Experimental Hematology
Volume 37, Issue 12 , Pages 1435-1444 , December 2009

Dasatinib inhibits the secretion of TNF-α following TLR stimulation in vitro and in vivo

  • Cara K. Fraser

      Affiliations

    • Hanson Institute, South Australia, Australia
    • Sansom Institute, The University of South Australia, South Australia, Australia
  • ,
  • Erin L. Lousberg

      Affiliations

    • Hanson Institute, South Australia, Australia
    • Sansom Institute, The University of South Australia, South Australia, Australia
  • ,
  • Raman Kumar

      Affiliations

    • Hanson Institute, South Australia, Australia
    • School of Medicine, The University of Adelaide, South Australia, Australia
  • ,
  • Timothy P. Hughes

      Affiliations

    • Department of Haematology, SA Pathology, South Australia, Australia
  • ,
  • Kerrilyn R. Diener

      Affiliations

    • Hanson Institute, South Australia, Australia
    • Sansom Institute, The University of South Australia, South Australia, Australia
  • ,
  • John D. Hayball

      Affiliations

    • Hanson Institute, South Australia, Australia
    • Sansom Institute, The University of South Australia, South Australia, Australia
    • School of Medicine, The University of Adelaide, South Australia, Australia
    • Corresponding Author InformationOffprint requests to: John D. Hayball, Ph.D., Sansom Institute, The University of South Australia, North Tce, Adelaide, South Australia 5000, Australia

Received 23 July 2009 ,Revised 31 August 2009 ,Accepted 22 September 2009.

References 

  1. Steinberg M. Dasatinib: a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Clin Ther. 2007;29:2289–2308
  2. Deguchi Y, Kimura S, Ashihara E, et al. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res. 2008;32:980–983
  3. Hantschel O, Rix U, Schmidt U, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci U S A. 2007;104:13283–13288
  4. Jefferies CA, Doyle S, Brunner C, et al. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem. 2003;278:26258–26264
  5. Le Q, Daniel R, Chung SW, et al. Involvement of C-Abl tyrosine kinase in lipopolysaccharide-induced macrophage activation. J Immunol. 1998;160:3330–3336
  6. Smolinska MJ, Horwood NJ, Page TH, Smallie T, Foxwell BM. Chemical inhibition of Src family kinases affects major LPS-activated pathways in primary human macrophages. Mol Immunol. 2008;45:990–1000
  7. Vandyke K, Dewar AL, Farrugia AN, et al. Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis. Leukemia. 2009;23:994–997
  8. Chapoval AI, Kamdar SJ, Kremlev SG, Evans R. CSF-1 (M-CSF) differentially sensitizes mononuclear phagocyte subpopulations to endotoxin in vivo: a potential pathway that regulates the severity of gram-negative infections. J Leukoc Biol. 1998;63:245–252
  9. Evans R, Kamdar SJ, Duffy TM, Fuller J. Synergistic interaction of bacterial lipopolysaccharide and the monocyte-macrophage colony-stimulating factor: potential quantitative and qualitative changes in macrophage-produced cytokine bioactivity. J Leukoc Biol. 1992;51:93–96
  10. Sweet MJ, Campbell CC, Sester DP, et al. Colony-stimulating factor-1 suppresses responses to CpG DNA and expression of toll-like receptor 9 but enhances responses to lipopolysaccharide in murine macrophages. J Immunol. 2002;168:392–399
  11. Das J, Chen P, Norris D, et al. 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem. 2006;49:6819–6832
  12. Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer. 2009;9:57–63
  13. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801
  14. Weighardt H, Holzmann B. Role of Toll-like receptor responses for sepsis pathogenesis. Immunobiology. 2007;212:715–722
  15. English BK, Ihle JN, Myracle A, Yi T. Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages. J Exp Med. 1993;178:1017–1022
  16. English BK, Orlicek SL, Mei Z, Meals EA. Bacterial LPS and IFN-gamma trigger the tyrosine phosphorylation of vav in macrophages: evidence for involvement of the hck tyrosine kinase. J Leukoc Biol. 1997;62:859–864
  17. Leu TH, Charoenfuprasert S, Yen CK, Fan CW, Maa MC. Lipopolysaccharide-induced c-Src expression plays a role in nitric oxide and TNFalpha secretion in macrophages. Mol Immunol. 2006;43:308–316
  18. Meng F, Lowell CA. Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn. J Exp Med. 1997;185:1661–1670
  19. Khadaroo RG, Kapus A, Powers KA, Cybulsky MI, Marshall JC, Rotstein OD. Oxidative stress reprograms lipopolysaccharide signaling via Src kinase-dependent pathway in RAW 264.7 macrophage cell line. J Biol Chem. 2003;278:47834–47841
  20. Stovall SH, Yi AK, Meals EA, Talati AJ, Godambe SA, English BK. Role of vav1- and src-related tyrosine kinases in macrophage activation by CpG DNA. J Biol Chem. 2004;279:13809–13816
  21. Achuthan A, Elsegood C, Masendycz P, Hamilton JA, Scholz GM. CpG DNA enhances macrophage cell spreading by promoting the Src-family kinase-mediated phosphorylation of paxillin. Cell Signal. 2006;18:2252–2261
  22. Johnsen IB, Nguyen TT, Ringdal M, et al. Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling. EMBO J. 2006;25:3335–3346
  23. Manukyan M, Nalbant P, Luxen S, Hahn KM, Knaus UG. RhoA GTPase activation by TLR2 and TLR3 ligands: connecting via Src to NF-kappaB. J Immunol. 2009;182:3522–3529
  24. Fraser CK, Blake SJ, Diener KR, et al. Dasatinib inhibits recombinant viral antigen-specific murine CD4+ and CD8 + T-cell responses and NK-cell cytolytic activity in vitro and in vivo. Exp Hematol. 2009;37:256–265
  25. Horwood NJ, Mahon T, McDaid JP, et al. Bruton's tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production. J Exp Med. 2003;197:1603–1611
  26. Taneichi H, Kanegane H, Sira MM, et al. Toll-like receptor signaling is impaired in dendritic cells from patients with X-linked agammaglobulinemia. Clin Immunol. 2008;126:148–154
  27. Lee KG, Xu S, Wong ET, Tergaonkar V, Lam KP. Bruton's tyrosine kinase separately regulates NFkappaB p65RelA activation and cytokine interleukin (IL)-10/IL-12 production in TLR9-stimulated B Cells. J Biol Chem. 2008;283:11189–11198
  28. Doyle SL, Jefferies CA, O'Neill LA. Bruton's tyrosine kinase is involved in p65-mediated transactivation and phosphorylation of p65 on serine 536 during NFkappaB activation by lipopolysaccharide. J Biol Chem. 2005;280:23496–23501
  29. Schmidt NW, Thieu VT, Mann BA, Ahyi AN, Kaplan MH. Bruton's tyrosine kinase is required for TLR-induced IL-10 production. J Immunol. 2006;177:7203–7210
  30. Luo FR, Yang Z, Camuso A, et al. Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure. Clin Cancer Res. 2006;12:7180–7186
