International Journal of Hematology

, Volume 74, Issue 1, pp 3–8 | Cite as

Cytokines: Past, Present, and Future

  • Joost J. OppenheimEmail author
Progress in hematology


This review provides an historical account of the discovery and development of cytokines. Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Although cytokines are occasionally produced constitutively, they are usually produced by virtually every nucleated cell type in response to injurious stimuli. Cytokines act on cells expressing complementary receptors. Cytokines have been assigned to various family groups based on the structural homologies of their receptors. This review shows how cytokine research evolved from phenomenological to molecular stages and from a focus on ligands to characterization of cytokine receptors.The advent of molecular biology, monoclonal antibodies, and microsequencing made it possible to obtain pure recombinant cytokine preparation for experimental and therapeutic applications. The development of targeted gene deletions revealed many cytokines to have unexpected pathophysiological functions.The identification of “virokines,” homologues that mimic cytokine ligands and receptors, has provided impetus to the founding of biotechnology companies aimed at developing cytokine agonists and antagonists for therapeutic applications. The discipline of cytokinology is now endowed with several journals, multiple annual meetings, and many devoted investigators. The explosion in cytokine information over the past 40 years has been enormous and full of surprises. If past be prologue, with the advent of genomics and proteomics the future should witness even greater progress.

Key words

Cytokines Interleukins Receptors Immunoregulation Chemotaxis Hematopoiesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Menkin V. Chemical basis of fever.Science. 1944;100:337–338.CrossRefPubMedGoogle Scholar
  2. 2.
    Bennett IL Jr, Beeson PB. Studies on the pathogenesis of fever. II. Characterization of fever-producing substances from polymorphonuclear leukocytes and from the fluid of sterile exudates.J Exp Med. 1953;98:493–508.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Levi-Montalcini R, Hamburger V. A diffusible agent of mouse sarcoma producing hyperplasia of sympathetic ganglia and hyperneurotization of the chick embryo.J Exp Zool. 1953;123:233–388.CrossRefGoogle Scholar
  4. 4.
    Isaacs A, Lindenmann J. Virus interference. I. Interferons.Proc R Soc Ser B Biol Sci. 1957;147:258–267.CrossRefGoogle Scholar
  5. 5.
    Gowans JL. The recirculation of lymphocytes from blood to lymph in the rat.J Physiol. 1959;146:54–69.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nowell PC. Phytohemagglutinin: an imitator of mitosis in cultures of normal human leukocytes.Cancer Res. 1960;20:462–467.PubMedGoogle Scholar
  7. 7.
    Pearmain G, Lycette RR, Fitzgerald PH. Tuberculin induced mitosis in peripheral blood leukocytes.Lancet. 1963;1:637–638.CrossRefPubMedGoogle Scholar
  8. 8.
    Bain ML, Vas M, Lowenstein L. The development of large immature mononuclear cells in mixed leukocyte cultures.Blood. 1964;23:108–116.PubMedGoogle Scholar
  9. 9.
    Kasakura S, Lowenstein L. A factor stimulating DNA synthesis derived from the medium of leukocyte cultures.Nature. 1965;208:794–795.CrossRefPubMedGoogle Scholar
  10. 10.
    David JR. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction.Proc Natl Acad Sci U S A. 1966;56:73–77.CrossRefGoogle Scholar
  11. 11.
    Bloom BR, Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity.Science. 1966;153:80–82.CrossRefPubMedGoogle Scholar
  12. 12.
    Ruddle NH,Waksman BH. Cytotoxic effect of lymphocyte-antigen interaction in delayed hypersensitivity.Science. 1967;157:1060–1062.CrossRefPubMedGoogle Scholar
  13. 13.
    Granger GA, Williams TW. Lymphocyte cytotoxicity in vitro: activation and release of a cytotoxic factor.Nature. 1968;218:1253–1254.CrossRefPubMedGoogle Scholar
  14. 14.
    Weiser WY, Temple TA, Witek-Giannotti JS, Remold HG, Clark CC, David JR. Molecular cloning of cDNA encoding a human macrophage migration inhibitory factor.Proc Natl Acad Sci U S A. 1989;86:7522–7526.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Nathan CF, Karnovksy ML, David JR. Alterations of macrophage functions by mediators from lymphocytes.J Exp Med. 1971;133:1356–1376.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Schreiber RD, Celada A. Molecular characterization of interferon γ as a macrophage activating factor. In: Pick E, ed.Lymphokines. London, UK: Acad Press; 1985:87–118.Google Scholar
