Macrophage control of normal and leukemic erythropoiesis: identification of the macrophage-derived erythroid suppressing activity as interleukin-1 and the mediator of its in vivo action as tumor necrosis factor.
Macrophages have been shown to directly influence the growth and development of mature erythroid progenitors (CFU-E) in normal and erythroleukemic mice. We examined the mechanism by which macrophages mediate their effect on in vivo erythropoiesis. As reported for whole macrophages, serum-free supernatants (SN) from normal resident peritoneal macrophages suppressed in vivo normal and conventional Friend virus (CFV)-infected CFU-E and caused clinical regression of CFV-induced leukemia in mice. Macrophage SN had no effect on the erythropoietin (EPO)-independent CFU-E characteristic of infection with the polycythemia-inducing strain of Friend virus (FVP), or progression of FVP leukemia. Using biochemical, immunologic, and functional assays, the erythrosuppressive factor in macrophage SN was identified as interleukin-1 alpha (IL-1 alpha). The in vivo erythroid suppressive effects of macrophages, macrophage SN, and IL-1 alpha were reversed by simultaneous treatment with EPO. IL-1 alpha itself had no effect on CFU-E colony formation in vitro. Pretreatment of animals with antibodies to murine tumor necrosis factor-alpha (TNF-alpha) completely abrogated the suppression of CFU-E by macrophages, macrophage SN, or human recombinant IL-1 alpha. These results suggest that macrophages regulate erythropoiesis by production of IL-1 alpha, which in turn mediates its in vivo suppressive effects on CFU-E through TNF.
Furmanski
P
P
Laboratory of Cell Biology, AMC Cancer Research Center, Denver, CO.
Johnson
C S
CS
D000818:Animals; D004731:Endotoxins / Q000494:pharmacology; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology*; D004915:Leukemia, Erythroblastic, Acute / Q000503:physiopathology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D004731:Endotoxins; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin