We analyzed the kinetics of leukocyte number, serum granulocyte colony stimulating factor (G-CSF) concentration, and G-CSF receptor expression in mice after recombinant human (rh) G-CSF treatment. Intraperitoneal (i.p.) injection with 200 mg/kg of cyclophosphamide (CP) induced a transient decrease of leukocyte number in peripheral blood and spleen. Daily i.p. inoculation of a low dose of rhG-CSF (μg/kg/day) from day 1 of CP injection for 8 days resulted in a significant increase of spleen cell number from day 5 to day 8, while serum rhG-CSF concentration decreased to an undetectable level on day 7. Furthermore, daily i.p. inoculation of high dose rhG-CSF (100 μg/kg/day) for 5 days to CP-injected mice induced a significant increase of leukocytes from day 3 to day 6 in both peripheral blood and spleen, and the increase was higher than that observed after low dose G-CSF treatment. In the course of the high dose rhG-CSF treatment, however, serum rhG-CSF concentration decreased from day 3, which is earlier than that decrease of serum rhG-CSF seen after low dose rhG-CSF treatment. A reverse transcription-polymerase reaction analysis of mRNA expression showed that spleen cells from high dose rhG-CSF-treated mice on day 4 and day 6 expressed more than 10 times higher levels of membrane G-CSF receptors than did those obtained before rhG-CSF treatment. All these results suggest that decrease of serum G-CSF during dairy G-CSF treatment does not always indicate neutralization of G-CSF, but implies that the inoculated G-CSF is still stimulating granulocytes and their precursors by binding to membrane G-CSF receptors which are up-regulated by G-CSF treatment. This observation is important when we measure pharmacokinetics of G-CSF in patients chronically injected with G-CSF.
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