title: Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor.
abstract: The antimicrobial and proinflammatory neutrophil granule protein cathepsin G (CaG) has been reported as a chemoattractant for human phagocytic leukocytes by using a putative G protein coupled receptor. In an effort to identify potential CaG receptor(s), we found that CaG-induced phagocyte migration was specifically attenuated by the bacterial chemotactic peptide fMLP, suggesting these two chemoattractants might share a receptor. In fact, CaG chemoattracts rat basophilic leukemia cells (RBL cells) expressing the high affinity human fMLP receptor FPR, but not parental RBL cells or cells transfected with other chemoattractant receptors. In addition, a specific FPR Ab and a defined FPR antagonist, cyclosporin H, abolished the chemotactic response of phagocytes and FPR-transfected cells to CaG. Furthermore, CaG down-regulated the cell surface expression of FPR in association with receptor internalization. Unlike fMLP, CaG did not induce potent Ca(2+) flux and was a relatively weaker activator of MAPKs through FPR. Yet CaG activated an atypical protein kinase C isozyme, protein kinase Czeta, which was essential for FPR to mediate the chemotactic activity of CaG. Thus, our studies identify CaG as a novel, host-derived chemotactic agonist for FPR and expand the functional scope of this receptor in inflammatory and immune responses.
authors.affiliation: Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Sun
authors.forename: Pablo
authors.initials: P
authors.lastname: Iribarren
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhou
authors.forename: Wanghua
authors.initials: W
authors.lastname: Gong
authors.forename: Edward H
authors.initials: EH
authors.lastname: Cho
authors.forename: Stephen
authors.initials: S
authors.lastname: Lockett
authors.forename: Oleg
authors.initials: O
authors.lastname: Chertov
authors.forename: Filip
authors.initials: F
authors.lastname: Bednar
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rogers
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D056649:Cathepsin G; D002403:Cathepsins / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology*; D003594:Cytoplasmic Granules / Q000201:enzymology*; D004789:Enzyme Activation; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology*; D010586:Phagocytes / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000502:physiology*; D012697:Serine Endopeptidases
chemical_list: D002630:Chemotactic Factors; D044042:Receptors, Formyl Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011493:Protein Kinase C; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat