Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cytokine–receptor pairing: accelerating discovery of cytokine function

Nature Reviews Drug Discovery volume 3, pages 160–170 (2004)Cite this article

Key Points

  • Cytokines are important in the regulation of haematopoiesis and immune responses. Regulated physiological processes include the survival and proliferation of haematopoietic progenitor cells, induction of their lineage-specific differentiation, functional activation of mature lymphocytes, the activation and regulation of innate and adaptive immune responses, as well as the selective induction of apoptosis.

  • Cytokines representing only a small number of protein families are crucial in these physiological processes, the regulation of which is important in many areas of disease management.

  • The significance of their regulatory roles is illustrated by the frequency with which cytokines and soluble cytokine receptors find application as therapeutic drugs. Protein drugs in these classes include erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), interferon (IFN)-α, IFN-β, human growth hormone (HGH) and ENBREL.

  • Over the past decade, many new 'orphan' members of cytokine and cytokine receptor families have been discovered through homology-based gene-sequence mining approaches. Such orphan genes have no biological annotation at the time of discovery and present a formidable challenge to elucidate function.

  • Advances in ligand/receptor pairing techniques have led to a recognition that systematic pairing of 'orphan' database-derived cytokines and/or cytokine receptors with their binding partners can lead to a marked acceleration in the elucidation of biological function. The tissue distribution of a receptor, and the biological activity of a ligand, can direct investigators rapidly towards regulatory function. The power of cytokine–receptor pairing to accelerate the understanding of function is illustrated with examples of candidate drug discoveries. Several of these discoveries, resulting from cytokine/receptor pairings, are currently advancing towards human clinical evaluation.

Abstract

Over the past decade, advances in both gene discovery and ligand-receptor pairing techniques have led to the recognition that systematic pairing of 'orphan' database-derived cytokines and/or cytokine receptors with their cognate partners can lead to a marked acceleration in the elucidation of biological function. The sometimes-restricted tissue distribution of the receptor, coupled with the highly specific bioactivity of the corresponding ligand, can direct investigators rapidly towards regulatory function and site-of-action studies. The power of cytokine–receptor pairing to accelerate the understanding of function will be illustrated, citing several examples of candidate drug discoveries. Several of these discoveries, resulting from cytokine–receptor pairings, are at present advancing towards human clinical evaluation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Diagram of cytokine receptor module (CRM) in the extracellular domains of class I and class II cytokine receptors.
Figure 2: Sequence publication years for helical cytokines and cytokine receptors.
Figure 3: The power of pairing in the IL-10 family.
Figure 4: Schematic representation of BAFF/APRIL system.

Similar content being viewed by others

References

  1. Boulay, J. -L., O'Shea, J. J. & Paul, W. E. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity 19, 159–163 (2003). A recent review of the class I cytokines and receptors.

    CAS  PubMed  Google Scholar 

  2. Renauld, J. -C. Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators. Nature Rev. Immunol. 3, 667–676 (2003). A recent review of class II cytokines and recptors.

    CAS  Google Scholar 

  3. Xu, W. et al. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc. Natl Acad. Sci. USA 98, 9511–9516 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Dumoutier, L., Lejeune, D., Colau, D. & Renauld, J. -C. Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J. Immunol. 166, 7090–7095 (2001).

    CAS  PubMed  Google Scholar 

  5. Kotenko, S. V. et al. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immunol. 166, 7096–7103 (2001).

    CAS  PubMed  Google Scholar 

  6. Borish, L. C. et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J. Allergy Clin. Immunol. 107, 963–970 (2001).

    CAS  PubMed  Google Scholar 

  7. Grünig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    PubMed  PubMed Central  Google Scholar 

  8. Fernandez-Botran, R. Soluble cytokine receptors: novel immunotherapeutic agents. Exp. Opin. Invest. Drugs 9, 497–514 (2000).

    CAS  Google Scholar 

  9. Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).

    CAS  PubMed  Google Scholar 

  10. Gross, J. A. et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404, 995–999 (2000).

    CAS  PubMed  Google Scholar 

  11. Thompson, J. S. et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 293, 2108–2111 (2001). References 10 and 11 report the pairing of TACI, BCMA, and BAFF–R with BAFF.

    Article  CAS  PubMed  Google Scholar 

  12. Kary, S. & Burmester, G. R. Anakinra: the first interleukin-1 inhibitor in the treatment of rheumatoid arthritis. Int. J. Clin. Pract. 57, 231–234 (2003).

