Identification of Human Cathepsin G As a Functional Target of Boswellic Acids from the Anti-Inflammatory Remedy Frankincense
| Autor: | Nicole Kather, Arne Henkel, Oliver Werz, Gisbert Schneider, Michael Karas, Lars Tausch, Johann Jauch, Carsten Skarke, Daniel Poeckel, Tobias Beckhaus, Ulf Siemoneit, Gerd Geisslinger, Lutz Franke, Bettina Hofmann, Carlo Angioni, Wolfgang Holtmeier |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Proteases Cathepsin G Proteolysis Molecular Sequence Data Immunology Pharmacology Binding Competitive Serine chemistry.chemical_compound Drug Delivery Systems medicine Animals Humans Immunology and Allergy Amino Acid Sequence Boswellia Cathepsin medicine.diagnostic_test Plant Extracts Hydrolysis Anti-Inflammatory Agents Non-Steroidal Serine Endopeptidases Elastase Chymase Cathepsins Triterpenes Biochemistry chemistry Ex vivo Protein Binding |
| Zdroj: | The Journal of Immunology. 183:3433-3442 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.0803574 |
| Popis: | Frankincense preparations, used in folk medicine to cure inflammatory diseases, showed anti-inflammatory effectiveness in animal models and clinical trials. Boswellic acids (BAs) constitute major pharmacological principles of frankincense, but their targets and the underlying molecular modes of action are still unclear. Using a BA-affinity Sepharose matrix, a 26-kDa protein was selectively precipitated from human neutrophils and identified as the lysosomal protease cathepsin G (catG) by mass spectrometry (MALDI-TOF) and by immunological analysis. In rigid automated molecular docking experiments BAs tightly bound to the active center of catG, occupying the same part of the binding site as the synthetic catG inhibitor JNJ-10311795 (2-[3-{methyl[1-(2-naphthoyl)piperidin-4-yl]amino}carbonyl)-2-naphthyl]-1-(1-naphthyl)-2-oxoethylphosphonic acid). BAs potently suppressed the proteolytic activity of catG (IC50 of ∼600 nM) in a competitive and reversible manner. Related serine proteases were significantly less sensitive against BAs (leukocyte elastase, chymotrypsin, proteinase-3) or not affected (tryptase, chymase). BAs inhibited chemoinvasion but not chemotaxis of challenged neutrophils, and they suppressed Ca2+ mobilization in human platelets induced by isolated catG or by catG released from activated neutrophils. Finally, oral administration of defined frankincense extracts significantly reduced catG activities in human blood ex vivo vs placebo. In conclusion, we show that catG is a functional and pharmacologically relevant target of BAs, and interference with catG could explain some of the anti-inflammatory properties of frankincense. |
| Databáze: | OpenAIRE |
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