Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1990 Aug;137(2):369–376.

Hematologic effects of recombinant murine granulocyte-macrophage colony-stimulating factor on the peripheral blood and bone marrow.

T R Ulich 1, J del Castillo 1, I McNiece 1, L Watson 1, S M Yin 1, J Andresen 1
PMCID: PMC1877618  PMID: 1696784

Abstract

Recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF) was noted to support rat bone marrow colony formation in vitro. The in vivo hematologic effects of a single intravenous injection of murine GM-CSF were therefore investigated. Doses of murine GM-CSF between 0.1 and 5 micrograms/rat caused an increasing leukocytosis that did not further increase with a dose of 25 micrograms/rat. In contrast, human GM-CSF at 25 micrograms/rat did not induce any significant peripheral hematologic effects. Murine GM-CSF induced peripheral neutrophilia and monocytosis, peaking between 4 and 8 hours and subsiding to baseline by 12 hours. Neutropenia and monocytopenia, which reached a nadir at 15 minutes, preceded the leukocytosis, suggesting that GM-CSF activates these leukocytes and causes transient intravascular margination. A mild lymphopenia occurred between 2 to 8 hours. The bone marrow at 6 hours after injection of GM-CSF demonstrated a variable and slight left-shifted myeloid hyperplasia most noticeable at the level of promyelocytes and myelocytes, suggesting a myeloproliferative effect. The marrow at 6 hours also demonstrated a decrease in mature neutrophils, documenting that the marrow contributes to the increased number of circulating neutrophils. Once-daily injection of GM-CSF for 7 days induced a repetitive daily neutrophilia of the same magnitude. The marrow after 1 week of injections did not show a generalized myeloid hyperplasia, but did show an increase in eosinophils and a decrease in lymphocytes. Granulocyte-macrophage colony-stimulating factor plus granulocyte colony-stimulating factor (G-CSF) have been reported to synergize in vitro in both mouse and human bone marrow colony assays. However GM-CSF plus G-CSF in vivo, administered as either a single injection or as daily injections for 1 week, were found in the present study to induce, at most, an additive effect on circulating numbers of neutrophils. It is concluded that murine GM-CSF will be useful in the rat model to study the in vivo hematoreconstitutive effects of GM-CSF alone and in combination with other hematologic growth factors. The relatively rapid kinetics and lesser magnitude of GM-CSF-induced neutrophilia and monocytosis, as compared to G-CSF and M-CSF, respectively, and the lesser myeloproliferative effect of GM-CSF in bone marrow smears, as compared to G-CSF, might be taken to suggest that GM-CSF's natural activity is predominantly as an inflammatory rather than a myeloproliferative factor.

