title: Human leukocyte elastase and cathepsin G are specific inhibitors of C5a-dependent neutrophil enzyme release and chemotaxis.
abstract: Circulating human neutrophils from patients with severe inflammatory disorders such as erysipelas and sepsis are specifically desensitized to complement factor C5a stimulation but not to stimulation with other stimuli like N-formyl-methionyl-leucyl-phenylalanine (FMLP), interleukin-8 (IL-8), leukotriene B4 (LTB4), or platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine). In this study, we raised the question whether factors released from polymorphonuclear leukocytes (PMNs) can specifically down-regulate C5a-dependent neutrophil functions. When neutrophils were preincubated with either neutrophil lysates or neutrophil degranulation supernatants, a complete inhibition of C5a-stimulated beta-glucuronidase release and chemotaxis could be observed, whereas FMLP-, IL-8-, LTB4- or PAF-dependent functions were not affected. Serine protease inhibitors like phenylmethylsulfonyl fluoride, antileukoprotease, or elafin abolished this effect. High-performance liquid chromatography of neutrophil degranulation supernatants revealed pronounced inhibition of C5a-dependent neutrophil functions in fractions exerting elastase or cathepsin G activity, but not in fractions exerting proteinase 3 activity. Using purified human leukocyte elastase (HLE), C5a responses like intracellular calcium influx, beta-glucuronidase release, and chemotaxis were also specifically inhibited. Our experiments show that the release of HLE or cathepsin G from neutrophils specifically down-regulates the responsiveness of neutrophils to C5a. Elastase and cathepsin G may therefore play an important role in the down-regulation of acute inflammation.
authors.affiliation: Department of Dermatology, University of Kiel, Kiel, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Tralau
authors.forename: Ulf
authors.initials: U
authors.lastname: Meyer-Hoffert
authors.forename: Jens-M
authors.initials: JM
authors.lastname: Schröder
authors.forename: Oliver
authors.initials: O
authors.lastname: Wiedow
mesh_terms: D000328:Adult; D020013:Calcium Signaling / Q000187:drug effects; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D002457:Cell Extracts / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D015936:Complement C5a / Q000378:metabolism / Q000494:pharmacology*; D003571:Cytochalasin B / Q000494:pharmacology; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012697:Serine Endopeptidases
chemical_list: D002457:Cell Extracts; D009842:Oligopeptides; D011480:Protease Inhibitors; D003571:Cytochalasin B; D010664:Phenylmethylsulfonyl Fluoride; C024998:N-formylnorleucyl-leucyl-4-phenylalanine; D015936:Complement C5a; D005966:Glucuronidase; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase