The Cathelicidin LL-37 Activates Human Mast Cells and Is Degraded by Mast Cell Tryptase: Counter-Regulation by CXCL4
| Autor: | Florian Schiemann, Frank Petersen, Jessica Mittelstädt, Ernst Brandt, Roland Gross, Buko Lindner, Jan Schulmistrat, Christian P. Sommerhoff |
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| Rok vydání: | 2009 |
| Předmět: |
Chemokine
Cell Degranulation medicine.medical_treatment Immunology Inflammation Biology Platelet Factor 4 Cathelicidin Cathelicidins medicine Humans Immunology and Allergy Mast Cells Lung Cells Cultured Feedback Physiological Protease Degranulation Cell biology Biochemistry Enzyme inhibitor biology.protein Tryptases Inflammation Mediators medicine.symptom Protein Processing Post-Translational Platelet factor 4 Antimicrobial Cationic Peptides |
| Zdroj: | The Journal of Immunology. 183:2223-2231 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.0803587 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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