  17. 17.
    Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson G. An endotoxin induced serum factor that causes necrosis of tumors.Proc Natl Acad Sci U S A. 1975;72:3666–3670.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gordon J, MacLean LD. A lymphocyte-stimulating factor produced in vitro.Nature. 1965;208:795–796.CrossRefPubMedGoogle Scholar
  19. 19.
    Kasakura S, Lowenstein L. DNA and RNA synthesis and the formation of blastogenic factor in mixed leukocyte cultures.Nature. 1967;215:80–81.CrossRefPubMedGoogle Scholar
  20. 20.
    Dumonde DC, Wolstencroft RA, Panayi GS, Matthew M, Morley J, Howson WT. Lymphokines: non-antibody mediators of cellular immunity generated by lymphocyte activation.Nature. 1969;224:38–42.CrossRefPubMedGoogle Scholar
  21. 21.
    Kasakura S. Heterogeneity of blastogenic factors produced in vitro by antigenically stimulated and unstimulated leukocytes.J Immunol. 1970;105:1162–1167.PubMedGoogle Scholar
  22. 22.
    Kasakura S. A blastogenic factor in unidirectional mixed leukocyte cultures with x-irradiated cells.Transplantation. 1971;11:117–121.CrossRefPubMedGoogle Scholar
  23. 23.
    Gery I, Gershon RK, Waksman BH. Potentiation of cultured mouse thymocyte responses by factors released by peripheral leukocytes.J Immunol. 1971;107:1778–1780.PubMedGoogle Scholar
  24. 24.
    Gery I, Waksman BH. Potentiation of lymphocyte responses to mitogens. II. The cellular source of potentiating mediators.J Exp Med. 1972;136:143–155.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Rosenwasser LJ, Dinarello CA, Rosenthal AS. Adherent cell function in murine T lymphocyte antigen recognition. IV. Enhancement of murine T-cell antigen recognition by human leukocytic pyrogen.J Exp Med. 1979;150:709–714.CrossRefPubMedGoogle Scholar
  26. 26.
    Cohen S, Bigazzi PE, Yoshida T. Similarities of T cell function in cell-mediated immunity and antibody production.Cell Immunol. 1974;12:150–159.CrossRefPubMedGoogle Scholar
  27. 27.
    Waksman BH. Modulation of immunity by soluble mediators.Pharmacol Ther A. 1978;2:623–672.Google Scholar
  28. 28.
    Oppenheim JJ, Gery I. From lymphodrek to IL 1.Immunol Today. 1993;14:232–234.CrossRefPubMedGoogle Scholar
  29. 29.
    Mizel SB, Farrar JJ. Revised nomenclature for antigen non-specific T cell proliferation and helper factors.Cell Immunol. 1970;48:433–436.CrossRefGoogle Scholar
  30. 30.
    Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows.Science. 1976;193:1007–1008.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zubler RM, Lowenthal JW, Erard F, Hashimoto N, Devos R, Mac Donald HR. Activated B cells express receptors for and proliferate in response to pure IL-2.J Exp Med. 1984;160:1170–1183.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ortaldo JRM, Mason AT, Gerard JP, et al. Effects of natural and recombinant IL 2 on regulation of IFNγ production and natural killer cell activity.J Immunol. 1984;133:779–783.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Oppenheim JJ, Gery I. Interleukin 1 is more than an interleukin.Immunol Today. 1982;3:113–119.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ihle JN, Pepersack L, Rebar L. Regulation of T cell differentiation: in vitro induction of 20a hydroxysteroid dehydrogenase in splenic lymphocytes from athymic mice by a unique lymphokine.J Immunol. 1981;126:2184–2189.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Taniguchi T, Ohno S, Fujii-Kuriyama Y, Muratmatsu M. The nucleotide sequence of human fibroblast interferon cDNA.Gene. 1980;10:11–15.CrossRefPubMedGoogle Scholar
  36. 36.
    Nagata S, Taira H, Hall A, et al. Synthesis in E. coli of a polypeptide with human leukocyte interferon activity.Nature. 1980;284:316–320.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gray PW, Leung DW, Pennica D, et al. Expression of human immune interferon cDNA inE. coli and monkey cells.Nature. 1982;285:503–508.CrossRefGoogle Scholar
  38. 38.
    Taniguchi T, Matsui H,Fujita T, et al. Structure and expression of a cloned cDNA for human interleukin-2.Nature. 1983;302:305–310.CrossRefPubMedGoogle Scholar
  39. 39.
    Leonard WJ, Depper JM, Crabtree GR, et al. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor.Nature. 1984;311:626–631.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Pennica D, Nedwin GE, Hayflick JS, et al. Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin.Nature. 1984;312:724–729.CrossRefPubMedGoogle Scholar
  41. 41.
    Gray PW, Aggarwal BB, Benton CV, et al. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor necrosis activity.Nature. 1984;312:721–724.CrossRefPubMedGoogle Scholar
  42. 42.
    Durum SK, Muegge K, eds.Contemporary Immunology: Cytokine Knockouts. Totowa, NJ: Pub Humana Press; 1998.Google Scholar
  43. 43.
    Nagata S. Apoptosis by death factor.Cell. 1997;88:355–365.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Derynck R, Jarrett JA, Chen EY, et al. Human transforming growth factor-B complementary DNA sequence and expression in normal and transformed cells.Nature. 1985;316:701–705.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Moore K, O’Garra A, de Waal Malefyt R, Viera P, Mosmann TR. Interleukin 10.Annu Rev Immunol. 1993;11:165–190.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ward PA, Remold HG, David JR. Leukotactic factor produced by sensitized lymphocytes.Science. 1969;163:1079–1081.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Luger TA, Charon JA, Colot M, Miksche M, Oppenheim JJ. Chemotactic properties of partially purified human epidermal cell-derived thymocyte activating factor CETAF for polymorphonuclear and mononuclear cells.J Immunol. 1983;13:816–820.Google Scholar
  48. 48.
    Sauder DN, Mounessa NL, Katz SI, Dinarello CA, Gallin JI. Chemotactic cytokines: the role of leukocyte pyrogen and ETAF in neutrophil chemotaxis.J Immunol. 1984;132:828–832.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Yoshimura T, Matsushima K,Tanaka S, et al. Purification of human monocyte-derived neutrophil chemotactic factor that shares sequence homology with other host defense cytokines.Proc Natl Acad Sci U S A. 1987;84:9233–9237.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Matsushima K, Morishita K, Yoshimura T, et al. Molecular cloning of cDNA for a human monocyte derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor.J Exp Med. 1988;167:1883–1893.CrossRefPubMedGoogle Scholar
  51. 51.
    Larsen CG, Anderson AO, Appella E, Oppenheim JJ, Matsushima K. Identity of chemotactic cytokine for T-lymphocytes with neutrophil activating protein (NAP-1): a candidate interleukin 8.Science. 1989;243:1464–1466.CrossRefPubMedGoogle Scholar
  52. 52.
    Hirano T, Yasukawa K, Harada H, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin.Nature. 1986;324:73–76.CrossRefPubMedGoogle Scholar
  53. 53.
    Zilberstein A, Ruggieri R, Korn JH, Revel M. Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines.EMBO J. 1986;5:2529–2537.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Street NE, Mosmann TR. Functional diversity of T lymphocytes due to secretion of different cytokine patterns.FASEB J. 1991;5:171–177.CrossRefPubMedGoogle Scholar
  55. 55.
    Yssel H, DeWaal MR, Roncarolo M-G, et al. IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells.J Immunol. 1992;149:2378–2384.PubMedGoogle Scholar
  56. 56.
    Hsieh GS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM. Listeria induced TH1 development in afjTCR transgenic CD4+ T cells occurs through macrophage production of IL-12.Science. 1992;260:547–549.CrossRefGoogle Scholar
  57. 57.
    Rincon M, Anguita J, Nakamura T, Fikrig E, Flavell RA. Interleukin (IL)-6 directs the differentiation of IL-4 producing CD4+ T cells.J Exp Med. 1997;185:461–469.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Oppenheim JJ, Neta R. Pathophysiological roles of cytokines in development, immunity and inflammation.FASEB J. 1994;8:158–162.CrossRefPubMedGoogle Scholar
  59. 59.
    Oppenheim JJ, Saklatvala J. Cytokines and their receptors. In: Oppenheim JJ, Rossio JL, Gearing AJH, eds.Clinical Applications of Cytokines. New York, NY: Oxford University Press; 1993:3–15.Google Scholar
  60. 60.
    Russell SM, Keegan AD, Harada N, et al. IL-2 receptor — chains. A functional component of the IL-4 receptor.Science. 1993;262:1880–1883.CrossRefPubMedGoogle Scholar
  61. 61.
    Miyajima A, Kitamura T, Harada N, Yokota T, Arai K-I. Cytokine receptors and signal transduction.Am Rev Immunol. 1992;10:298–332.Google Scholar
  62. 62.
    Taga T, Kishimoto T. GP130 and the interleukin-6 family of cytokines.Annu Rev Immunol. 1997;15:797–819.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2001

Authors and Affiliations

  1. 1.Laboratory of Molecular Immunoregulation, Division of Basic SciencesNational Cancer Institute, Frederick Cancer Research and Development CenterFrederick, MarylandUSA

Personalised recommendations