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The Cathelicidin LL-37 Activates Human Mast Cells and Is Degraded by Mast Cell Tryptase: Counter-Regulation by CXCL4¹

Florian Schiemann^2,*, Ernst Brandt^*, Roland Gross^*, Buko Lindner, Jessica Mittelstädt^*, Christian P. Sommerhoff, Jan Schulmistrat^* and Frank Petersen^*

^* Department of Immunology and Cell Biology, Department of Molecular Infection Biology, Research Center Borstel, Borstel, Germany, and Department of Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-Universität, München, Germany

The cathelicidin LL-37 represents a potent antimicrobial and cell-stimulating agent, most abundantly expressed in peripheral organs such as lung and skin during inflammation. Because mast cells (MC) overtake prominent immunomodulatory roles in these organs, we wondered whether interactions exist between MC and LL-37. In this study, we show for the first time to our knowledge that physiological concentrations of LL-37 induce degranulation in purified human lung MC. Intriguingly, as a consequence LL-37 rapidly undergoes limited cleavage by a released protease. The enzyme was identified as β-tryptase by inhibitor studies and by comparison to the recombinant protease. Examining the resulting LL-37 fragments for their functional activity, we found that none of the typical capacities of intact LL-37, i.e., MC degranulation, bactericidal activity, and neutralization of LPS, were retained. Conversely, we found that another inflammatory protein, the platelet-derived chemokine CXCL4, protects LL-37 from cleavage by β-tryptase. Interestingly, CXCL4 did not act as a direct enzyme inhibitor, but destabilized active tetrameric β-tryptase by antagonizing the heparin component required for the integrity of the tetramer. Altogether our results suggest that interaction of LL-37 and MC initiates an effective feedback loop to limit cathelicidin activity during inflammation, whereas CXCL4 may represent a physiological counter-regulator of β-tryptase activity.

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 in part by Deutsche Forschungsgemeinschaft, Sonderforschungsbereich, Transregio 22, Projekt A11 (to F.S., E.B., and F.P.) and Projekt Z1 (to B.L.).

² Address correspondence and reprint requests to Dr. Florian Schiemann, Department of Cell Biology and Immunology, Research Center Borstel, Parkallee 22, 23795 Borstel, Germany. E-mail address: florian.schiemann{at}novartis.com

³ Abbreviations used in this paper: MC, mast cell; MS, mass spectrometry.