Prevention of Interleukin-8-Induced Mobilization of Hematopoietic Progenitor Cells in Rhesus Monkeys by Inhibitory Antibodies against the Metalloproteinase Gelatinase B (MMP-9)

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-09, Vol.96 (19), p.10863-10868
• Main Authors: Johannes F. M. Pruijt, Fibbe, Willem E., veer, Laurens Later, Pieters, Reagan A., Ivan J. D. Lindley, Paemen, Liesbet, Masure, Stefan, Willemze, Roel, Opdenakker, Ghislain
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Antigens, CD34 - metabolism; Biological Sciences; Blood; Blood plasma; Boluses; Bone marrow; Collagenases - blood; Collagenases - immunology; Collagenases - physiology; Colony forming units assay; Dose-Response Relationship, Drug; Enzymes; Flow Cytometry; Hematopoietic stem cell mobilization; Hematopoietic Stem Cells - physiology; Humans; Interleukin-8 - pharmacology; Kinetics; Macaca mulatta; Matrix Metalloproteinase 9; Medical research; Molecules; Monkeys & apes; Neutrophils; Neutrophils - metabolism; Pretreatment; Rats; Recombinant Proteins - metabolism; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.19.10863

Previously, we demonstrated that IL-8 induces rapid mobilization of hematopoietic progenitor cells (HPC) from the bone marrow of rhesus monkeys. Because activation of neutrophils by IL-8 induces the release of gelatinase B (MMP-9), which is involved in the degradation of extracellular matrix molecules, we hypothesized that MMP-9 release might induce stem cell mobilization by cleaving matrix molecules to which stem cells are attached. Rhesus monkeys were treated with a single i.v. injection of 0.1 mg/kg human IL-8, which resulted in a 10- to 100-fold increase in HPC within 30 min after injection. Zymographic analysis revealed a dramatic instantaneous increase in the plasma levels of MMP-9, followed by the increase in circulating HPC. Enzyme levels decreased at 2 h after injection of IL-8, simultaneously with the decrease in the numbers of circulating HPC. To test the hypothesis that MMP-9 induction was involved in HPC mobilization, rhesus monkeys were treated with a highly specific inhibitory monoclonal anti-gelatinase B antibody. Anti-gelatinase B at a dose of 1-2 mg/kg completely prevented the IL-8-induced mobilization of HPC, whereas a dose of 0.1 mg/kg had only a limited effect. Preinjection of inhibitory antibodies did not preclude the IL-8-induced production and secretion of MMP-9. Pretreatment with an irrelevant control antibody did not affect IL-8-induced mobilization, showing that the inhibition by the anti-gelatinase B antibody was specific. In summary, IL-8 induces the rapid systemic release of MMP-9 with concurrent mobilization of HPC that is prevented by pretreatment with an inhibitory anti-gelatinase B antibody, indicating that MMP-9 is involved as a mediator of the IL-8-induced mobilization of HPC.