title: Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact.
abstract: Chemokines are mediators in inflammatory and autoimmune disorders. Aminoterminal truncation of chemokines results in altered specific activities and receptor recognition patterns. Truncated forms of the CXC chemokine interleukin (IL)-8 are more active than full-length IL-8 (1-77), provided the Glu-Leu-Arg (ELR) motif remains intact. Here, a positive feedback loop is demonstrated between gelatinase B, a major secreted matrix metalloproteinase (MMP-9) from neutrophils, and IL-8, the prototype chemokine active on neutrophils. Natural human neutrophil progelatinase B was purified to homogeneity and activated by stromelysin-1. Gelatinase B truncated IL-8(1-77) into IL-8(7-77), resulting in a 10- to 27-fold higher potency in neutrophil activation, as measured by the increase in intracellular Ca(++) concentration, secretion of gelatinase B, and neutrophil chemotaxis. This potentiation correlated with enhanced binding to neutrophils and increased signaling through CXC chemokine receptor-1 (CXCR1), but it was significantly less pronounced on a CXCR2-expressing cell line. Three other CXC chemokines-connective tissue-activating peptide-III (CTAP-III), platelet factor-4 (PF-4), and GRO-alpha-were degraded by gelatinase B. In contrast, the CC chemokines RANTES and monocyte chemotactic protein-2 (MCP-2) were not digested by this enzyme. The observation of differing effects of neutrophil gelatinase B on the proteolysis of IL-8 versus other CXC chemokines and on CXC receptor usage by processed IL-8 yielded insights into the relative activities of chemokines. This led to a better understanding of regulator (IL-8) and effector molecules (gelatinase B) of neutrophils and of mechanisms underlying leukocytosis, shock syndromes, and stem cell mobilization by IL-8. (Blood. 2000;96:2673-2681)
authors.affiliation: Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: P E
authors.initials: PE
authors.lastname: Van den Steen
authors.forename: P
authors.initials: P
authors.lastname: Proost
authors.forename: A
authors.initials: A
authors.lastname: Wuyts
authors.forename: J
authors.initials: J
authors.lastname: Van Damme
authors.forename: G
authors.initials: G
authors.lastname: Opdenakker
mesh_terms: D000595:Amino Acid Sequence; D001779:Blood Coagulation Factors / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D018946:Chemokine CCL5 / Q000032:analysis; D054412:Chemokine CCL8; D054360:Chemokine CXCL1; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D005246:Feedback; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D018945:Monocyte Chemoattractant Proteins / Q000032:analysis; D009504:Neutrophils / Q000201:enzymology*; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides; D010978:Platelet Factor 4 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D023062:Receptors, Interleukin-8A / Q000502:physiology; D013379:Substrate Specificity
chemical_list: D001779:Blood Coagulation Factors; C515453:CCL8 protein, human; C475829:CXCL1 protein, human; D018946:Chemokine CCL5; D054412:Chemokine CCL8; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004792:Enzyme Precursors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D018945:Monocyte Chemoattractant Proteins; D010446:Peptide Fragments; D010455:Peptides; D023062:Receptors, Interleukin-8A; D010978:Platelet Factor 4; C009862:connective tissue-activating peptide; C018329:low affinity platelet factor 4; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9