Full text

PDF
369

Images in this article

372Figure 2
on p.372

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aglietta M., Piacibello W., Sanavio F., Stacchini A., Aprá F., Schena M., Mossetti C., Carnino F., Caligaris-Cappio F., Gavosto F. Kinetics of human hemopoietic cells after in vivo administration of granulocyte-macrophage colony-stimulating factor. J Clin Invest. 1989 Feb;83(2):551–557. doi: 10.1172/JCI113917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bradley T. R., Hodgson G. S., Rosendaal M. The effect of oxygen tension on haemopoietic and fibroblast cell proliferation in vitro. J Cell Physiol. 1978 Dec;97(3 Pt 2 Suppl 1):517–522. doi: 10.1002/jcp.1040970327. [DOI] [PubMed] [Google Scholar]
  3. Brandt S. J., Peters W. P., Atwater S. K., Kurtzberg J., Borowitz M. J., Jones R. B., Shpall E. J., Bast R. C., Jr, Gilbert C. J., Oette D. H. Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. N Engl J Med. 1988 Apr 7;318(14):869–876. doi: 10.1056/NEJM198804073181401. [DOI] [PubMed] [Google Scholar]
  4. Burgess A. W., Camakaris J., Metcalf D. Purification and properties of colony-stimulating factor from mouse lung-conditioned medium. J Biol Chem. 1977 Mar 25;252(6):1998–2003. [PubMed] [Google Scholar]
  5. Burgess A. W., Metcalf D. The nature and action of granulocyte-macrophage colony stimulating factors. Blood. 1980 Dec;56(6):947–958. [PubMed] [Google Scholar]
  6. Chervenick P. A., Boggs D. R., Marsh J. C., Cartwright G. E., Wintrobe M. M. Quantitative studies of blood and bone marrow neutrophils in normal mice. Am J Physiol. 1968 Aug;215(2):353–360. doi: 10.1152/ajplegacy.1968.215.2.353. [DOI] [PubMed] [Google Scholar]
  7. DiPersio J., Billing P., Kaufman S., Eghtesady P., Williams R. E., Gasson J. C. Characterization of the human granulocyte-macrophage colony-stimulating factor receptor. J Biol Chem. 1988 Feb 5;263(4):1834–1841. [PubMed] [Google Scholar]
  8. Donahue R. E., Wang E. A., Stone D. K., Kamen R., Wong G. G., Sehgal P. K., Nathan D. G., Clark S. C. Stimulation of haematopoiesis in primates by continuous infusion of recombinant human GM-CSF. 1986 Jun 26-Jul 2Nature. 321(6073):872–875. doi: 10.1038/321872a0. [DOI] [PubMed] [Google Scholar]
  9. Fabian I., Bleiberg I., Riklis I., Kletter Y. Enhanced reconstitution of hematopoietic organs in irradiated mice, following their transplantation with bone marrow cells pretreated with recombinant interleukin 3. Exp Hematol. 1987 Dec;15(11):1140–1144. [PubMed] [Google Scholar]
  10. Gabrilove J. L. Introduction and overview of hematopoietic growth factors. Semin Hematol. 1989 Apr;26(2 Suppl 2):1–4. [PubMed] [Google Scholar]
  11. Gasson J. C., Weisbart R. H., Kaufman S. E., Clark S. C., Hewick R. M., Wong G. G., Golde D. W. Purified human granulocyte-macrophage colony-stimulating factor: direct action on neutrophils. Science. 1984 Dec 14;226(4680):1339–1342. doi: 10.1126/science.6390681. [DOI] [PubMed] [Google Scholar]
  12. Gough N. M., Gough J., Metcalf D., Kelso A., Grail D., Nicola N. A., Burgess A. W., Dunn A. R. Molecular cloning of cDNA encoding a murine haematopoietic growth regulator, granulocyte-macrophage colony stimulating factor. 1984 Jun 28-Jul 4Nature. 309(5971):763–767. doi: 10.1038/309763a0. [DOI] [PubMed] [Google Scholar]
  13. HULSE E. V. QUANTITATIVE CELL COUNTS OF THE BONE MARROW AND BLOOD AND THEIR SECULAR VARIATIONS IN THE NORMAL ADULT RAT. Acta Haematol. 1964 Jan;31:50–63. doi: 10.1159/000209613. [DOI] [PubMed] [Google Scholar]
  14. Mayer P., Lam C., Obenaus H., Liehl E., Besemer J. Recombinant human GM-CSF induces leukocytosis and activates peripheral blood polymorphonuclear neutrophils in nonhuman primates. Blood. 1987 Jul;70(1):206–213. [PubMed] [Google Scholar]
  15. McNiece I. K., Robinson B. E., Quesenberry P. J. Stimulation of murine colony-forming cells with high proliferative potential by the combination of GM-CSF and CSF-1. Blood. 1988 Jul;72(1):191–195. [PubMed] [Google Scholar]
  16. McNiece I. K., Stewart F. M., Deacon D. M., Quesenberry P. J. Synergistic interactions between hematopoietic growth factors as detected by in vitro mouse bone marrow colony formation. Exp Hematol. 1988 Jun;16(5):383–388. [PubMed] [Google Scholar]
  17. McNiece I., Andrews R., Stewart M., Clark S., Boone T., Quesenberry P. Action of interleukin-3, G-CSF, and GM-CSF on highly enriched human hematopoietic progenitor cells: synergistic interaction of GM-CSF plus G-CSF. Blood. 1989 Jul;74(1):110–114. [PubMed] [Google Scholar]