    CAS  PubMed  Google Scholar 

  13. Dinarello, C. A. Interleukin-18, a proinflammatory cytokine. Eur. Cytokine Netw. 11, 483–486 (2000).

    CAS  PubMed  Google Scholar 

  14. Rozwarski, D. A. et al. Structural comparisons among the short-chain helical cytokines. Structure 2, 159–173 (1994).

    CAS  PubMed  Google Scholar 

  15. Wiley, S. R. et al. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 15, 837–846 (2001).

    CAS  PubMed  Google Scholar 

  16. Cosman, D. A family of ligands for the TNF receptor superfamily. Stem Cells 12, 440–455 (1994).

    CAS  PubMed  Google Scholar 

  17. Bazan, J. F. Structural design and molecular evolution of a cytokine receptor superfamily. Proc. Natl Acad. Sci. USA 87, 6934–6938 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Pennica, D. et al. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc. Natl Acad. Sci. USA 92, 1142–1146 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen, Q. et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature 407, 916–920 (2000).

    CAS  PubMed  Google Scholar 

  20. Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002). References 19 and 20 describe the TH1-deficient phenotype of mice lacking WSX1/TCCR, and the biology of the WSX1/TCCR ligand, IL-27. In this case, the knockout phenotype was predictive of ligand function.

    CAS  PubMed  Google Scholar 

  21. Knappe, A., Hör, S., Wittmann, S. & Fickenscher, H. Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with Herpesvirus saimiri. J. Virol. 74, 3881–3887 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Parrish-Novak, J. et al. Interleukins 19, 20, and 24 signal through two distinct receptor complexes. J. Biol. Chem. 277, 47517–47523 (2002).

    CAS  PubMed  Google Scholar 

  23. Kotenko, S. V. The family of IL-10-related cytokines and their receptors: related, but to what extent? Cytokine Growth Factor Rev. 13, 233–240 (2002).

    Google Scholar 

  24. Cosman, D. et al. Cloning, sequence and expression of human interleukin-2 receptor. Nature 312, 768–771 (1984).

    CAS  PubMed  Google Scholar 

  25. Leonard, W. J. et al. Molecular-cloning and expression of cDNAs for the human interleukin-2 receptor. Nature 311, 626–631 (1984).

    CAS  PubMed  Google Scholar 

  26. Leung, D. W. et al. Growth hormone receptor and serum binding protein: purification, cloning, and expression. Nature 330, 537–543 (1987).

    CAS  PubMed  Google Scholar 

  27. D'Andrea, A. D., Lodish, H. F. & Wong, G. G. Expression cloning of the murine erythropoietin receptor. Cell 57, 277–285 (1989).

    CAS  PubMed  Google Scholar 

  28. Gearing, D. P., King, J. A., Gough, N. M. & Nicola, N. A. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 8, 3667–3676 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Harada, N. et al. Expression cloning of a cDNA encoding the murine interleukin 4 receptor based on ligand binding. Proc. Natl Acad. Sci. USA 87, 857–861 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Takaki, S. et al. Molecular cloning and expression of the murine interleukin-5 receptor. EMBO J. 9, 4367–4374 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yamasaki, K. et al. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science 241, 825–828 (1988).

    CAS  PubMed  Google Scholar 

  32. Goodwin, R. G. et al. Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell 60, 941–951 (1990).

    CAS  PubMed  Google Scholar 

  33. Yang, Y. C. et al. Human IL-3 (multi-CSF)- identification by expression cloning of a novel hematopoietic growth-factor related to murine IL-3. Cell 47, 3–10 (1986).

    CAS  PubMed  Google Scholar 

  34. Wong, G. G. et al. Human GM-CSF: molecular cloning of the complementary-DNA and purification of the natural and recombinant proteins. Science 228, 810–815 (1985).

    CAS  PubMed  Google Scholar 

  35. Davis, S. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996). Details a new cell-based binding assay that expedites expression cloning of ligands based on binding with soluble receptor.

    CAS  PubMed  Google Scholar 

  36. Wendling, F., Varlet, P., Charon, M. & Tambourin, P. MPLV: a retrovirus complex inducing an acute myeloproliferative leukemic disorder in adult mice. Virology 149, 242–246 (1986).

    CAS  PubMed  Google Scholar 

  37. Souyri, M. et al. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell 63, 1137–1147 (1990).

    CAS  PubMed  Google Scholar 

  38. Vigon, I. et al. Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc. Natl Acad. Sci. USA 89, 5640–5644 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Methia, N., Louache, F., Vainchenker, W. & Wendling, F. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood 82, 1395–1401 (1993).

