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Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN- Response to Lipopolysaccharide and Staphylococcal Enterotoxin B¹

Rosemarijn Renckens^2,*,, Jennie M. Pater^*, and Tom van der Poll^*,

^* Center for Infection and Immunity Amsterdam, and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Plasminogen activator inhibitor type-1 (PAI-1) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Systemic inflammation is invariably associated with elevated circulating levels of PAI-1, and during human sepsis plasma PAI-1 concentrations predict an unfavorable outcome. Knowledge about the functional role of PAI-1 in a systemic inflammatory response syndrome is highly limited. In this study, we determined the role of endogenous PAI-1 in cytokine release induced by administration of LPS or staphylococcal enterotoxin B (SEB). Both LPS and SEB elicited secretion of PAI-1 into the circulation of normal wild-type (Wt) mice. Relative to Wt mice, PAI-1 gene-deficient (PAI-1^–/–) mice demonstrated strongly elevated plasma IFN- concentrations after injection of either LPS or SEB. In addition, PAI-1^–/– splenocytes released more IFN- after incubation with LPS or SEB than Wt splenocytes. Both PAI-1^–/– CD4⁺ and CD8⁺ T cells produced more IFN- upon stimulation with SEB. LPS-induced IFN- release in mice deficient for uPA, the uPA receptor, or tPA was not different from IFN- release in LPS-treated Wt mice. These results identify a novel function of PAI-1 during systemic inflammation, where endogenous PAI-1 serves to inhibit IFN- release by a mechanism that does not depend on its interaction with uPA/uPA receptor or tPA.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Netherlands Heart Foundation (2001B114; to R.R.).

² Address correspondence and reprint requests to Dr. Rosemarijn Renckens, Center for Experimental and Molecular Medicine, Academic Medical Center, Room G2-132, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: r.renckens{at}amc.uva.nl

³ Abbreviations used in this paper: PAI-1, plasminogen activator inhibitor type-1; uPA, urokinase-type plasminogen activator; tPA, tissue-type plasminogen activator; SEB, staphylococcal enterotoxin B; Wt, wild type; CBA, cytometric bead array; IC, intracellular.