Overview of Approaches to the Identification of Inhibitors of Cytokine Action

Joseph R. Woska,1, Jeanne Magram1

1 Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 1.31
DOI:  10.1002/0471141755.ph0131s27
Online Posting Date:  January, 2005
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


Cytokines are key regulatory molecules that serve as critical mediators of cell‐to‐cell communication. They play a central role in immune function and are important molecular targets for drug discovery because of their dysregulation in immune disease. Initial attempts to develop agents that block the actions of cytokines focused on identifying small‐molecule antagonists that would directly compete with these cytokines for their cognate receptors. These efforts were, for the most part, unsuccessful. Outlined in this unit are strategies for developing new approaches. The first section describes strategies for how one might build a conceptual framework to approach this problem. The second section focuses on the technical approaches that can be utilized to accomplish the strategies outlined in the first section. These concepts are illustrated using interleukin‐2 (IL‐2) as a prototype, since there is a substantial body of knowledge regarding this cytokine, including information on its functions, signaling pathways, and physiological effects in normal and diseased tissue.

Keywords: cytokines; antagonists; assays

PDF or HTML at Wiley Online Library

Table of Contents

  • Strategic Approaches
  • Technical Approaches
  • Conclusions
  • Literature Cited
  • Figures
  • Tables
PDF or HTML at Wiley Online Library


PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
   Borish, L.C. and Steinke, J.W. 2003. Cytokines and chemokines. J Allergy Clin. Immunol. 111:S460‐475.
   Coligan, J.E., Kruisbeek, A.M., Margulies, D.H., Shevach, E.M., and Strober, W. (eds.) 2004. Current Protocols in Immunology. John Wiley & Sons, Hoboken, N.J.
   Constant, S.L. and Bottomly, K. 1997. Induction of TH1 and TH2 CD4+ T cell responses: The alternate approaches. Annu. Rev. Immunol. 15:297‐322.
   Depper, J.M., Leonard, W.J., Robb, R.J., Waldmann, T.A., and Greene, W.C. 1983. Blockade of the interleukin‐2 receptor by anti‐Tac antibody: inhibition of human lymphocyte activation. J. Immunol. 131:690‐696.
   Dong, C., Davis, R.J., and Flavell, R.A. 2002. MAP kinases in the immune response. Annu. Rev. Immunol. 20:55‐72.
   Fields, R.D. and Lancaster, M.V. 1993. Dual attribute continuous monitoring of cell proliferation/cytotoxicity. Am. Biotechnol. Lab. 11:48‐50.
   Isakov, N. and Altman, A. 2002. Protein kinase Cθ in T cell activation. Annu. Rev. Immunol. 20:761‐794.
   Janeway, C.A. Jr. and Travers, P. 1996. Immunobiology: The Immune System in Health and Disease, 2nd ed. Current Biology/Garland Publishing, London and New York.
   Kanof, M., Smith, P.D., and Zola, H. 1996. Isolation of whole mononuclear cells from peripheral blood and cord blood. In Current Protocols in Immunology (J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, and W. Strober, eds.) pp. 7.1.1‐7.1.7. John Wiley & Sons, Hoboken, N.J.
   Kirken, R.A. and Wang, Y.L. 2003. Molecular actions of sirolimus: Sirolimus and mTor. Transplant Proc. 35: S227‐230.
   Queen, C., Schneider, W.P., Selick, H.E., Payne, P.W., Landolfi, N.F., Duncan, J.F., Avdalovic, N.M., Levitt, M., Junghans, R.P., and Waldmann, T.A. 1989. A humanized antibody that binds to the interleukin‐2 receptor. Proc. Natl. Acad. Sci. U.S.A. 86:10029‐10033.
   Rao, A., Luo, C., and Hogan, P.G. 1997. Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 15:707‐747.
   Robb, R.J., Munck, A., and Smith, K.A. 1981. T cell growth factor receptors: Quantitation, specificity, and biological relevance. J. Exp. Med. 154:1455‐1474.
   Romagnani, S. 1994. Lymphokine production by human T cells in disease states. Annu. Rev. Immunol. 12:227‐257.
   Rowland‐Jones, S.L. and McMichael, A.J. (eds.) 2000. Lymphocytes: A Practical Approach, 2nd ed. Oxford University Press Inc., New York.
   Seder, R.A. and Paul, W.E. 1994. Acquisition of lymphokine‐producing phenotype by CD4+ T cells. Annu. Rev. Immunol. 12:635‐673.
   Thome, M. and Tschopp, J. 2003. TCR‐induced NF‐κB activation: a crucial role for Carma1, Bcl10 and MALT1. Trends Immunol. 24:419‐424.
   Thomson, A.W. and Lotze, M.T. (eds.) 2003. The Cytokine Handbook, 4th ed. Academic Press, San Diego.
PDF or HTML at Wiley Online Library