Negative regulators of in vivo erythropoiesis: interaction of IL-1 alpha and TNF-alpha and the lack of a strict requirement for T or NK cells for their activity.
The macrophage-derived cytokines interleukin 1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) have significant effects on hematopoiesis in vitro and in vivo. Studies in our laboratory have demonstrated that, in vivo, IL-1 alpha and TNF-alpha suppress late stage erythropoiesis while stimulating the macrophage-granulocyte lineage. In the present studies, we have examined the mechanisms of these effects. Normal mice were treated with a single dose of either recombinant murine IL-1 alpha or TNF-alpha (1.25 x 10(6) or 10(5) U/mouse i.p., respectively) with or without pretreatment of the animals with monoclonal anti-murine TNF-alpha antibody at a dose that has been shown to be capable of abrogating endogenous TNF activity induced by lipopolysaccharide (LPS). After 5 days, effects on late-stage erythropoiesis and macrophage formation were measured by determining the number of their progenitors, erythroid colony-forming units (CFU-E) and macrophage colony-forming units (CFU-M), in the spleen. Anti-TNF-alpha antibody treatment significantly abrogated CFU-E suppression by IL-1 alpha but had no effect on the IL-1 alpha-induced stimulation of CFU-M. IL-1 alpha and TNF-alpha suppressed CFU-E in vivo and stimulated CFU-M in the spleens of T-cell- and natural killer (NK)-cell-deficient mice. Neither cytokine suppressed CFU-E colony formation in vitro. These results demonstrate that IL-1 alpha-induced suppression of CFU-E is mediated through induction of TNF-alpha, IL-1 alpha stimulation of CFU-M was independent of TNF-alpha, and the in vivo hematopoietic effects of these cytokines do not strictly require intact T- and NK-cell function for activity.
Johnson
C S
CS
Department of Otolaryngology, University of Pittsburgh, School of Medicine, Pennsylvania 15213.
Pourbohloul
S C
SC
Furmanski
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D004920:Erythropoiesis / Q000187:drug effects / Q000502:physiology*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism* / Q000502:physiology
D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha