Plasminogen activator inhibitor-1 stimulates macrophage activation through Toll-like Receptor-4.
While inflammation is often associated with increased Plasminogen Activator Inhibitor-1 (PAI-1), the functional consequences of PAI-1 in inflammation have yet to be fully determined. The aim of this study was to establish the in vivo relevance of PAI-1 in inflammation. A mouse model of systemic inflammation was employed in wild-type (WT) and PAI-1 deficient (PAI-1(-/-)) mice. Mice survival, macrophage infiltration into the lungs, and plasma levels of pro-inflammatory cytokines were assessed after lipopolysaccharide (LPS) infusion. In vitro experiments were conducted to examine changes in LPS-induced inflammatory responses after PAI-1 exposure. PAI-1 was shown to regulate inflammation, in vivo, and affect macrophage infiltration into lungs. Further, PAI-1 activated macrophages, and increased pro-inflammatory cytokines at both the mRNA and protein levels in these cells. The effect of PAI-1 on macrophage activation was dose-dependent and LPS-independent. Proteolytic inhibitory activity and Lipoprotein Receptor-related Protein (LRP) and vitronectin (VN) binding functions, were not involved in PAI-1-mediated activation of macrophages. However, the effect of PAI-1 on macrophage activation was partially blocked by a TLR4 neutralizing antibody. Furthermore, PAI-1-induced Tumor Necrosis Factor-alpha (TNF-α) and Macrophage Inflammatory Protein-2 (MIP-2) expression was reduced in TLR4(-/-) macrophages compared to WT macrophages. These results demonstrate that PAI-1 is involved in the regulation of host inflammatory responses through Toll-like Receptor-4 (TLR4)-mediated macrophage activation.
W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, 46556, United States.
Kamlesh K
KK
Gupta
W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, 46556, United States.
Zhi
Z
Xu
W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, 46556, United States; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, United States.
Francis J
FJ
Castellino
W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, 46556, United States; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, United States. Electronic address: vploplis@nd.edu.
Victoria A
VA
Ploplis
D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
Cytokines; Inflammation; Lipopolysaccharide; Sepsis