IL-8 receptor antagonist: basic research and clinical utility

  • John R. White
  • Henry M. Sarau
Part of the Progress in Inflammation Research book series (PIR)


Inflammatory cells are thought to be instrumental in the pathophysiology of diseases and the control of their recruitment and activation appears to be an attractive strategy for therapeutic intervention. Chemokines are a family of small molecular weight (7–15 kDa) proteins that in conjunction with adhesion molecules play a crucial role in leukocyte recruitment, cellular activation and proliferation at sites of inflammation. Chemokines are produced by a variety of cell types, including leukocytic and non-leukocytic cells, usually in response to antigens, irritants and other cytokines. Interleukin-8 (CXCL8) was the first member to be identified of this new family of proinflammatory chemokines that now constitute over 45 members. Chemokines produce their biological effects by interacting with greater than 18 G protein coupled cell surface receptors. A few chemokines bind selectively to a single receptor but other chemokines bind to more than one receptor [1, 2]. CXCL8 belongs to a subgroup of chemokines known as ELR+ chemokines because of the Glu4-Leu5-Arg6 amino acid sequence between positions 4 and 6. Other members of this group include CXCL1, 2, 3, 5, 6, and 7. A diverse variety of biological effects are attributed to CXCL8 and related ELR+ chemokines, including several involving inflammatory cell activation and chemotaxis, production of reactive oxygen species, increased expression of the integrin CD11b-CD18, enhancement of cell adhesion to endothelial cells, promotion of angiogenesis, modulation of histamine and lipid mediator release as well as azurophil granule release [3].


Chronic Obstructive Pulmonary Disease Chronic Obstructive Pulmonary Disease Patient Respir Crit CXCR2 Antagonist Chronic Obstructive Pulmonary Disease Lung 
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.


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  1. 1.
    Puneet P, Moochhala S, Bhatia M (2005) Chemokines in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 288: L3–L15PubMedCrossRefGoogle Scholar
  2. 2.
    Carter PH (2002) Chemokine receptor antagonism as an approach to anti-inflammatory therapy: ‘just right’ or plain wrong? Curr Opin Chem Biol 6: 510–525PubMedCrossRefGoogle Scholar
  3. 3.
    Baggiolini M (1993) Chemotactic and inflammatory cytokines — CXC and CC proteins. Adv Exp Med Biol 351: 1–11PubMedGoogle Scholar
  4. 4.
    Baggiolini M, Dewald B, Moser B (1994) Interleukin-8 and related chemotactic cytokines — CXC and CC chemokines. Adv Immunol 55: 97–179PubMedGoogle Scholar
  5. 5.
    Mukaida N, Harada A, Matsushima K (1995) A novel leukocyte chemotactic and activating cytokine, interleukin-8 (IL-8). Cancer Treat Res 80: 261–286PubMedGoogle Scholar
  6. 6.
    Altstaedt J, Kirchner H, Rink L (1996) Cytokine production of neutrophils is limited to interleukin-8. Immunology 89: 563–568PubMedCrossRefGoogle Scholar
  7. 7.
    Ryu J-S, Kang J-H, Jung S-Y, Shin M-H, Kim J-M, Park H, Min D-Y (2004) Production of interleukin-8 by human neutrophils stimulated with Trichomonas vaginalis. Infect Immun 72: 1326–1332PubMedCrossRefGoogle Scholar
  8. 8.
    Arbabi S, Rosengart MR, Garcia I, Jelacic S, Maier RV (1999) Priming interleukin 8 production: role of platelet-activating factor and p38. Arch Surg 134: 1348–1353PubMedCrossRefGoogle Scholar
  9. 9.
    Moller A, Lippert U, Lessmann D, Kolde G, Hamann K, Welker P, Schadendorf D, Rosenbach T, Luger T, Czarnetzki BM (1993) Human mast cells produce IL-8. J Immunol 151: 3261–3266PubMedGoogle Scholar
  10. 10.
    Burns MJ, Sellati TJ, Teng EI, Furie MB (1997) Production of interleukin-8 (IL-8) by cultured endothelial cells in response to Borrelia burgdorferi occurs independently of secreted [corrected] IL-1 and tumor necrosis factor alpha and is required for subsequent transendothelial migration of neutrophils [published erratum appears in Infect Immun (1997) Jun; 65(6): 2508]. Infect Immun 65: 1217–1222PubMedGoogle Scholar
  11. 11.
