Prevention of interleukin-8-induced mobilization of hematopoietic progenitor cells in rhesus monkeys by inhibitory antibodies against the Metalloproteinase gelatinase B (MMP-9)

Previously, we demonstrated that IL-8 induces rapid mobilization of hematop oietic progenitor cells (HPC) from the bone marrow of rhesus monkeys. Becau se activation of neutrophils by IL-8 induces the release of gelatinase B (M MP-9), which is involved in the degradation of extracellular matrix molecul es, we hypothesized that MMP-9 release might induce stem cell mobilization by cleaving matrix molecules to which stem cells are attached. Rhesus monke ys 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 injectio n. Zymographic analysis revealed a dramatic instantaneous increase in the p lasma 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 de crease in the numbers of circulating HPC, To test the hypothesis that MMP-9 induction was involved in HPC mobilization, rhesus monkeys were treated wi th 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 pr oduction and secretion of MMP-9, Pretreatment with an irrelevant control an tibody did not affect IL-8-induced mobilization, showing that the inhibitio n 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 tha t is prevented by pretreatment with an inhibitory anti-gelatinase B antibod y, indicating that MMP-9 is involved as a mediator of the IL-8-induced mobi lization of HPC.