Secondary Cytokines Interact in Sequence with Interleukin-1α (IL-1α) With or Without Macrophage Colony-Stimulating Factor (M-CSF) to Further Accelerate Granulopoietic Recovery in Myelosuppressed Animals

Abstract

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.

Chlorella vulgaris treatment ameliorates the suppressive effects of single and repeated stressors on hematopoiesis

“…Both IL-6 and IL-1a have synergistic activity with CSFs in stimulating hematopoiesis, thus contributing to the maintenance of neutrophil maturation and viability (Eaves et al, 1991;Dinarello, 1996;Muench et al, 1992). Studies in the literature demonstrate that IL-1a accelerates both granulopoietic and thrombopoietic recovery in 5-fluorouracil myelosuppressed mice (Kovacs et al, 1997). However, in contrast to what we observed with HP and CFU-GM numbers, the decrease caused by SST and RST on the levels of these cytokines was of equal magnitude.…”

Immunohematopoietic modulation by oral β-1,3-glucan in mice infected with Listeria monocytogenes

“…Among several factors involved in the control of hematopoiesis, IL-6 plays critical role in the generation and maintenance of myelopoiesis in murine LTBMC [52], being considered a survival factor to hematopoietic stem cells [53]. Studies in the literature demonstrate that this cytokine accelerates both granulopoietic and thrombopoietic recovery in the 5-fluorouracil myelossupressed mice [54]. Both IL-6 and IL-1α have multiple roles, including a synergistic activity with CSFs to stimulate hematopoiesis [28,54,55].…”

“…Studies in the literature demonstrate that this cytokine accelerates both granulopoietic and thrombopoietic recovery in the 5-fluorouracil myelossupressed mice [54]. Both IL-6 and IL-1α have multiple roles, including a synergistic activity with CSFs to stimulate hematopoiesis [28,54,55]. Treatment with Imunoglucan® increased the ability of stromal cells from infected mice to produce IL-6 and IL-1α, which was consistent with the increased ability of the stromal cell layer to display CFU-GM in vitro.…”

β‐1,3‐Glucan given orally modulates immunomyelopoietic activity and enhances the resistance of tumour‐bearing mice

“…39 Studies in the literature demonstrate that this IL-1a accelerated both granulopoietic and thrombopoietic recovery in 5-fluorouracil-myelosuppressed mice. 40 Both IL-6 and IL-1a have multiple roles, including a synergistic activity with CSFs to stimulate haematopoiesis. 22,41 Treatment with Imunoglucan restored the ability of stromal cells from tumour-bearing mice to produce IL-6 and IL-1a, which is consistent with the increased ability of the stromal cell layer to display CFU-GM in vitro.…”