Secondary cytokines interact in sequence with interleukin-1alpha (IL-1alpha) with or without macrophage colony-stimulating factor (M-CSF) to further accelerate granulopoietic recovery in myelosuppressed animals.
Interleukin-1alpha (IL-1), by itself, accelerates both granulopoietic and thrombopoietic recovery in the 5-fluorouracil (5-FU) myelosuppressed mouse (FUM). As a primary cytokine, IL-1 also interacts in concert with macrophage colony-stimulating factor (M-CSF) to synergistically enhance hematopoietic recovery in the FUM. As part of our continuing interest in cytokine sequencing, studies were carried out to determine whether the addition of several secondary cytokines (GM-CSF, IL-3, and IL-6) to IL-1 (+/-M-CSF) would further enhance the stimulatory effects of the primary cytokine(s) on hematopoietic recovery in FUM. Throughout these studies, IL-1 (+/-M-CSF) was administered for 2 days to the FUM, and the secondary cytokines were given either in concert (days 1 and 2) or in sequence (days 3-6) or both with the primary cytokine(s). Based on the magnitude of 7-day post-5-FU granulocyte recovery, the results demonstrated that the synergistic effects of IL-1 + M-CSF treatment on granulopoietic recovery in FUM could not be duplicated by substituting either IL-3, IL-6, or GM-CSF for M-CSF. Nonetheless, the secondary cytokines were observed to enhance the stimulatory effects of IL-1 under the following administration schedules: (1) 2 days of IL-1, followed by a sequential treatment (days 3-6) with either IL-3 or IL-6, (2) 2 days of IL-1 + GM-CSF followed by an additional 4 days of GM-CSF alone, and (3) 2 days of IL-1 + GM-CSF followed by 3-4 days of a combination of GM-CSF and either IL-3 or IL-6. Although these cytokine treatment schedules led to an enhanced granulocyte recovery (vs. IL-1 alone) in FUM, the day 7 granulocyte numbers never exceeded those observed after 2 days of IL-1 + M-CSF. Similarly, granulocyte recovery in FUM receiving 2 days of IL-1 + M-CSF followed by either GM-CSF or IL-3 also was significantly greater than that observed with IL-1 + M-CSF alone. In contrast, however, the sequential administration of IL-6 with IL-1 + M-CSF, unlike IL-1, failed to further enhance granulopoietic recovery, suggesting that there may be an antagonism between IL-6 and M-CSF in the FUM. In summary, therefore, the secondary cytokines were found to interact more effectively when they were administered in sequence, rather than in concert, with both IL-1 and IL-1 + M-CSF.
Kovacs
C J
CJ
Department of Radiation Oncology, Leo W. Jenkins Cancer Center, East Carolina University School of Medicine, Greenville, NC 27858, USA.
Evans
M J
MJ
Daly
B M
BM
Thomas-Patterson
D
D
Johnke
R M
RM
Powell
D S
DS
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects*; D006410:Hematopoiesis / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors
D016207:Cytokines; D007375:Interleukin-1; D007377:Interleukin-3; D015850:Interleukin-6; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005472:Fluorouracil