a and IL-6, pulmonary transvascular protein permeability, and lung water content in response to LPS. We demonstrated that endothelial p120 modulates lung innate immune function by interfering with the association of TLR4 with its adaptor MyD88 to block TLR4 signaling and NF-kB activation in endothelial cells. In conclusion, these studies have uncovered a novel innate immune function of endothelial p120 in downregulating the lung inflammatory response to endotoxin through the suppression of TLR4 signaling. S epsis resulting from bacterial infection is the most common cause of acute lung injury (ALI) (1). Bacterial LPS (en-dotoxin) triggers a generalized inflammatory response that subsequently leads to multiple organ dysfunction syndrome (1, 2). The pulmonary vascular endothelium is a key target and a critical participant in the pathogenesis of sepsis-induced lung inflammation and injury. Binding of LPS to TLR4 results in loss of endo-thelial barrier and expression of cell-surface adhesion proteins such as ICAM-1 through MyD88-dependent and-independent signaling pathways (3). Recruitment of the adaptor protein MyD88 initiates early activation of NF-kB, whereas MyD88-independent pathway leads to delayed NF-kB activation (4) and rapid activation of IFN regulatory factor 3 (5, 6). Upon TLR4 activation, MyD88 induces the association with IL-1R–associated kinase-4 (IRAK-4) and IRAK-1 and recruitment of TNFR-associated factor 6 (TRAF6) to IRAK-1 (7–9). The IRAK-4/ IRAK-1/TRAF6 complex dissociates from TLR4 and interacts with TGF-b–activated kinase 1 complex, which activates IkB kinases, leading to phosphorylation and degradation of IkB and release and translocation of NF-kB to the nucleus (10). The outcome of LPS/TLR4 signaling is the production of proinflamma-tory cytokines and upregulation of endothelial adhesion molecules , which, if unchecked, induces tissue injury (11). p120-Catenin (p120) is a member of the catenin subfamily …