    CAS  PubMed  Google Scholar 

  40. Skoda, R. C. et al. Murine c-mpl: a member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal. EMBO J. 12, 2645–2653 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bartley, T. D. et al. identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell 77, 1117–1124 (1994).

    CAS  PubMed  Google Scholar 

  42. de Sauvage, F. J. et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 369, 533–538 (1994).

    CAS  PubMed  Google Scholar 

  43. Lok, S. et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 369, 565–568 (1994). References 41–43 report the cloning of thrombopoietin.

    CAS  PubMed  Google Scholar 

  44. Kaushansky, K. et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 369, 568–571 (1994).

    CAS  PubMed  Google Scholar 

  45. Kelemen, E., Scerhati, I. & Tanos, B. Demonstration and some properties of human thrombopoietin in thrombocythaemic sera. Acta Haematol. 20, 350–355 (1958).

    CAS  PubMed  Google Scholar 

  46. Ozaki, K., Kikly, K., Michalovich, D., Young, P. R. & Leonard, W. J. Cloning of a type I cytokine receptor most related to the IL-2 receptor β chain. Proc. Natl Acad. Sci. USA 97, 11439–11444 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57–63 (2000).

    CAS  PubMed  Google Scholar 

  48. Asao, H. et al. Cutting edge: the common γ-chain is an indispensible subunit of the IL-21 receptor complex. J. Immunol. 167, 1–5 (2001).

    CAS  PubMed  Google Scholar 

  49. Habib, T., Weinberg, K. & Kaushansky, K. The common γ chain (γc) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3. Biochemistry 41, 8725–8731 (2002).

    CAS  PubMed  Google Scholar 

  50. Nelson, A. et al. Anti–tumor effects of interleukin 21. Blood 100, A158 (2002).

    Google Scholar 

  51. Moore, P. A. et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285, 260–263 (1999).

    CAS  PubMed  Google Scholar 

  52. Schneider, P. et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J. Exp. Med. 189, 1747–1756 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hahne, M. et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates cell growth. J. Exp. Med. 188, 1185–1190 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ware, C. F. APRIL and BAFF connect autoimmunity and cancer. J. Exp. Med. 192, F35–F37 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. von Bülow, G. -U. & Bram, R. J. NF-AT activation by a CAML-interacting member of the tumor necrosis factor receptor superfamily. Science 278, 138–141 (1997).

    PubMed  Google Scholar 

  56. Laâbi, Y. et al. A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma. EMBO J. 11, 3897–3904 (1992).

    PubMed  PubMed Central  Google Scholar 

  57. Gross, J. A. et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease: impaired B cell maturation in mice lacking BLyS. Immunity 15, 289–302 (2001).

    CAS  PubMed  Google Scholar 

  58. Marsters, S. A. et al. Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI. Curr. Biol. 10, 785–788 (2000).

    CAS  PubMed  Google Scholar 

  59. von Bülow, G. -U., van Deursen, J. M. & Bram, R. J. Regulation of the T-independent humoral response by TACI. Immunity 14, 573–582 (2001).

    PubMed  Google Scholar 

  60. Yan, M. et al. Activation and accumulation of B cells in TACI-deficient mice. Nature Immunol. 2, 638–643 (2001).

    CAS  Google Scholar 

  61. Xu, S. & Lam, K. -P. B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. Mol. Cell. Biol. 21, 4067–4074 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Yan, M. et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr. Biol. 11, 1547–1552 (2001).

    CAS  PubMed  Google Scholar 

  63. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    CAS  PubMed  Google Scholar 

  64. Gallagher, G. et al. Cloning, expression, and initial characterisation of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun. 1, 442–450 (2000).

    CAS  PubMed  Google Scholar 

  65. Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19 (2001).

    CAS  PubMed  Google Scholar 

  66. Dumoutier, L., Louahed, J. & Renauld, J. -C. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-19. J. Immunol. 164, 1814–1819 (2000).

    CAS  PubMed  Google Scholar 

  67. Jiang, H., Lin, J. J., Su, Z. Z., Goldstein, N. I. & Fisher, P. B. Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 11, 2477–2486 (1995).

    CAS  PubMed  Google Scholar 

  68. Kotenko, S. V. et al. Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J. 16, 5894–5903 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Dumoutier, L. et al. Cutting Edge: STAT activation by IL-19, IL-20 and mda-7 through IL–20 receptor complexes of two types. J. Immunol. 167, 3545–3549 (2001).

