Mechanisms underlying hematopoietic stem cell mobilization induced by the CXC chemokine interleukin-8.

Abstract

The CXC chemokine interleukin-8 induces rapid mobilization of hematopoietic progenitor cells in mice and monkeys. Antibodies against the beta 2-integrin leukocyte function-associated antigen-1 completely blocked interleukin-8-induced mobilization. This was not due to a direct effect on the hematopoietic progenitor cells, as leukocyte function-associated antigen-1 was found not to be expressed on hematopoietic progenitor cells. Additional experiments showed that interleukin-8 induces the rapid release of the metalloproteinase gelatinase B, concurrent with the mobilization of hematopoietic progenitor cells. Mobilization could be completely prevented by anti-gelatinase B antibodies. Because neutrophils express leukocyte function-associated antigen-1 and high affinity interleukin-8 receptors, and release gelatinase B upon stimulation with interleukin-8, we hypothesized that neutrophils are key mediators in interleukin-8-induced stem cell mobilization. Further studies showed that mobilization by interleukin-8 was completely absent in mice rendered neutropenic with anti-granulocytic antibodies. Taken together, these data are consistent with an essential role for neutrophils in interleukin-8-induced stem cell mobilization.