    Smith RS, Fedyk ER, Springer TA, Mukaida N, Iglewski BH, Phipps RP (2001) IL-8 production in human lung fibroblasts and epithelial cells activated by the Pseudomonas autoinducer N-3-Oxododecanoyl homoserine lactone is transcriptionally regulated by NF-kappaB and Activator Protein-2. J Immunol 167: 366–374PubMedGoogle Scholar
  12. 12.
    Li J, Ireland GW, Farthing PM, Thornhill MH (1996) Epidermal and oral keratinocytes are induced to produce RANTES and IL-8 by cytokine stimulation. J Invest Dermatol 106: 661–666PubMedCrossRefGoogle Scholar
  13. 13.
    Gomez-Quiroz LE, Paris R, Lluis JM, Bucio L, Souza V, Hernandez E, Gutierrez M, Santiago M, Garcia-Ruiz C, Fernandez-Checa JC et al (2005) Differential modulation of interleukin 8 by interleukin 4 and interleukin 10 in HepG2 cells treated with acetaldehyde. Liver Int 25: 122–130PubMedCrossRefGoogle Scholar
  14. 14.
    Rougier F, Cornu E, Praloran V, Denizot Y (1998) IL-6 and IL-8 production by human bone marrow stromal cells. Cytokine 10: 93–97PubMedCrossRefGoogle Scholar
  15. 15.
    Schulte R, Grassl GA, Preger S, Fessele S, Jacobi CA, Schaller M, Nelson PJ, Autenrieth IB (2000) Yersinia enterocolitica invasin protein triggers IL-8 production in epithelial cells via activation of Rel p65-p65 homodimers. FASEB J 14: 1471–1484PubMedCrossRefGoogle Scholar
  16. 16.
    Subauste MC, Jacoby DB, Richards SM, Proud D (1995) Infection of a human respiratory epithelial cell line with rhinovirus. Induction of cytokine release and modulation of susceptibility to infection by cytokine exposure. J Clin Invest 96: 549–557PubMedGoogle Scholar
  17. 17.
    Kaplanski G, Teysseire N, Farnarier C, Kaplanski S, Lissitzky JC, Durand JM, Soubeyrand J, Dinarello CA, Bongrand P (1995) IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway. J Clin Invest 96: 2839–2844PubMedGoogle Scholar
  18. 18.
    Van den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G (2000) Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 96: 2673–2681PubMedGoogle Scholar
  19. 19.
    Van Den Steen PE, Wuyts A, Husson SJ, Proost P, Van Damme J, Opdenakker G (2003) Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities. Eur J Biochem 270: 3739–3749CrossRefGoogle Scholar
  20. 20.
    Mukaida N (2000) Interleukin-8: an expanding universe beyond neutrophil chemotaxis and activation. Int J Hematol 72: 391–398PubMedGoogle Scholar
  21. 21.
    Moser B, Dewald B, Barella L, Schumacher C, Baggiolini M, Clark-Lewis I (1993) Interleukin-8 antagonists generated by N-terminal modification. J Biol Chem 268: 7125–7128PubMedGoogle Scholar
  22. 22.
    Li F, Zhang X, Gordon JR (2002) CXCL8((3-73))K11R/G31P antagonizes ligand binding to the neutrophil CXCR1 and CXCR2 receptors and cellular responses to CXCL8/IL-8. Biochem Biophys Res Commun 293: 939–944PubMedCrossRefGoogle Scholar
  23. 23.
    Jones SA, Dewald B, Clark-Lewis I, Baggiolini M (1997) Chemokine antagonists that discriminate between interleukin-8 receptors. Selective blockers of CXCR2. J Biol Chem 272: 16166–16169PubMedCrossRefGoogle Scholar
  24. 24.
    Zagorski J, Wahl SM (1997) Inhibition of acute peritoneal inflammation in rats by a cytokine-induced neutrophil chemoattractant receptor antagonist. J Immunol 159: 1059–1062PubMedGoogle Scholar
  25. 25.
    Huang S, Mills L, Mian B, Tellez C, McCarty M, Yang XD, Gudas JM, Bar-Eli M (2002) Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 161: 125–134PubMedGoogle Scholar
  26. 26.
    Yang XD, Corvalan JR, Wang P, Roy CM, Davis CG (1999) Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states. J Leukoc Biol 66: 401–410PubMedGoogle Scholar
  27. 27.