    CAS  PubMed  Google Scholar 

  70. Xie, M. -H. et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J. Biol. Chem. 275, 31335–31339 (2000).

    CAS  PubMed  Google Scholar 

  71. Aggarwal, S., Xie, M. H., Maruoka, M., Foster, J. & Gurney, A. L. Acinar cells of the pancreas are a target of interleukin-22. J. Interferon Cytokine Res. 21, 1047–1053 (2001).

    CAS  PubMed  Google Scholar 

  72. Wolk, K., Kunz, S., Asadullah, K. & Sabat, R. Cutting Edge: immune cells as sources and targets of the IL-10 family members? J. Immunol. 168, 5397–5402 (2002).

    CAS  PubMed  Google Scholar 

  73. Ghilardi, N. et al. A novel type I cytokine receptor is expressed on monocytes, signals proliferation, and activates STAT-3 and STAT-5. J. Biol. Chem. 277, 16831–16836 (2002).

    CAS  PubMed  Google Scholar 

  74. Sprecher, C. A. et al. Cloning and characterization of a novel class I cytokine receptor. Biochem. Biophys. Res. Comm. 246, 82–90 (1998).

    CAS  PubMed  Google Scholar 

  75. Rennert, P. et al. A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth. J. Exp. Med. 192, 1677–1683 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Pan, G. et al. Identification and functional characterization of DR6, a novel death domain-containing TNF receptor. FEBS Lett. 431, 351–356 (1998).

    CAS  PubMed  Google Scholar 

  77. Liu, J. et al. Enhanced CD4+ T cell proliferation and Th2 cytokine production in DR6-deficient mice. Immunity 15, 23–34 (2001).

    CAS  PubMed  Google Scholar 

  78. Schmidt, C. S. et al. Enhanced B cell expansion, survival, and humoral responses by targeting death receptor 6. J. Exp. Med. 197, 51–62 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhao, H. et al. Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice. J. Exp. Med. 194, 1441–1448 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kojima, T. et al. TROY, a newly identified member of the tumor necrosis factor receptor superfamily, exhibits a homology with Edar and is expressed in embryonic skin and hair follicles. J. Biol. Chem. 275, 20742–20747 (2000).

    CAS  PubMed  Google Scholar 

  81. Hu, S., Tamada, K., Ni, J., Vincenz, C. & Chen, L. Characterization of TNFRSF19, a novel member of the tumor necrosis factor receptor superfamily. Genomics 62, 103–107 (1999).

    CAS  PubMed  Google Scholar 

  82. Sica, G. L. et al. RELT, a new member of the tumor necrosis factor receptor superfamily, is selectively expressed in hematopoietic tissues and activates transcription factor NF-κB. Blood 97, 2702–2707 (2001).

    CAS  PubMed  Google Scholar 

  83. Li, H. et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 family. Proc. Natl Acad. Sci. USA 97, 773–778 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Aggarwal, S. & Gurney, A. L. IL-17: prototype member of an emerging cytokine family. J. Leukoc. Biol. 71, 1–8 (2002).

    CAS  PubMed  Google Scholar 

  85. Hurst, S. D. et al. New IL-17 family members promote TH1 or TH2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 169, 443–453 (2002).

    CAS  PubMed  Google Scholar 

  86. Kawaguchi, M. et al. Identification of a novel cytokine, ML-1, and its expression in subjects with asthma. J. Immunol. 167, 4430–4435 (2001).

    CAS  PubMed  Google Scholar 

  87. Pan, G. et al. Forced expression of muring IL-17E induces growth retardation, jaundice, a TH2-biased response, and multiorgan inflammation in mice. J. Immunol. 167, 6559–6567 (2001).

    CAS  PubMed  Google Scholar 

  88. Lee, J. et al. IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J. Biol. Chem. 276, 1660–1664 (2001).

    CAS  PubMed  Google Scholar 

  89. Shi, Y. et al. A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity. J. Biol. Chem. 275, 19167–19176 (2000).

    CAS  PubMed  Google Scholar 

  90. Yang, R. -B. et al. A novel interleukin-17 receptor-like protein identified in human umbilical vein endothelial cells antagonizes basic fibroblast growth factor-induced signaling. J. Biol. Chem. 278, 33232–33238 (2003).

