The CXC chemokine interleukin-8 (IL-8͞CXCL8) induces rapid mobilization of hematopoietic progenitor cells (HPCs). Previously we showed that mobilization could be prevented completely in mice by pretreatment with neutralizing antibodies against the ␤2-integrin LFA-1 (CD11a). In addition, murine HPCs do not express LFA-1, indicating that mobilization requires a population of accessory cells. Here we show that polymorphonuclear cells (PMNs) serve as key regulators in IL-8-induced HPC mobilization. The role of PMNs was studied in mice rendered neutropenic by administration of a single injection of antineutrophil antibodies. Absolute neutropenia was observed up to 3-5 days with a rebound neutrophilia at day 7. The IL-8-induced mobilizing capacity was reduced significantly during the neutropenic phase, reappeared with recurrence of the PMNs, and was increased proportionally during the neutrophilic phase. In neutropenic mice, the IL-8-induced mobilizing capacity was restored by the infusion of purified PMNs but not by infusion of mononuclear cells. Circulating metalloproteinase gelatinase B (MMP-9) levels were detectable only in neutropenic animals treated with PMNs in combination with IL-8, showing that in vivo activated PMNs are required for the restoration of mobilization. However, IL-8-induced mobilization was not affected in MMP-9-deficient mice, indicating that MMP-9 is not indispensable for mobilization. These data demonstrate that IL-8-induced mobilization of HPCs requires the in vivo activation of circulating PMNs.metalloproteinases ͉ MMP-9 ͉ adhesion molecules ͉ bone marrow ͉ G-CSF

IntroductionTo reduce the risk of infections in neutropenic patients a combination of protective isolation and gut decontamination by oral administration of antibiotics is often used. [1][2][3][4] Since it has been shown that selective elimination of the major potentially pathogenic microorganisms from the digestive tract is as effective or even superior to total decontamination in preventing infections in neutropenic patients, 5-8 selective gut decontamination 9 or partial antibiotic decontamination 10 mainly directed against aerobic Gram-negative rods and fungi is usually applied. The various antibiotics used for selective decontamination can be divided into 2 main groups, those that are absorbed 11-13 after oral administration (eg, cotrimoxazole, quinolones) and those that are not absorbed 2-4 after oral administration (eg, polymyxin, colistin, aminoglycosides).Mobilized hematopoietic progenitor cells (HPCs) are increasingly used for hematopoietic recovery instead of bone marrow to allow rapid hematopoietic recovery after autologous and allogeneic transplantation. [14][15][16][17][18] An increasing number of different growth factors and chemokines such as granulocyte colony-stimulating factor (G-CSF), 19,20 granulocyte-macrophage colony-stimulating factor (GM-CSF), 19,21 stem cell factor (SCF), 22 flt3 ligand (FL), 23 interleukin-1 (IL-1), 24 26 and thrombopoietin 27 when either administered alone or in combination 28 are capable of mobilizing peripheral blood progenitor cells. In the clinical setting, the growth factor G-CSF has become the standard for autologous as well as allogeneic peripheral blood stem cell transplantation. [29][30][31] Although patients receiving selective gut decontamination or systemic antibiotic treatment while concurrently being treated with G-CSF are able to mobilize peripheral blood progenitor cells, little is known of the effect of antibiotics on the efficacy of mobilization.Endotoxins are ubiquitously present and constitute an important component of the normal intestinal flora and are known to induce HPC mobilization. [32][33][34] We therefore hypothesized that low levels of endotoxins passing through the intestinal mucosa into the blood may contribute to the levels of circulating HPCs. Here, we used a mouse model to study the effects of selective antibiotic decontamination on cytokine-induced stem cell mobilization. We found that the ability to mobilize in response to IL-8, G-CSF, or FL was significantly reduced in animals receiving endotoxin binding antibiotics or antibiotics that modulate the anaerobic flora. The mobilizing capacity was partially restored after adding endotoxins to the drinking water of decontaminated mice. These observations indicate that endotoxins are involved as cofactors in cytokineinduced hematopoietic stem cell mobilization. Supported by a grant from the Fund for Scientific Research FWO-Vlaanderen, the "Geconcerteerde Onderzoeks Acties" (GAO), and by the Dutch Cancer Society (NKB-RUL 99-2029).Reprints: Willem E. Fibbe, Department of Hematology, Lei...