    White JR, Lee JM, Young PR, Hertzberg RP, Jurewicz AJ, Chaikin MA, Widdowson J, Foley JJ, Martin LD, Griswold DE (1998) Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration. J Biol Chem 273: 10095–10098PubMedCrossRefGoogle Scholar
  28. 28.
    Glynn PC, Henney E, Hall IP (2002) The selective CXCR2 antagonist SB272844 blocks interleukin-8 and growth-related oncogene-alpha-mediated inhibition of spontaneous neutrophil apoptosis. Pulm Pharmacol Ther 15: 103–110PubMedCrossRefGoogle Scholar
  29. 29.
    Hay DW, Sarau HM (2001) Interleukin-8 receptor antagonists in pulmonary diseases. Curr Opin Pharmacol 1: 242–247PubMedCrossRefGoogle Scholar
  30. 30.
    Podolin PL, Bolognese BJ, Foley JJ, Schmidt DB, Buckley PT, Widdowson KL, Jin Q, White JR, Lee JM, Goodman RB et al (2002) A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J Immunol 169: 6435–6444PubMedGoogle Scholar
  31. 31.
    Milatovic S, Nanney LB, Yu Y, White JR, Richmond A (2003) Impaired healing of nitrogen mustard wounds in CXCR2 null mice. Wound Repair Regen 11: 213–219PubMedCrossRefGoogle Scholar
  32. 32.
    Stevenson CS, Coote K, Webster R, Johnston H, Atherton HC, Nicholls A, Giddings J, Sugar R, Jackson A, Press NJ et al (2005) Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect. Am J Physiol Lung Cell Mol Physiol 288: L514–L522PubMedCrossRefGoogle Scholar
  33. 33.
    Jin Q, Nie H, McCleland BW, Widdowson KL, Palovich MR, Elliott JD, Goodman RM, Burman M, Sarau HM, Ward KW et al (2004) Discovery of potent and orally bioavailable N,N’-diarylurea antagonists for the CXCR2 chemokine receptor. Bioorg Med Chem Lett 14: 4375–4378PubMedCrossRefGoogle Scholar
  34. 34.
    Widdowson KL, Elliott JD, Veber DF, Nie H, Rutledge MC, McCleland BW, Xiang JN, Jurewicz AN, Hertzberg RP, Foley JJ et al (2004) Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor. J Med Chem 47: 1319–1321PubMedCrossRefGoogle Scholar
  35. 35.
    Cutshall NS, Ursino R, Kucera KA, Latham J, Ihle NC (2001) Nicotinamide N-oxides as CXCR2 antagonists. Bioorg Med Chem Lett 11: 1951–1954PubMedCrossRefGoogle Scholar
  36. 36.
    Cutshall NS, Kucera KA, Ursino R, Latham J, Ihle NC (2002) Nicotinanilides as inhibitors of neutrophil chemotaxis. Bioorg Med Chem Lett 12: 1517–1520PubMedCrossRefGoogle Scholar
  37. 37.
    Baxter A, Bennion C, Bent J, Boden K, Brough S, Cooper A, Kinchin E, Kindon N, McInally T, Mortimore M et al (2003) Hit-to-lead studies: the discovery of potent, orally bioavailable triazolethiol CXCR2 receptor antagonists. Bioorg Med Chem Lett 13: 2625–2628PubMedCrossRefGoogle Scholar
  38. 38.
    Li JJ, Carson KG, Trivedi BK, Yue WS, Ye Q, Glynn RA, Miller SR, Connor DT, Roth BD, Luly JR et al (2003) Synthesis and structure-activity relationship of 2-amino-3-heteroaryl-quinoxalines as non-peptide, small-molecule antagonists for interleukin-8 receptor. Bioorg Med Chem 11: 3777–3790PubMedCrossRefGoogle Scholar
  39. 39.
    Casilli F, Bianchini A, Gloaguen I, Biordi L, Alesse E, Festuccia C, Cavalieri B, Strippoli R, Cervellera MN, Di Bitondo R et al (2005) Inhibition of interleukin-8 (CXCL8/IL-8) responses by repertaxin, a new inhibitor of the chemokine receptors CXCR1 and CXCR2. Biochem Pharmacol 69: 385–394PubMedCrossRefGoogle Scholar
  40. 40.
