Tumor Necrosis Factor α and the Anemia of Chronic Disease: Effects of Chronic Exposure to TNF on Erythropoiesis in Vivo

  • G. D. Roodman
  • R. A. Johnson
  • U. Clibon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 271)


The anemia of chronic disease is associated with conditions in which macrophage activation occurs. Activated marrow macrophages suppress erythropoiesis in vitro, and produce tumor necrosis factor (TNF). Therefore we tested the effects of chronic in vivo exposure to TNF to determine if it were a candidate for a mediator of the anemia of chronic disease. Nude mice were inoculated with CHO cells expressing the human TNF gene, or with control cells containing the transfection vector alone. The TNF mice promptly became reticulocytopenic, and after 3 weeks their corrected reticulocytes were 2.6±.7% compared to 7.3±4% in control mice. The hematocrit at 3 weeks was 28.4±1.7% in TNF mice compared to 46±8% in control mice. This anemia was also associated with low serum iron and normal iron stores and increased erythropoietin levels. The TNF mice showed an absolute monocytosis with twice the number of circulating monocytes as control mice. The TNF mice also became mildly thrombocytopenic. Marrow CFU-E and BFU-E were profoundly decreased (1.2±2xl0* vs 8.6±2xl04 CFU-E per femur, and 6.5±lxl02 vs 8.5±.2xl04 BFU-E per femur). Splenic CFU-E and BFU-E were similarly depressed. In contrast, marrow CFU-GM and CFU-GEMM were not affected. Administration of recombinant human erythropoietin to these mice failed to reverse the suppressed erythropoiesis in mice bearing TNF producing tumors. These data demonstrated that TNF preferentially inhibits erythropoiesis in vivo, and may be important in the pathogenesis of the anemia of chronic disease.


Control Mouse Recombinant Human Erythropoietin Erythroid Progenitor Erythropoietin Level Tumor Necrosis Factor Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    . Lee, G.R. 1983. The anemia of chronic disease. Seminars In Hematology 20: 61.PubMedGoogle Scholar
  2. 2.
    . Douglas, S.W., J.W. Adamson. 1975. The anemia of chronic disorders: Studies of marrow regulation and iron metabolism. Blood 45: 55.PubMedGoogle Scholar
  3. 3.
    . Zarrebi, M.H., R. Lysik, J. Distefano, S. Zucker. 1977. The anemia of chronic disorders: Studies of iron reutilization in the anemia of experimental malignancy and chronic inflammation. Br. J. Hemat. 35: 647.CrossRefGoogle Scholar
  4. 4.
    . Kuhns, W.J., C.J. Gubler, G.E. Cartwright, M.M. Wintrobe. 1950. The anemia of infection XIV, Response to massive doses of intravenously administered saccharated oxide of iron. J. Clin. Invest. 29: 1505.PubMedCrossRefGoogle Scholar
  5. 5.
    . Ward, W.P., J.E. Kurnick, M.J. Pisarczyk. 1971. Serum level of erythropoietin in anemia associated with chronic infection, malignancy and primary hematopoietic disease. J. Clin. Invest. 50: 332.PubMedCrossRefGoogle Scholar
  6. 6.
    . Alexanian, R. 1972. Erythropoietin excretion of hemolytic anemia and in the hypoferremia of chronic disease. Blood 40: 946(a) (Abstr.).Google Scholar
  7. 7.
    . Cartwright, G.E., G.R. Lee. 1971. The janemia of chronic disorders. Br, J. Hematol. 21: 147.CrossRefGoogle Scholar
  8. 8.
    . Broxmeyer, H.E., L. Lu, E. Platzer, C. Feit, L. Juliano, B.Y. Rubin. 1983. Comparative analysis of the influences of human gamma, alpha and beta interferons on human multipotential (CFU-GEMM), erythroid (BFU-E) and granulocytes (CFU-GM) progenitor cells. J. Immunol. 131: 1300.PubMedGoogle Scholar
  9. 9.
    . Gordon, L.I., W.J. Miller, R.F. Branda, E.D. Zanjani, H.S. Jacob. 1980. Regulation of erythroid colony formation by bone marrow macrophages. Blood 55: 1047.PubMedGoogle Scholar
  10. 10.
