The role of metalloproteinases and adhesion molecules in interleukin-8-induced stem-cell mobilization

The chemokine interleukin-8 (IL-8) is a potent chemoattractant and activator of neutrophils. Upon systemic injection, IL-8 induces an immediate neutropenia followed by a rebound granulocytosis. In this report, we discuss the effects of IL-8 on the mobilization of hematopoietic stem cells. Within 20 minutes following a single intraperitoneal injection in mice, IL-8 induces the mobilization of hematopoietic progenitor cells (HPC) with colony-forming, radioprotective, and long-term lymphomyeloid resubpopulating ability. Mobilization can be specifically prevented by pretreatment with antibodies against the beta2 integrin LFA-1 (CD11a). In monkeys, IL-8 Induces the rapid release of the metalloproteinase gelatinase-B concurrent with the mobilization of HPC. The latter effect can be prevented by blocking gelatinase-B activity using specific monoclonal antibodies, suggesting the involvement of gelatinase-B as a mediator of HPC mobilization. These results are consistent with the hypothesis that neutrophils are major regulators of stem-cell mobilization through the release of metalloproteinases (MMPs) that cleave extracellular matrix molecules to which HPC are attached.