    Bertini R, Allegretti M, Bizzarri C, Moriconi A, Locati M, Zampella G, Cervellera MN, Di Cioccio V, Cesta MC, Galliera E et al (2004) Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc Natl Acad Sci USA 101: 11791–11796PubMedCrossRefGoogle Scholar
  41. 41.
    Strieter RM, Belperio JA, Burdick MD, Sharma S, Dubinett SM, Keane MP (2004) CXC chemokines: angiogenesis, immunoangiostasis, and metastases in lung cancer. Ann NY Acad Sci 1028: 351–360PubMedCrossRefGoogle Scholar
  42. 42.
    Strieter RM, Belperio JA, Phillips RJ, Keane MP (2004) CXC chemokines in angiogenesis of cancer. Semin Cancer Biol 14: 195–200PubMedCrossRefGoogle Scholar
  43. 43.
    Rosenkilde MM, Schwartz TW (2004) The chemokine system-a major regulator of angiogenesis in health and disease. Apmis 112: 481–495PubMedCrossRefGoogle Scholar
  44. 44.
    Scheibenbogen C, Mohler T, Haefele J, Hunstein W, Keilholz U (1995) Serum interleukin-8 (IL-8) is elevated in patients with metastatic melanoma and correlates with tumour load. Melanoma Res 5: 179–181PubMedCrossRefGoogle Scholar
  45. 45.
    Haghnegahdar H, Du J, Wang D, Strieter RM, Burdick MD, Nanney LB, Cardwell N, Luan J, Shattuck-Brandt R, Richmond A (2000) The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma. J Leukoc Biol 67: 53–62PubMedGoogle Scholar
  46. 46.
    Li A, Dubey S, Varney ML, Dave BJ, Singh RK (2003) IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170: 3369–3376PubMedGoogle Scholar
  47. 47.
    McCawley LJ, Matrisian LM (2000) Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6: 149–156PubMedCrossRefGoogle Scholar
  48. 48.
    Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6: 447–458PubMedCrossRefGoogle Scholar
  49. 49.
    Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, Xue YY, Buechi L, Walz A, Richmond A, Strieter RM (2000) The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. J Immunol 165: 5269–5277PubMedGoogle Scholar
  50. 50.
    Heidemann J, Ogawa H, Dwinell MB, Rafiee P, Maaser C, Gockel HR, Otterson MF, Ota DM, Lugering N, Domschke W et al (2003) Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem 278: 8508–8515PubMedCrossRefGoogle Scholar
  51. 51.
    Keane MP, Belperio JA, Xue YY, Burdick MD, Strieter RM (2004) Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 172: 2853–2860PubMedGoogle Scholar
  52. 52.
    Yamamoto C, Yoneda T, Yoshikawa M, Fu A, Tokuyama T, Tsukaguchi K, Narita N (1997) Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest 112: 505–510PubMedGoogle Scholar
  53. 53.
    Hill AT, Bayley D, Stockley RA (1999) The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med 160: 893–898PubMedGoogle Scholar
  54. 54.
    Keatings VM, Collins PD, Scott DM, Barnes PJ (1996) Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 153: 530–534PubMedGoogle Scholar
  55. 55.
    Traves SL, Culpitt SV, Russell RE, Barnes PJ, Donnelly LE (2002) Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD. Thorax 57: 590–595PubMedCrossRefGoogle Scholar
  56. 56.
    Pesci A, Balbi B, Majori M, Cacciani G, Bertacco S, Alciato P, Donner CF (1998) Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 12: 380–386PubMedCrossRefGoogle Scholar
  57. 57.
    Williams TJ, Jose PJ (2001) Neutrophils in chronic obstructive pulmonary disease. Novartis Found Symp 234: 136–141PubMedGoogle Scholar
  58. 58.
    Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, Dales RE (2001) Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163: 349–355PubMedGoogle Scholar
  59. 59.
    Drost EM, Skwarski KM, Sauleda J, Soler N, Roca J, Agusti A, MacNee W (2005) Oxidative stress and airway inflammation in severe exacerbations of COPD. Thorax 60: 293–300PubMedCrossRefGoogle Scholar
  60. 60.
    Wedzicha JA (2001) Mechanisms of exacerbations. Novartis Found Symp 234: 84–93PubMedCrossRefGoogle Scholar
  61. 61.