    . Roodman, G.D., V.W. Horadam, T.L. Wright. 1983. Inhibition of erythroid colony formation by autologous bone marrow adherent cell from patients with the anemia of chronic disease. Blood 62: 406.PubMedGoogle Scholar
  11. 11.
    . Zanjani, E.D., P.B. McGlave, S.F. Davies, M. Banisadre, M.E. Kaplan, G.S. Sarosi. 1982. In vitro suppression of erythropoiesis by bone marrow adherent cells from some patients with fungal infection. Br. J. Hematol. 50: 479.CrossRefGoogle Scholar
  12. 12.
    . Nathan, C.F. 1987. Secretory products of macrophages. J. Clin. Invest. 79: 319.PubMedCrossRefGoogle Scholar
  13. 13.
    . Collart, M.A., D. Belin, J.D. Vassalli, P. Vassali. 1987. Modulations of functional activity in differentiated macrophages are accompanied by early and transient increase or decrease in c-fos gene transcription. J. Immunol. 139: 949.PubMedGoogle Scholar
  14. 14.
    . Decker, T., M.L. Lohmann-Matthes, G.E. Gifford. 1987. Cell associated tumor necrosis factor (TNF) as a killing mechanism of activated cytotoxic macrophages. J. Immunol. 138: 957.PubMedGoogle Scholar
  15. 15.
    . Beutler, B., J. Mahoney, N.L. Trang, P. Pekela, A. Cerami. 1985. Purification of cachetin, a lipoprotein-lipase suppressing hormone secreted by endotoxin induced RAW 264.7 cells. J. Exp. Med. 161: 984.PubMedCrossRefGoogle Scholar
  16. 16.
    . Akàhane, K., T. Hosoi, A. Urabe, M. Kawakama, F. Takaku. 1987. Effects of recombinant human tumor necrosis factor (rhTNF) on normal human and mouse hemopoietic progenitor cells. Intl. J. Cell Cloning 5: 16.CrossRefGoogle Scholar
  17. 17.
    . Roodman, G.D., A. Bird, D. Hutzler, W. Montgomery. 1987. Tumor necrosis factor-a and hematopoietic progenitors: The effects of tumor necrosis factor on the growth of erythroid progenitors CFU-E and BFU-E and the hematopoietic cell lines K562, HL60, HEL cells. Exp. Hematol. 15: 928.Google Scholar
  18. 18.
    . Murphy, M., G. Perussia, G. Trinchieri. 1988. Effects of recombinant tumor necrosis factor, lymphotoxin, and immune interferon on proliferation and differentiation of enriched hemotopoietic precursor cells. Exp. Hematol. 16: 131.Google Scholar
  19. 19.
    . Wei, H., K. Tracy, K. Manogue, N. Nguyen, Y. Fong, D. Hesse, B. Beutler, R. Solomon, A. Cerami, S. Lowry. 1987. Cachetin mediates suppressed food intake and anemia during chronic administration. Federation Proceedings 46: 5963.Google Scholar
  20. 20.
    . Blick, M., S.A. Sherwin, M. Rosenblum, J. Gutterman. 1987. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res. 47: 2986.PubMedGoogle Scholar
  21. 21.
    . Oliff, A., D. Defeo-Jones, M. Boyer, D. Martinez, D. Kiefer, G. Vuocolo, A. Wolfe, S.H. Socher. 1987. Tumors secreting human TNF/cachectin induce cachexia in nude mice. Cell 50: 555.PubMedCrossRefGoogle Scholar
  22. 22.
    . Tsujimoto, M., Y.K. Yip, J. Vilcek. 1985. Tumor necrosis factor: Specific binding and internalization in sensitive and resistant cells. Proc. Natl. Acad. Sci. USA. 82: 7626.PubMedCrossRefGoogle Scholar
  23. 23.
    . Birgegard G., 0. Miller, J. Caro, A. Ersler. 1982. Serum erythropoietin levels by radioimmunoassay in polycythemia. Scand. J. Haematol. 29: 161.Google Scholar
  24. 24.
    . Iscove, N.N., F. Sieber, K.H. Winterhalter. 1974, Erythroid colony formation in cultures of mouse and human bone marrow: Analyses of the requirement for erythropoietin by gel filtration and affinity chromotography on agarose-concavalin A. J. Cell Physiol. 83: 309.PubMedCrossRefGoogle Scholar
  25. 25.
