SECONDARY CYTOKINES INTERACT IN SEQUENCE WITH INTERLEUKIN-1-ALPHA (IL-1-ALPHA) WITH OR WITHOUT MACROPHAGE-COLONY-STIMULATING FACTOR (M-CSF)TO FURTHER ACCELERATE GRANULOPOIETIC RECOVERY IN MYELOSUPPRESSED ANIMALS

Interleukin-1 alpha (IL-1), by itself, accelerates both granulopoietic and thrombopoietic recovery in the 5-fluorouracil (5-FU) myelosuppres sed mouse (FUM). As a primary cytokine, IL-1 also interacts in concert ,vith macrophage colony-stimulating factor (M-CSF) to synergistically enhance hematopoietic recovery in the FUM. As part of our continuing i nterest 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 effect s of the primary cytokine(s) on hematopoietic recovery in FUM. Through out 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 r esults demonstrated that the synergistic effects of IL-1 + M-CSF treat ment on granulopoietic recovery in FUM could not be duplicated by subs tituting either IL-3, IL-6, or GM-CSF for M-CSF. Nonetheless, the seco ndary cytokines were observed to enhance the stimulatory effects of IL -1 under the following administration schedules: (1) 2 days of IL-1, f ollowed 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-CS F alone, and (3) 2 days of IL-1 + GM-CSF followed by 3-4 days of a com bination of GM-CSF and either IL-3 or IL-6. Although these cytokine tr eatment schedules led to an enhanced granulocyte recovery (vs. IL-1 al one) in FUM, the day 7 granulocyte numbers never exceeded those observ ed after 2 days of IL-1 + M-CSF. Similarly, granulocyte recovery in FU M receiving 2 days of IL-1 + M-CSF followed by either GM-CSF or IL-3 a lso was significantly greater than that observed with IL-1 + M-CSF alo ne. In contrast, however, the sequential administration of IL-6 with I L-1 + M-CSF, unlike IL-1, failed to further enhance granulopoietic rec overy, suggesting that there may be an antagonism between IL-6 and M-C SF in the FUM. In summary, therefore, the secondary cytokines were fou nd to interact more effectively when they were administered in sequenc e, rather than in concert, with both IL-1 and IL-1 + M-CSF.