    Pryor WA, Dooley MM, Church DF (1985) Mechanisms of cigarette smoke toxicity: the inactivation of human alpha-1-proteinase inhibitor by nitric oxide/isoprene mixtures in air. Chem Biol Interact 54: 171–183PubMedCrossRefGoogle Scholar
  62. 62.
    Barnes PJ (2003) Cytokine-directed therapies for the treatment of chronic airway diseases. Cytokine Growth Factor Rev 14: 511–522PubMedCrossRefGoogle Scholar
  63. 63.
    Reutershan J, Ley K (2004) Bench-to-bedside review: acute respiratory distress syndrome — how neutrophils migrate into the lung. Crit Care 8: 453–461PubMedCrossRefGoogle Scholar
  64. 64.
    Martin TR (1999) Lung cytokines and ARDS: Roger S. Mitchell Lecture. Chest 116: 2S–8SPubMedCrossRefGoogle Scholar
  65. 65.
    Goodman RB, Strieter RM, Martin DP, Steinberg KP, Milberg JA, Maunder RJ, Kunkel SL, Walz A, Hudson LD, Martin TR (1996) Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med 154: 602–611PubMedGoogle Scholar
  66. 66.
    Pallister I, Dent C, Topley N (2002) Increased neutrophil migratory activity after major trauma: a factor in the etiology of acute respiratory distress syndrome? Crit Care Med 30: 1717–1721PubMedCrossRefGoogle Scholar
  67. 67.
    Kurdowska AK, Geiser TK, Alden SM, Dziadek BR, Noble JM, Nuckton TJ, Matthay MA (2002) Activity of pulmonary edema fluid interleukin-8 bound to alpha(2)-macroglobulin in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 282: L1092–L1098PubMedGoogle Scholar
  68. 68.
    Jobe AH, Ikegami M (1998) Mechanisms initiating lung injury in the preterm. Early Hum Dev 53: 81–94PubMedCrossRefGoogle Scholar
  69. 69.
    Deng H, Mason SN, Auten RL Jr (2000) Lung inflammation in hyperoxia can be prevented by antichemokine treatment in newborn rats. Am J Respir Crit Care Med 162: 2316–2323PubMedGoogle Scholar
  70. 70.
    Auten RL, Richardson RM, White JR, Mason SN, Vozzelli MA, Whorton MH (2001) Nonpeptide CXCR2 antagonist prevents neutrophil accumulation in hyperoxia-exposed newborn rats. J Pharmacol Exp Ther 299: 90–95PubMedGoogle Scholar
  71. 71.
    Broxmeyer HE, Kohli L, Kim CH, Lee Y, Mantel C, Cooper S, Hangoc G, Shaheen M, Li X, Clapp DW (2003) Stromal cell-derived factor-1/CXCL12 directly enhances survival/ antiapoptosis of myeloid progenitor cells through CXCR4 and G(alpha)i proteins and enhances engraftment of competitive, repopulating stem cells. J Leukoc Biol 73: 630–638PubMedCrossRefGoogle Scholar
  72. 72.
    Zhu YM, Webster SJ, Flower D, Woll PJ (2004) Interleukin-8/CXCL8 is a growth factor for human lung cancer cells. Br J Cancer 91: 1970–1976PubMedCrossRefGoogle Scholar
  73. 73.
    Gillitzer R, Ritter U, Spandau U, Goebeler M, Brocker EB (1996) Differential expression of GRO-alpha and IL-8 mRNA in psoriasis: a model for neutrophil migration and accumulation in vivo. J Invest Dermatol 107: 778–782PubMedCrossRefGoogle Scholar
  74. 74.
    Goebeler M, Toksoy A, Spandau U, Engelhardt E, Brocker EB, Gillitzer R (1998) The C-X-C chemokine Mig is highly expressed in the papillae of psoriatic lesions. J Pathol 184: 89–95PubMedCrossRefGoogle Scholar
  75. 75.
    Benoit S, Toksoy A, Brocker EB, Gillitzer R, Goebeler M (2004) Treatment of recalcitrant pustular psoriasis with infliximab: effective reduction of chemokine expression. Br J Dermatol 150: 1009–1012PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2007

Authors and Affiliations

  • John R. White
    • 1
  • Henry M. Sarau
    • 2
  1. 1.Biopharmaceutical CEDDGlaxoSmithKlineKing of PrussiaUSA
  2. 2.Respiratory and Inflammation CEDDGlaxoSmithKlineKing of PrussiaUSA

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