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 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.
Pruijt
J F
JF
Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Fibbe
W E
WE
Laterveer
L
L
Pieters
R A
RA
Lindley
I J
IJ
Paemen
L
L
Masure
S
S
Willemze
R
R
Opdenakker
G
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018952:Antigens, CD34 / Q000378:metabolism; D017364:Collagenases / Q000097:blood / Q000276:immunology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology*; D007700:Kinetics; D008253:Macaca mulatta; D020780:Matrix Metalloproteinase 9; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D016209:Interleukin-8; D011994:Recombinant Proteins; D017364:Collagenases; D020780:Matrix Metalloproteinase 9