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J. Biol. Chem., Vol. 279, Issue 50, 51880-51887, December 10, 2004

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The Microglia-activating Potential of Thrombin

THE PROTEASE IS NOT INVOLVED IN THE INDUCTION OF PROINFLAMMATORY CYTOKINES AND CHEMOKINES^*

Uwe-Karsten Hanisch¶, Denise van Rossum, Yiheng Xie||, Klaus Gast**, Rolf Misselwitz, Seppo Auriola, Gundars Goldsteins¶¶, Jari Koistinaho¶¶||||, Helmut Kettenmann, and Thomas Möller||

From the Departments of Cellular Neurosciences and Biopolymer Spectroscopy, Max Delbrück Center for Molecular Medicine, D-13092 Berlin, Germany, the Institute for Neuropathology, University of Göttingen, D-37075 Göttingen, Germany, the ^||Department of Neurology, School of Medicine, University of Washington, Seattle, Washington 98195-6465, the ^**Department of Physical Biochemistry, Potsdam University, D-14476 Potsdam, Germany, the Department of Pharmaceutical Chemistry and the ^¶¶A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland, and the ^||||Department of Oncology, Kuopio University Hospital, FIN-70211 Kuopio, Finland

The serine protease thrombin is known as a blood coagulation factor. Through limited cleavage of proteinase-activated receptors it can also control growth and functions in various cell types, including neurons, astrocytes, and microglia (brain macrophages). A number of previous studies indicated that thrombin induces the release of proinflammatory cytokines and chemokines from microglial cells, suggesting another important role for the protease beyond hemostasis. In the present report, we provide evidence that this effect is not mediated by any proteolytic or non-proteolytic mechanism involving thrombin proper. Inhibition of the enzymatic thrombin activity did not affect the microglial release response. Instead the cyto-/chemokine-inducing activity solely resided in a high molecular weight protein fraction that could be isolated in trace amounts even from apparently homogenous - and -thrombin preparations. High molecular weight material contained thrombin-derived peptides as revealed by mass spectrometry but was devoid of thrombin-like enzymatic activity. Separated from the high molecular weight fraction by fast protein liquid chromatography, enzymatically intact - and -thrombin failed to trigger any release. Our findings may force a revision of the notion that thrombin itself is a direct proinflammatory release signal for microglia. In addition, they could be relevant for the study of other cellular activities and their assignment to this protease.

Received for publication, July 22, 2004 , and in revised form, September 13, 2004.

^* This work was supported by German Research Foundation Grant DFG/SFB507 (to U.-K. H. and H. K.) and NINDS, National Institutes of Health Grant NS44337 (to T. M.). 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.

^¶ To whom correspondence should be addressed: Inst. for Neuropathology, University of Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. Tel.: 49-551-396520; Fax: 49-551-398472; E-mail: ukhanisch{at}med.uni-goettingen.de.

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