    CAS  PubMed  Google Scholar 

  91. Zhu, Y. et al. Cloning, expression, and initial characterization of a novel cytokine-like gene family. Genomics 80, 144–150 (2002).

    CAS  PubMed  Google Scholar 

  92. Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    CAS  PubMed  Google Scholar 

  93. Altschul, S. F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucl. Acids Res. 25, 3389–3402 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Sonnhammer, E. L., Eddy, S. R., Birney, E., Bateman, A. & Durbin, R. Pfam: multiple sequence alignments and HMM-profiles of protein domains. Nucl. Acids Res. 26, 320–322 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Jaroszewski, L., Rychlewski, L., Zhang, B. & Godzik, A. Fold prediction by a hierarchy of sequence, threading, and modeling methods. Protein Sci. 7, 1431–1440 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Aloy, P., Stark, A., Hadley, C. & Russell, R. B. Predictions without templates: new folds, secondary structure, and contacts in CASP5. Proteins 53 (Suppl. 6), 436–456 (2003).

    CAS  PubMed  Google Scholar 

  97. Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).

    CAS  PubMed  Google Scholar 

  98. Hubbard, T. et al. The Ensembl genome database project. Nucl. Acids Res. 30, 38–41 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Bono, H., Kasukawa, T., Furuno, M., Hayashizaki, Y. & Okazaki, Y. FANTOM DB: database of functional annotation of RIKEN mouse cDNA clones. Nucl. Acids Res. 30, 116–118 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Bibby, K., Davis, J. & Jones, C. Biopharmaceuticals — moving to centre stage. BioPeople North American Biotechnology Industry and Suppliers' Guide, IMS Global Consulting (2003).

Download references

Acknowledgements

The authors wish to thank G. McKnight and M. Bernard for assistance and information relevant to the current clinical development status of cytokines discussed in this review.

Author information

Authors and Affiliations

  1. Cytokine Biology Program, ZymoGenetics, Inc., 1201 Eastlake Avenue, East Seattle, 98102, Washington, USA

    Don Foster, Julia Parrish-Novak & Wenfeng Xu

  2. Department of BioInformatics, ZymoGenetics, Inc., 1201 Eastlake Avenue, East Seattle, 98102, Washington, USA

    Brian Fox

Authors
  1. Don Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julia Parrish-Novak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenfeng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Don Foster.

Ethics declarations

Competing interests

All of the authors are employed by, and hold stock options in, Zymogenetics, Inc.

Supplementary information

Related links

Related links

DATABASES

LocusLink

APRIL

BAFF

BCMA

CNTF

DR6

EPO

G-CSF

GLMR

GM-CSF

IFN-α

IFN-β

IFN-γ

IL-1

IL-2

IL-11

IL-17

IL-18

IL-20

IL-20RA

IL-20RB

IL-21

IL-21R

IL-22

IL-22R

IL-26

LIF

TACI

TGF-b

TNF

TROY

WSX1

FURTHER INFORMATION

Encyclopedia of Life Sciences

Cytokines

Cytokines as mediators of disease

Cytokine receptors

Glossary

IMMUNOGLOBULIN (IG) FUSION

Many proteins can be engineered to have a long circulating half-life, thereby prolonging their therapeutic benefits. One popular strategy has been to fuse the gene of to a portion of a stable antibody structure (Ig), which confers a favourable therapeutic profile.

ORPHAN

Genes with no known function, often discovered through mining sequence databases are most frequently initially described only in terms of their structure.

PARALOGUES

A set of homologous genes within a single species which have diverged from each other via gene duplication. Paralogous genes frequently acquire completely independent biological functions after duplication.

SEQUENCE MOTIF

Well-conserved sequence similarities (or 'motifs') found in most or all members of a given gene family. The 'WSXWS' motif is a penta-peptide sequence conserved in nearly all class I cytokine receptors.

GENE KNOCKOUT

The deletion of both copies of a gene from the genome of an experimental organism. The physiological alterations seen in such 'knockout' organisms can be attributed to the gene deletion, but are frequently be complicated by effects on abnormal embryonic development.

PLATELET HAEMATOPOIESIS

The synthesis and maturation of platelet cells from progenitor stem cells. Specific cytokines from peripheral tissues regulate the rates of synthesis for each lineage of blood cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Foster, D., Parrish-Novak, J., Fox, B. et al. Cytokine–receptor pairing: accelerating discovery of cytokine function. Nat Rev Drug Discov 3, 160–170 (2004). https://doi.org/10.1038/nrd1305

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1305

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing