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Cytokines: Past, Present, and Future

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Abstract

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.

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References

  1. Menkin V. Chemical basis of fever.Science. 1944;100:337–338.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  4. Isaacs A, Lindenmann J. Virus interference. I. Interferons.Proc R Soc Ser B Biol Sci. 1957;147:258–267.

    Article  CAS  Google Scholar 

  5. Gowans JL. The recirculation of lymphocytes from blood to lymph in the rat.J Physiol. 1959;146:54–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Nowell PC. Phytohemagglutinin: an imitator of mitosis in cultures of normal human leukocytes.Cancer Res. 1960;20:462–467.

    CAS  PubMed  Google Scholar 

  7. Pearmain G, Lycette RR, Fitzgerald PH. Tuberculin induced mitosis in peripheral blood leukocytes.Lancet. 1963;1:637–638.

    Article  CAS  PubMed  Google Scholar 

  8. Bain ML, Vas M, Lowenstein L. The development of large immature mononuclear cells in mixed leukocyte cultures.Blood. 1964;23:108–116.

    CAS  PubMed  Google Scholar 

  9. Kasakura S, Lowenstein L. A factor stimulating DNA synthesis derived from the medium of leukocyte cultures.Nature. 1965;208:794–795.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  11. Bloom BR, Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity.Science. 1966;153:80–82.

    Article  PubMed  CAS  Google Scholar 

  12. Ruddle NH,Waksman BH. Cytotoxic effect of lymphocyte-antigen interaction in delayed hypersensitivity.Science. 1967;157:1060–1062.

    Article  PubMed  CAS  Google Scholar 

  13. Granger GA, Williams TW. Lymphocyte cytotoxicity in vitro: activation and release of a cytotoxic factor.Nature. 1968;218:1253–1254.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Nathan CF, Karnovksy ML, David JR. Alterations of macrophage functions by mediators from lymphocytes.J Exp Med. 1971;133:1356–1376.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Gordon J, MacLean LD. A lymphocyte-stimulating factor produced in vitro.Nature. 1965;208:795–796.

    Article  PubMed  CAS  Google Scholar 

  19. Kasakura S, Lowenstein L. DNA and RNA synthesis and the formation of blastogenic factor in mixed leukocyte cultures.Nature. 1967;215:80–81.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  21. Kasakura S. Heterogeneity of blastogenic factors produced in vitro by antigenically stimulated and unstimulated leukocytes.J Immunol. 1970;105:1162–1167.

    PubMed  CAS  Google Scholar 

  22. Kasakura S. A blastogenic factor in unidirectional mixed leukocyte cultures with x-irradiated cells.Transplantation. 1971;11:117–121.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  27. Waksman BH. Modulation of immunity by soluble mediators.Pharmacol Ther A. 1978;2:623–672.

    Google Scholar 

  28. Oppenheim JJ, Gery I. From lymphodrek to IL 1.Immunol Today. 1993;14:232–234.

    Article  PubMed  CAS  Google Scholar 

  29. Mizel SB, Farrar JJ. Revised nomenclature for antigen non-specific T cell proliferation and helper factors.Cell Immunol. 1970;48:433–436.

    Article  Google Scholar 

  30. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows.Science. 1976;193:1007–1008.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  33. Oppenheim JJ, Gery I. Interleukin 1 is more than an interleukin.Immunol Today. 1982;3:113–119.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  35. Taniguchi T, Ohno S, Fujii-Kuriyama Y, Muratmatsu M. The nucleotide sequence of human fibroblast interferon cDNA.Gene. 1980;10:11–15.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  42. Durum SK, Muegge K, eds.Contemporary Immunology: Cytokine Knockouts. Totowa, NJ: Pub Humana Press; 1998.

    Google Scholar 

  43. Nagata S. Apoptosis by death factor.Cell. 1997;88:355–365.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  45. Moore K, O’Garra A, de Waal Malefyt R, Viera P, Mosmann TR. Interleukin 10.Annu Rev Immunol. 1993;11:165–190.

    Article  PubMed  CAS  Google Scholar 

  46. Ward PA, Remold HG, David JR. Leukotactic factor produced by sensitized lymphocytes.Science. 1969;163:1079–1081.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Street NE, Mosmann TR. Functional diversity of T lymphocytes due to secretion of different cytokine patterns.FASEB J. 1991;5:171–177.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Oppenheim JJ, Neta R. Pathophysiological roles of cytokines in development, immunity and inflammation.FASEB J. 1994;8:158–162.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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. Taga T, Kishimoto T. GP130 and the interleukin-6 family of cytokines.Annu Rev Immunol. 1997;15:797–819.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Joost J. Oppenheim.

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Oppenheim, J.J. Cytokines: Past, Present, and Future. Int J Hematol 74, 3–8 (2001). https://doi.org/10.1007/BF02982543

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