COMBINED INTERLEUKIN-1-BETA INTERLEUKIN-6 TREATMENT IN MICE - SYNERGISTIC MYELOSTIMULATORY ACTIVITY AND MYELORESTORATIVE EFFECT AFTER CYCLOPHOSPHAMIDE-INDUCED MYELOSUPPRESSION

We have studied the effects of single and combined treatment with reco mbinant human interleukin 1 beta (IL-1 beta) and recombinant human int erleukin-6 (IL-6) on spleen and bone marrow hematopoiesis in normal an d cyclophosphamide-treated mice. Injection of IL-1 beta alone resulted in a significant increase in the number of granulocytes and splenic p rogenitors [burst-forming units-erythroid (BFU-E) and colony-forming u nits-granulomonocytic (CFU-GM)] as compared with control mice but did not markedly enhance the number of bone marrow BFU-E and CFU-GM. IL-6 alone had little effect on the number of splenic progenitors but signi ficantly increased the number of marrow BFU-E and CFU-GM, especially a fter a 6-day cytokine treatment, Combined daily administration of IL-1 beta and IL-6 for 3 days resulted in a synergistic stimulation of hem atopoiesis as evaluated by the number of spleen and bone marrow CFU-GM and BFU-E colonies, Likewise, IL-1 beta/IL-6 markedly enhanced the nu mber of circulating neutrophils, whereas each cytokine alone had littl e or no effect. When the numbers of spleen progenitors and peripheral granulocytes were determined 1 day after the last injection, a synergi stic myelostimulatory effect of combined IL-1 beta/IL-6 treatment was observed at all doses (IL-1 beta, 0.25-0.5 mu g; IL-6, 1-20 mu g). Fur thermore, combined treatment with IL-1 beta/IL-6 accelerated and poten tiated the recovery of myeloid cells after cyclophosphamide injection, whereas the single regimen treatment was not effective. Particularly, the rebound of WBC (especially neutrophilic granulocytes) after cyclo phosphamide treatment was markedly enhanced by the combined treatment, whereas the single regimen was ineffective. Altogether these results may contribute to the development of combination therapies with cytoki nes and antiblastic agents in the treatment of cancer patients.