  18. Metcalf D., Johnson G. R., Burgess A. W. Direct stimulation by purified GM-CSF of the proliferation of multipotential and erythroid precursor cells. Blood. 1980 Jan;55(1):138–147. [PubMed] [Google Scholar]
  19. Morstyn G., Lieschke G. J., Sheridan W., Layton J., Cebon J., Fox R. M. Clinical experience with recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor. Semin Hematol. 1989 Apr;26(2 Suppl 2):9–13. [PubMed] [Google Scholar]
  20. Ulich T. R., del Castillo J., Busser K., Guo K. Z., Yin S. M. Acute in vivo effects of IL-3 alone and in combination with IL-6 on the blood cells of the circulation and bone marrow. Am J Pathol. 1989 Oct;135(4):663–670. [PMC free article] [PubMed] [Google Scholar]
  21. Ulich T. R., del Castillo J., Guo K., Souza L. The hematologic effects of chronic administration of the monokines tumor necrosis factor, interleukin-1, and granulocyte-colony stimulating factor on bone marrow and circulation. Am J Pathol. 1989 Jan;134(1):149–159. [PMC free article] [PubMed] [Google Scholar]
  22. Ulich T. R., del Castillo J., Keys M., Granger G. A., Ni R. X. Kinetics and mechanisms of recombinant human interleukin 1 and tumor necrosis factor-alpha-induced changes in circulating numbers of neutrophils and lymphocytes. J Immunol. 1987 Nov 15;139(10):3406–3415. [PubMed] [Google Scholar]
  23. Ulich T. R., del Castillo J., Keys M., Granger G. A. Recombinant human alpha lymphotoxin (tumor necrosis factor-beta) induces peripheral neutrophilia and lymphopenia in the rat. Am J Pathol. 1987 Jul;128(1):5–12. [PMC free article] [PubMed] [Google Scholar]
  24. Ulich T. R., del Castillo J., Ni R. X., Bikhazi N., Calvin L. Mechanisms of tumor necrosis factor alpha-induced lymphopenia, neutropenia, and biphasic neutrophilia: a study of lymphocyte recirculation and hematologic interactions of TNF alpha with endogenous mediators of leukocyte trafficking. J Leukoc Biol. 1989 Feb;45(2):155–167. doi: 10.1002/jlb.45.2.155. [DOI] [PubMed] [Google Scholar]
  25. Ulich T. R., del Castillo J., Ni R. X., Bikhazi N. Hematologic interactions of endotoxin, tumor necrosis factor alpha (TNF alpha), interleukin 1, and adrenal hormones and the hematologic effects of TNF alpha in Corynebacterium parvum-primed rats. J Leukoc Biol. 1989 Jun;45(6):546–557. doi: 10.1002/jlb.45.6.546. [DOI] [PubMed] [Google Scholar]
  26. Ulich T. R., del Castillo J., Souza L. Kinetics and mechanisms of recombinant human granulocyte-colony stimulating factor-induced neutrophilia. Am J Pathol. 1988 Dec;133(3):630–638. [PMC free article] [PubMed] [Google Scholar]
  27. Ulich T. R., del Castillo J., Watson L. R., Yin S. M., Garnick M. B. In vivo hematologic effects of recombinant human macrophage colony-stimulating factor. Blood. 1990 Feb 15;75(4):846–850. [PubMed] [Google Scholar]
  28. Ulich T. R., del Castillo J., Yin S. Tumor necrosis factor exerts dose-dependent effects on erythropoiesis and myelopoiesis in vivo. Exp Hematol. 1990 May;18(4):311–315. [PubMed] [Google Scholar]
  29. Vadhan-Raj S., Buescher S., LeMaistre A., Keating M., Walters R., Ventura C., Hittelman W., Broxmeyer H. E., Gutterman J. U. Stimulation of hematopoiesis in patients with bone marrow failure and in patients with malignancy by recombinant human granulocyte-macrophage colony-stimulating factor. Blood. 1988 Jul;72(1):134–141. [PubMed] [Google Scholar]
  30. Vadhan-Raj S., Keating M., LeMaistre A., Hittelman W. N., McCredie K., Trujillo J. M., Broxmeyer H. E., Henney C., Gutterman J. U. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N Engl J Med. 1987 Dec 17;317(25):1545–1552. doi: 10.1056/NEJM198712173172501. [DOI] [PubMed] [Google Scholar]
  31. Weisbart R. H., Kacena A., Schuh A., Golde D. W. GM-CSF induces human neutrophil IgA-mediated phagocytosis by an IgA Fc receptor activation mechanism. Nature. 1988 Apr 14;332(6165):647–648. doi: 10.1038/332647a0. [DOI] [PubMed] [Google Scholar]
  32. Williams D. E., Bicknell D. C., Park L. S., Straneva J. E., Cooper S., Broxmeyer H. E. Purified murine granulocyte/macrophage progenitor cells express a high-affinity receptor for recombinant murine granulocyte/macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1988 Jan;85(2):487–491. doi: 10.1073/pnas.85.2.487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wong G. G., Witek J. S., Temple P. A., Wilkens K. M., Leary A. C., Luxenberg D. P., Jones S. S., Brown E. L., Kay R. M., Orr E. C. Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. Science. 1985 May 17;228(4701):810–815. doi: 10.1126/science.3923623. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES