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The microglia-activating potential of thrombin: The protease is not involved in the induction of proinflammatory cytokines and chemokines

Item Type:Article
Title:The microglia-activating potential of thrombin: The protease is not involved in the induction of proinflammatory cytokines and chemokines
Creators Name:Hanisch, U.K. and van Rossum, D. and Xie, Y. and Gast, K. and Misselwitz, R. and Ariola, S. and Goldsteins, G. and Koistinaho, J. and Kettenmann, H. and Moeller, T.
Abstract: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 α- and γ-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 α-and γ-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.
Keywords:Amino Acid Sequence, Chemokines, Cultured Cells, Cytokines, Inflammation Mediators, Kinetics, Microglia, Molecular Sequence Data, Molecular Weight, Proteinase-Activated Receptors, Thrombin, Animals, Cattle, Mice
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:279
Number:50
Page Range:51880-51887
Date:27 September 2004
Official Publication:https://doi.org/10.1074/jbc.M408318200
PubMed:View item in PubMed

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