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Agonists of Proteinase-Activated Receptor-2 Enhance IFN--Inducible Effects on Human Monocytes: Role in Influenza A Infection¹

Micha Feld^2,*, Victoria M. Shpacovitch^2,3,*, Christina Ehrhardt, Claus Kerkhoff, Morley D. Hollenberg, Nathalie Vergnolle, Stephan Ludwig and Martin Steinhoff^*

^* Department of Dermatology, Interdisziplinäres Zentrum für Klinische Forschung Münster, and Boltzmann Institute for Immunobiology of the Skin, Department of Molecular Virology, Zentrum für Molekularbiologie der Entzündung, and Department of Experimental Dermatology, University of Münster, Münster, Germany; and Canadian Institutes of Health Research Proteinases and Inflammation Network, Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada

Proteinase-activated receptor-2 (PAR₂) is expressed by different types of human leukocytes and involved in the development of inflammatory and infectious diseases. However, its precise role in the regulation of human monocyte and macrophage function during viral infection remains unclear. Also, the ability of PAR₂ agonists to enhance the effects induced by immune mediators during infection or inflammation is still poorly investigated. Therefore, we investigated the ability of a PAR₂ agonist to enhance IFN--induced suppression of influenza A virus replication in human monocytes. We found that this effect correlates with an increased abundance of IB after costimulation of cells with PAR₂ agonist and IFN-. Remarkably, coapplication of PAR₂ agonist and IFN- also enhances the effects of IFN- on IFN--inducible protein 10 kDa release, and CD64 and Vβ3 surface expression by human monocytes. Together, these findings indicate a potentially protective role of PAR₂ activation during the progression of influenza A virus infection. This effect could be associated with the ability of PAR₂ agonists to enhance IFN--induced protective effects on human monocytes.

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 grants from the Interdisziplinäres Zentrum für Klinische Forschung Münster (Stei2/027/06), German Research Foundation (SFB 293-A14, SFB492-B13, STE 1014/2-2), CERIES (Paris) (to M.S.), SFB 293 (to S.L.), Innovative Medizinische Forschung (University of Münster; Grant SH 120709, to V.M.S.), and Canadian Institutes of Health Research (Operating and Proteinases and Inflammation Network grants to M.D.H.).

² M.F. and V.M.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Victoria Shpacovitch, Department of Dermatology and Ludwig-Boltzmann-Institute for Immunobiology of the Skin, University of Münster, von-Esmarch-Strasse 58, 48149 Münster, Germany. E-mail address: shpacovi{at}ukmuenster.de

⁴ Abbreviations used in this paper: PAR₂, proteinase-activated receptor 2; IL-1ra, IL-1 receptor antagonist; IP-10, IFN--inducible protein 10 kDa; MFI, mean fluorescence intensity; PAR₂-cAP, PAR₂-tc-activating peptide; PAR₂-cRP, PAR₂-tc-reverse peptide; MOI, multiplicity of infection.

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