In vivo hematopoietic effects of tumor necrosis factor-alpha in normal and erythroleukemic mice: characterization and therapeutic applications.
The effects of recombinant, macrophage-derived, murine tumor necrosis factor-alpha (TNF-alpha) on hematopoiesis in vivo has been examined in normal mice and in Friend virus (FV)-induced erythroleukemic mice. Intravenous (IV) administration of a single dose of recombinant murine TNF-alpha (10(5) U per mouse) significantly suppressed normal and leukemic late-stage erythropoiesis as measured by numbers of mature erythroid colony forming cells (CFU-E) in the bone marrow and spleen and by peripheral blood reticulocyte counts. In normal animals, the immature erythroid (BFU-E), macrophage (CFU-M), and granulocyte-macrophage (CFU-GM) compartments were significantly stimulated by TNF-alpha in both the bone marrow and the spleen. In the bone marrow of leukemic mice, the BFU-E, CFU-GM, and CFU-M progenitor cell compartments were also stimulated by treatment with the monokine. In the spleens of leukemic mice (the primary site of FV leukemia cell accumulation), relative numbers of BFU-E and CFU-GM were increased by TNF-alpha, while those of CFU-M were suppressed. TNF-alpha caused a rapid decrease in the markedly elevated spleen weights of progressively leukemic mice, and in multiple doses it caused complete clinical disease regression in a significant percentage of leukemic animals. The combination of TNF-alpha with interferon-gamma (IFN-gamma) increased the incidence of leukemia regression, compared with TNF-alpha alone. These results show that TNF-alpha exerts a suppressive influence on late-stage erythropoiesis in vivo and suggest that this effect might be exploited in the treatment of acute erythroleukemia, erythroid hyperplasias, and related diseases.
Johnson
C S
CS
Department of Cell Biology, AMC Cancer Research Center, Denver, CO 80214.
Chang
M J
MJ
Furmanski
P
P
D000818:Animals; D002460:Cell Line; D003864:Depression, Chemical; D004920:Erythropoiesis / Q000187:drug effects*; D005622:Friend murine leukemia virus; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013163:Splenomegaly / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha