Advertisement

Chemokines as drug targets

  • Amanda E. I. Proudfoot
  • Christine A. Power
  • Matthias Schwarz
  • Timothy N. C. Wells
Part of the Progress in Inflammation Research book series (PIR)

Abstract

The question of how the migration of cells can be specifically controlled was first addressed at least 15 years ago with the identification of the neutrophil chemattractant, IL-8, and the monocyte attractants, MCP-1 and MIP-1α. The rapid expansion of this family of proteins, known as chemoattractant cytokines and re-named chemokines, showed that the idea of one chemokine being responsible for the recruitment of a single cell type was over simplistic in most cases.

Keywords

Human Immunodeficiency Virus Experimental Autoimmune Encephalomyelitis Chemokine Receptor Small Molecule Inhibitor Chemokine Receptor Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    McKinnon M, Proudfoot AEI, Wells TNC, Solari R (1996) Strategies for the discovery of cytokine receptor antagonists. Drug News Perspect 9: 389–398Google Scholar
  2. 2.
    Teran LM, Noso N, Carroll M, Davies DE, Holgate S, Schroder JM (1996) Eosinophil recruitment following allergen challenge is associated with the release of the chemokine RANTES into asthmatic airways. J Immunol 157: 1806–1812PubMedGoogle Scholar
  3. 3.
    Ying S, Meng Q, Zeibecoglou K, Robinson DS, Macfarlane A, Humbert M, Kay AB (1999) Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics. J Immunol 163: 6321–6329PubMedGoogle Scholar
  4. 4.
    Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VAQ, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JLR (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 103: 807–815PubMedGoogle Scholar
  5. 5.
    Balashov KE, Rottman JB, Weiner HL, Hancock WW (1999) CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1 alpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA 96: 6873–6878PubMedCrossRefGoogle Scholar
  6. 6.
    Schroder JM (1997) Identification and structural characterization of chemokines in lesional skin material of patients with inflammatory skin disease. Methods Enzymol 288: 266–297PubMedGoogle Scholar
  7. 7.
    Broaddus VC, Hebert CA, Vitangcol RV, Hoeffel JM, Bernstein MS, Boylan AM (1992) Interleukin-8 is a major neutrophil chemotactic factor in pleural liquid of patients with empyema. Am Rev Respir Dis 146: 825–830PubMedGoogle Scholar
  8. 8.
    Nakamura H, Weiss ST, Israel E, Luster AD, Drazen JM, Lilly CM (1999) Eotaxin and impaired lung function in asthma. Am J Respir Crit Care Med 160: 1952–1956PubMedGoogle Scholar
  9. 9.
    Renzoni EA, Abraham DJ, Howat S, Shi-Wen X, Sestini P, Bou-Gharios G, Wells AU, Veeraraghavan S, Nicholson AG, Denton CP et al (2004) Gene expression profiling reveals novel TGFbeta targets in adult lung fibroblasts. Respir Res 5: 24PubMedCrossRefGoogle Scholar
  10. 10.
    Kennedy KJ, Strieter RM, Kunkel SL, Lukacs NW, Karpus WJ (1998) Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1 alpha and monocyte chemotactic protein-1. J Neuroimmunol 92: 98–108PubMedCrossRefGoogle Scholar
  11. 11.
    Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, Smiley ST, Ling M, Gerard NP, Gerard C (2000) Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J Exp Med 192: 1515–1520PubMedCrossRefGoogle Scholar
  12. 12.
    Rottman JB, Slavin AJ, Silva R, Weiner HL, Gerard CG, Hancock WW (2000) Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol 30: 2372–2377PubMedCrossRefGoogle Scholar
  13. 13.
    Fife BT, Huffnagle GB, Kuziel WA, Karpus WJ (2000) CC chemokine receptor 2 is Critical for induction of experimental autoimmune. J Exp Med 192: 899–905PubMedCrossRefGoogle Scholar
  14. 14.
    Izikson L, Klein RS, Charo IF, Weiner HL, Luster AD (2000) Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med 192: 1075–1080PubMedCrossRefGoogle Scholar
  15. 15.
    Huang D, Wang J, Kivisakk P, Rollins BJ, Ransohoff RM (2001) Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific t helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J Exp Med 193: 713–726PubMedCrossRefGoogle Scholar
  16. 16.
    Peters W, Charo IF (2001) Involvement of chemokine receptor 2 and its ligand, monocyte chemoattractant protein-1, in the development of atherosclerosis: lessons from knockout mice. Curr Opin Lipidol 12: 175–180PubMedCrossRefGoogle Scholar
  17. 17.
    Gosling J, Slaymaker S, Gu L, Tseng S, Zlot CH, Young SG, Rollins BJ, Charo IF (1999) MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 103: 773–778PubMedCrossRefGoogle Scholar
  18. 18.
    Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C et al (1996) Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene [see comments]. Nature 382: 722–725PubMedCrossRefGoogle Scholar
  19. 19.
    Humbles AA, Lloyd CM, McMillan SJ, Friend DS, Xanthou G, McKenna EE, Ghiran S, Gerard NP, Yu C, Orkin SH et al (2004) A critical role for eosinophils in allergic airways remodeling. Science 305: 1776–1779PubMedCrossRefGoogle Scholar
  20. 20.
    Lee JJ, Dimina D, Macias MP, Ochkur SI, McGarry MP, O’Neill KR, Protheroe C, Pero R, Nguyen T, Cormier SA et al (2004) Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305: 1773–1776PubMedCrossRefGoogle Scholar
  21. 21.
    Dragic T, Trkola A, Thompson DA, Cormier EG, Kajumo FA, Maxwell E, Lin SW, Ying W, Smith SO, Sakmar TP et al (2000) A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci USA 97: 5639–5644PubMedCrossRefGoogle Scholar
  22. 22.
    Cox MA, Jenh CH, Gonsiorek W, Fine J, Narula SK, Zavodny PJ, Hipkin RW (2001) Human interferon-inducible 10-kDa protein and human interferon-inducible T cell alpha chemoattractant are allotopic ligands for human CXCR3: differential binding to receptor states. Mol Pharmacol 59: 707–715PubMedGoogle Scholar
  23. 23.
    Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI (1991) Structure and functional expression of a human interleukin-8 receptor. Science 253: 1278–1280PubMedCrossRefGoogle Scholar
  24. 24.
    Murphy PM, Tiffany HL (1991) Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science 253: 1280–1283PubMedCrossRefGoogle Scholar
  25. 25.
    Mellor GW, Fogarty SJ, O’Brien MS, Congreve M, Banks MN, Mills KM, Jefferies B, Houston JG (1997) Searching for chemokine receptor binding antagonists by high throughput screening. J Biomolecular Screening 2: 153–157CrossRefGoogle Scholar
  26. 26.
    White JR, Lee JM, Young PR, Hertzberg RP, Jurewicz AJ, Chaikin MA, Widdowson K, Foley JJ, Martin LD, Griswold DE et al (1998) Identification of a potent, selective nonpeptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration. J Biol Chem 273: 10095–10098PubMedCrossRefGoogle Scholar
  27. 27.
    Solari R, Offord RE, Remy S, Aubry JP, Wells TN, Whitehorn E, Oung T, Proudfoot AE (1997) Receptor-mediated endocytosis of CC-chemokines. J Biol Chem 272: 9617–9620PubMedCrossRefGoogle Scholar
  28. 28.
    Hesselgesser J, Ng HP, Liang M, Zheng W, May K, Bauman JG, Monahan S, Islam I, Wei GP, Ghannam A et al (1998) Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor. J Biol Chem 273: 15687–15692PubMedCrossRefGoogle Scholar
  29. 29.
    Schwarz MK, Wells TN (2002) New therapeutics that modulate chemokine networks. Nat Rev Drug Discov 1: 347–358PubMedCrossRefGoogle Scholar
  30. 30.
    Gao Z, Metz WA (2003) Unraveling the chemistry of chemokine receptor ligands. Chem Rev 103: 3733–3752PubMedCrossRefGoogle Scholar
  31. 31.
    Liang M, Mallari C, Rosser M, Ng HP, May K, Monahan S, Bauman JG, Islam I, Ghannam A, Buckman B et al (2000) Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem 275: 19000–19008PubMedCrossRefGoogle Scholar
  32. 32.
    Liang M, Rosser M, Ng HP, May K, Bauman JG, Islam I, Ghannam A, Kretschmer PJ, Pu H, Dunning L et al (2000) Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor. Eur J Pharmacol 389: 41–49PubMedCrossRefGoogle Scholar
  33. 33.
    Horuk R, Shurey S, Ng HP, May K, Bauman JG, Islam I, Ghannam A, Buckman B, Wei GP, Xu W et al (2001) CCR1-specific non-peptide antagonist: efficacy in a rabbit allograft rejection model. Immunol Lett 76: 193–201PubMedCrossRefGoogle Scholar
  34. 34.
    Anders HJ, Vielhauer V, Frink M, Linde Y, Cohen CD, Blattner SM, Kretzler M, Strutz F, Mack M, Grone HJ et al (2002) A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Invest 109: 251–259PubMedCrossRefGoogle Scholar
  35. 35.
    Horvath C, Welt FG, Nedelman M, Rao P, Rogers C (2002) Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted. Circ Res 90: 488–494PubMedCrossRefGoogle Scholar
  36. 36.
    Mahler DA, Huang S, Tabrizi M, Bell GM (2004) Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest 126: 926–934PubMedCrossRefGoogle Scholar
  37. 37.
    Gong JH, Clark-Lewis I (1995) Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminal residues. J Exp Med 181: 631–640PubMedCrossRefGoogle Scholar
  38. 38.
    Zhang Y, Rollins BJ (1995) A dominant negative inhibitor indicates that monocyte chemoattractant protein 1 functions as a dimer. Mol Cell Biol 15: 4851–4855PubMedGoogle Scholar
  39. 39.
    Gong JH, Ratkay LG, Waterfield JD, Clark LI (1997) An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J Exp Med 186: 131–137PubMedCrossRefGoogle Scholar
  40. 40.
    Wada T, Furuichi K, Sakai N, Iwata Y, Kitagawa K, Ishida Y, Kondo T, Hashimoto H, Ishiwata Y, Mukaida N et al (2004) Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol 15: 940–948PubMedCrossRefGoogle Scholar
  41. 41.
    Kitamoto S, Egashira K (2002) Gene therapy targeting monocyte chemoattractant protein-1 for vascular disease. J Atheroscler Thromb 9: 261–265PubMedGoogle Scholar
  42. 42.
    Proudfoot AE (2002) Chemokine receptors: multifaceted therapeutic targets. Nat Rev Immunol 2: 106–115PubMedCrossRefGoogle Scholar
  43. 43.
    Proudfoot AE, Buser R, Borlat F, Alouani S, Soler D, Offord RE, Schroder JM, Power CA, Wells TN (1999) Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors. J Biol Chem 274: 32478–32485PubMedCrossRefGoogle Scholar
  44. 44.
    Simmons G, Clapham PR, Picard L, Offord RE, Rosenkilde MM, Schwartz TW, Buser R, Wells TNC, Proudfoot AEI (1997) Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276: 276–279PubMedCrossRefGoogle Scholar
  45. 45.
    Kawamura T, Bruse SE, Abraha A, Sugaya M, Hartley O, Offord RE, Arts EJ, Zimmerman PA, Blauvelt A (2004) PSC-RANTES blocks R5 human immunodeficiency virus infection of Langerhans cells isolated from individuals with a variety of CCR5 diplotypes. J Virol 78: 7602–7609PubMedCrossRefGoogle Scholar
  46. 46.
    Lederman MM, Veazey RS, Offord R, Mosier DE, Dufour J, Mefford M, Piatak M Jr., Lifson JD, Salkowitz JR, Rodriguez B et al (2004) Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 306: 485–487PubMedCrossRefGoogle Scholar
  47. 47.
    Rot A (1993) Neutrophil attractant/activation protein-1 (interleukin-8) induces in vitro neutrophil migration by haptotactic mechanism. Eur J Immunol 23: 303–306PubMedCrossRefGoogle Scholar
  48. 48.
    Hoogewerf AJ, Kuschert GS, Proudfoot AE, Borlat F, Clark-Lewis I, Power CA, Wells TN (1997) Glycosaminoglycans mediate cell surface oligomerization of chemokines. Biochemistry (Mosc) 36: 13570–13578CrossRefGoogle Scholar
  49. 49.
    Kuschert GS, Coulin F, Power CA, Proudfoot AE, Hubbard RE, Hoogewerf AJ, Wells TN (1999) Glycosaminoglycans interact selectively with chemokines and modulate receptor binding and cellular responses. Biochemistry (Mosc) 38: 12959–12968CrossRefGoogle Scholar
  50. 50.
    Proudfoot AEI, Handel TM, Johnson Z, Lau EK, LiWang P, Clark L, Borlat F, Wells TNC, Kosco-Vilbois MH (2003) Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc Natl Acad Sci USA 100: 1885–1890PubMedCrossRefGoogle Scholar
  51. 51.
    Johnson Z, Kosco-Vilbois MH, Herren S, Cirillo R, Muzio V, Zaratin P, Carbonatto M, Mack M, Smailbegovic A, Rose M et al (2004) Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. J Immunol 173: 5776–5785PubMedGoogle Scholar
  52. 52.
    Baltus T, Weber KS, Johnson Z, Proudfoot AE, Weber C (2003) Oligomerization of RANTES is required for CCR1-mediated arrest but not CCR5-mediated transmigration of leukocytes on inflamed endothelium. Blood 102: 1985–1988PubMedCrossRefGoogle Scholar
  53. 53.
    Shaw JP, Johnson Z, Borlat F, Zwahlen C, Kungl AJ, Roulin K, Harrenga A, Wells TN, Proudfoot AE (2004) The X-ray structure of RANTES: heparin-derived disaccharides allows the rational design of chemokine inhibitors. Structure 12: 2081–2093PubMedCrossRefGoogle Scholar
  54. 54.
    Wagner L, Yang OO, Garcia-Zepeda EA, Ge Y, Kalams SA, Walker BD, Pasternack MS, Luster AD (1998) β-Chemokines are released from HIV-1-specific cytolytic granules complexed to potreoglycans. Nature 391: 908–911PubMedCrossRefGoogle Scholar
  55. 55.
    Bruhl H, Cihak J, Stangassinger M, Schlondorff D, Mack M (2001) Depletion of CCR5-expressing cells with bispecific antibodies and chemokine toxins: a new strategy in the treatment of chronic inflammatory diseases and HIV. J Immunol 166: 2420–2426PubMedGoogle Scholar
  56. 56.
    Schuh JM, Blease K, Bruhl H, Mack M, Hogaboam CM (2003) Intrapulmonary targeting of RANTES/CCL5-responsive cells prevents chronic fungal asthma. Eur J Immunol 33: 3080–3090PubMedCrossRefGoogle Scholar
  57. 57.
    Eisenberg SP, Brewer MT, Verderber E, Heimdal P, Brandhuber BJ, Thompson RC (1991) Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism. Proc Natl Acad Sci USA 88: 5232–5236PubMedCrossRefGoogle Scholar
  58. 58.
    Seckinger P, Dayer JM (1992) Natural inhibitors of TNF. Immunol Ser 56: 217–236PubMedGoogle Scholar
  59. 59.
    Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M (1999) Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 10: 127–136PubMedCrossRefGoogle Scholar
  60. 60.
    Alcami A (2003) Viral mimicry of cytokines, chemokines and their receptors. Nat Rev Immunol 3: 36–50PubMedCrossRefGoogle Scholar
  61. 61.
    Liu L, Dai E, Miller L, Seet B, Lalani A, Macauley C, Li X, Virgin HW, Bunce C, Turner P et al (2004) Viral chemokine-binding proteins inhibit inflammatory responses and aortic allograft transplant vasculopathy in rat models. Transplantation 77: 1652–1660PubMedCrossRefGoogle Scholar
  62. 62.
    Pyo R, Jensen KK, Wiekowski MT, Manfra D, Alcami A, Taubman MB, Lira SA (2004) Inhibition of intimal hyperplasia in transgenic mice conditionally expressing the chemokine-binding protein M3. Am J Pathol 164: 2289–2297PubMedGoogle Scholar
  63. 63.
    Hajnicka V, Kocakova P, Slavikova M, Slovak M, Gasperik J, Fuchsberger N, Nuttall PA (2001) Anti-interleukin-8 activity of tick salivary gland extracts. Parasite Immunol 23: 483–489PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2007

Authors and Affiliations

  • Amanda E. I. Proudfoot
    • 1
  • Christine A. Power
    • 1
  • Matthias Schwarz
    • 1
  • Timothy N. C. Wells
    • 1
  1. 1.Serono Pharmaceutical Research InstitutePlan-les OuatesSwitzerland

Personalised recommendations