title: Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases.
abstract: The cysteine protease cathepsin C (CatC) activates granule-associated proinflammatory serine proteases in hematopoietic precursor cells. Its early inhibition in the bone marrow is regarded as a new therapeutic strategy for treating proteolysis-driven chronic inflammatory diseases, but its complete inhibition is elusive in vivo Controlling the activity of CatC may be achieved by directly inhibiting its activity with a specific inhibitor or/and by preventing its maturation. We have investigated immunochemically and kinetically the occurrence of CatC and its proform in human hematopoietic precursor cells and in differentiated mature immune cells in lung secretions. The maturation of proCatC obeys a multistep mechanism that can be entirely managed by CatS in neutrophilic precursor cells. CatS inhibition by a cell-permeable inhibitor abrogated the release of the heavy and light chains from proCatC and blocked ∼80% of CatC activity. Under these conditions the activity of neutrophil serine proteases, however, was not abolished in precursor cell cultures. In patients with neutrophilic lung inflammation, mature CatC is found in large amounts in sputa. It is secreted by activated neutrophils as confirmed through lipopolysaccharide administration in a nonhuman primate model. CatS inhibitors currently in clinical trials are expected to decrease the activity of neutrophilic CatC without affecting those of elastase-like serine proteases.
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France, Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Center for Lung Research (DZL), 81377 Munich and Max Planck Institute of Neurobiology, 82152 Planegg-Martinsried, Germany.
authors.forename: Yveline
authors.initials: Y
authors.lastname: Hamon
authors.affiliation: Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Legowska
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Hervé
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dallet-Choisy
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Marchand-Adam
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Vanderlynden
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Demonte
authors.affiliation: Queen's University Belfast, Lisburn Road, Belfast, BT9 7BL, United Kingdom, and.
authors.forename: Rich
authors.initials: R
authors.lastname: Williams
authors.affiliation: Queen's University Belfast, Lisburn Road, Belfast, BT9 7BL, United Kingdom, and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scott
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Heuzé-Vourc'h
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Lalmanach
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Center for Lung Research (DZL), 81377 Munich and Max Planck Institute of Neurobiology, 82152 Planegg-Martinsried, Germany.
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.affiliation: Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Lesner
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Gauthier
authors.affiliation: From the INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, 37032, Tours, France, brice.korkmaz@inserm.fr.
authors.forename: Brice
authors.initials: B
authors.lastname: Korkmaz
mesh_terms: D000818:Animals; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018922:HL-60 Cells; D006801:Humans; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D017207:Rats, Sprague-Dawley; D013183:Sputum / Q000378:metabolism
chemical_list: C533918:CTSC protein, human; D020789:Cathepsin C; C533919:Ctsc protein, mouse; C533920:Ctsc protein, rat
keywords: cysteine protease; inflammation; neutrophil; protease; protease inhibitor; serine protease