    . Nakahata, T., M. Ogawa. 1982. Clonal origin of murine hematopoietic colonies with apparent restriction to granulocyte-macrophage-megakaryocytes (GMM) differentiation. J. Cell Physiol. 111: 239.PubMedCrossRefGoogle Scholar
  26. 26.
    . Humphries, R.K., A.C. Eaves, C.J. Eaves. 1979. Characterization of a primitive erythropoietic progenitor found in mouse marrow before and after several weeks in culture. Blood 53: 746.PubMedGoogle Scholar
  27. 27.
    . Karnoviky, M.J., L. Roots. 1964. A “direct-coloring” thiocholine method for cholinesterasese. J. Histochem Cytochem. 12: 219.CrossRefGoogle Scholar
  28. 28.
    . Jackson, C.W. 1973. Cholinesterase as a possible marker for early cells of the megakaryocytic series. Blood 42: 413.PubMedGoogle Scholar
  29. 29.
    . Murase, T., T. Hotta, H. Saito, R. Ohno. 1987. Effect of recombinant human tumor necrosis factor on the colony growth of human leukemia progenitor cells and normal hematopoietic progenitor cells. Blood 69: 467.PubMedGoogle Scholar
  30. 30.
    . Abboud, S.L., S.L. Gerson, N.A. Berger. 1987. The effect of tumor necrosis factor on normal human hematopoietic progenitors. Cancer 60: 2965.PubMedCrossRefGoogle Scholar
  31. 31.
    . Broxmeyer, H.E., D.E. Williams, L. Lu, S. Cooper, S.L. Anderson, G.S. Beyer, R. Hoffman, B.Y. Rubin. 1986. The suppressive influences of human tumor necrosis factor on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: Synergism of tumor necrosis factor and interferon y. J. of Immunology 136: 4487.Google Scholar
  32. 32.
    . Koeffler, H.P., J. Gasson, J. Raynard, L. Souza, N. Shepard, R. Munker. 1987. Recombinant human TNF-a stimulates production of granulocyte colony-stimulating factor. Blood 70: 55.PubMedGoogle Scholar
  33. 33.
    . Munker, R., J. Gasson, M. Ogawa, H.P. Koeffler. 1986. Recombinant human TNF induces production of granulocyte-macrophage colony-stimulating factor. Nature 323: 79.PubMedCrossRefGoogle Scholar
  34. 34.
    . Broudy, V.C., K. Kaushansky, G.M. Segal, J.M. Harlan, J.W. Adamson. 1986. Tumor necrosis factor a stimulates human endothelial cells to produce granulocyte/macrophage colony stimulating factor. Proc. Natl. Acad. Sci., USA 83: 7467.PubMedCrossRefGoogle Scholar
  35. 35.
    . Oster, W., A. Lindermann, S. Horn, R. Mertelsmann, F. Herman. 1987. Tumor necrosis factor (TNF)-alpha but not TNF-beta induces secretion of colony stimulating factor for macrophages (CSF-1) by human monocytes. Blood 70: 1700.PubMedGoogle Scholar
  36. 36.
    . Munker, R., P. Koeffler. 1987. In vitro action of tumor necrosis factor on myeloid leukemia cells. Blood 69: 1102.Google Scholar
  37. 37.
    . Teppo, A.M., C.P.J. Maury. 1987. Radioimmunoassay of tumor necrosis factor in serum. Clin. Chem. 33: 2024.Google Scholar
  38. 38.
    . Aderka, D., S. Fisher, Y. Levo, H. Holtman, T. Hahn, D. Wallach. 1985. Cachetin/tumor-necrosis factor production by cancer patients. Lancet 2: 1190.PubMedCrossRefGoogle Scholar
  39. 39.
    . Feldman, L., CM. Cohen, N. Dainiak. 1986. In vitro release of physically separable factors from monocytes that exert opposing effects on erythropoiesis. Blood 67: 1454.Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • G. D. Roodman
    • 1
  • R. A. Johnson
    • 2
  • U. Clibon
    • 1
  1. 1.Research Service and Geriatric Research, Education, and Clinical CenterVeterans Administration HospitalSan AntonioUSA
  2. 2.Wilford Hall USAF Medical CenterSan AntonioUSA

Personalised recommendations