Kinetics and mechanisms of recombinant human granulocyte-colony stimulating factor-induced neutrophilia

Recombinant human granulocyte colony stimulating factor (G-CSF) injected intravenously in rats causes an initial peripheral neutropenia between 3 and 15 minutes and a subsequent neutrophilia beginning at 0.5 hours, peaking between 12 and 24 hours, and subsiding to normal between 30 and 36 hours. A striking hypersegmentation of neutrophil nuclei is observed between 30 and 48 hours. The bone marrow at 4 and 12 hours exhibits an increase in number, mitoses, size, and cytoplasmic granulation of myeloblasts and promyelocytes but a decrease in mature neutrophils, demonstrating that G-CSF acts not only as a mitogen and growth factor for early cells in the myeloid series but also as a releasing factor for mature marrow neutrophils. The bone marrow at 48 hours contains slightly increased numbers of myelocytes and metamyelocytes and large numbers of hypersegmented neutrophils. Dexamethasone and gamma-interferon inhibit the magnitude of G-CSF-induced neutrophilia, suggesting that endogenous glucocorticosteroids and gamma-interferon, both which are released along with G-CSF in vivo during endotoxemia, may play a negative feedback role in the endogenous regulation of granulopoiesis. G-CSF may act in concert with other monokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) to induce the changes in circulating numbers of leukocytes noted during endotoxemia.