  31. Kamath AV, Wang J, Lee FY, Marathe PH. Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Cancer Chemother Pharmacol. 2008;61:365–376
  32. Luo FR, Barrett YC, Yang Z, et al. Identification and validation of phospho-SRC, a novel and potential pharmacodynamic biomarker for dasatinib (SPRYCEL), a multi-targeted kinase inhibitor. Cancer Chemother Pharmacol. 2008;62:1065–1074
  33. Tracey KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science. 1986;234:470–474
  34. Remick DG, Bolgos GR, Siddiqui J, Shin J, Nemzek JA. Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock. 2002;17:463–467
  35. Kerfoot SM, Kubes P. Local coordination verses systemic disregulation: complexities in leukocyte recruitment revealed by local and systemic activation of TLR4 in vivo. J Leukoc Biol. 2005;77:862–867
  36. Sheridan BC, McIntyre RC, Moore EE, Meldrum DR, Agrafojo J, Fullerton DA. Neutrophils mediate pulmonary vasomotor dysfunction in endotoxin-induced acute lung injury. J Trauma. 1997;42:391–396discussion 396–397
  37. Welbourn CR, Young Y. Endotoxin, septic shock and acute lung injury: neutrophils, macrophages and inflammatory mediators. Br J Surg. 1992;79:998–1003
  38. Quintas-Cardama A, Kantarjian H, Cortes J. Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov. 2007;6:834–848
  39. Blake SJ, Bruce Lyons A, Fraser CK, Hayball JD, Hughes TP. Dasatinib suppresses in vitro natural killer cell cytotoxicity. Blood. 2008;111:4415–4416
  40. Blake S, Hughes TP, Mayrhofer G, Lyons AB. The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro. Clin Immunol. 2008;127:330–339
  41. Schade AE, Schieven GL, Townsend R, et al. Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood. 2008;111:1366–1377
  42. Weichsel R, Dix C, Wooldridge L, et al. Profound inhibition of antigen-specific T-cell effector functions by dasatinib. Clin Cancer Res. 2008;14:2484–2491
  43. Wang X, Hochhaus A, Kantarjian HM, et al. Dasatinib pharmacokinetics and exposure-response (E-R): Relationship to safety and efficacy in patients (pts) with chronic myeloid leukemia (CML). J Clin Oncol. 2008;26:abstr 3590
  44. Jabbour E, Cortes J, Kantarjian H. Dasatinib for the treatment of Philadelphia chromosome-positive leukaemias. Expert Opin Investig Drugs. 2007;16:679–687
  45. Garcia-Munoz R, Galar A, Moreno C, et al. Parvovirus B19 acute infection and a reactivation of cytomegalovirus and herpesvirus 6 in a chronic myeloid leukemia patient during treatment with dasatinib (BMS-354825). Leuk Lymphoma. 2007;48:2461–2464
  46. Horwood NJ, Page TH, McDaid JP, et al. Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. J Immunol. 2006;176:3635–3641
  47. Napolitani G, Bortoletto N, Racioppi L, Lanzavecchia A, D'Oro U. Activation of src-family tyrosine kinases by LPS regulates cytokine production in dendritic cells by controlling AP-1 formation. Eur J Immunol. 2003;33:2832–2841
  48. Hasko G, Nemeth ZH, Szabo C, Zsilla G, Salzman AL, Vizi ES. Isoproterenol inhibits Il-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages. Brain Res Bull. 1998;45:183–187
  49. Hasko G, Szabo C, Nemeth ZH, Kvetan V, Pastores SM, Vizi ES. Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J Immunol. 1996;157:4634–4640
  50. Hasko G, Szabo C, Nemeth ZH, Lendvai B, Vizi ES. Modulation by dantrolene of endotoxin-induced interleukin-10, tumour necrosis factor-alpha and nitric oxide production in vivo and in vitro. Br J Pharmacol. 1998;124:1099–1106
  51. Szabo C, Hasko G, Zingarelli B, et al. Isoproterenol regulates tumour necrosis factor, interleukin-10, interleukin-6 and nitric oxide production and protects against the development of vascular hyporeactivity in endotoxaemia. Immunology. 1997;90:95–100
  52. Bennouna S, Denkers EY. Microbial antigen triggers rapid mobilization of TNF-alpha to the surface of mouse neutrophils transforming them into inducers of high-level dendritic cell TNF-alpha production. J Immunol. 2005;174:4845–4851
  53. Pugin J, Schurer-Maly CC, Leturcq D, Moriarty A, Ulevitch RJ, Tobias PS. Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci U S A. 1993;90:2744–2748
  54. von Asmuth EJ, Dentener MA, Bazil V, Bouma MG, Leeuwenberg JF, Buurman WA. Anti-CD14 antibodies reduce responses of cultured human endothelial cells to endotoxin. Immunology. 1993;80:78–83
  55. Loppnow H, Stelter F, Schonbeck U, et al. Endotoxin activates human vascular smooth muscle cells despite lack of expression of CD14 mRNA or endogenous membrane CD14. Infect Immun. 1995;63:1020–1026
  56. Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987;330:662–664
  57. Alexander HR, Sheppard BC, Jensen JC, et al. Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis. J Clin Invest. 1991;88:34–39
  58. Fisher CJ, Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med. 1996;334:1697–1702
  59. Marshall JC. Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat Rev Drug Discov. 2003;2:391–405
  60. Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat Rev Drug Discov. 2005;4:854–865
  61. Bozza FA, Salluh JI, Japiassu AM, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11:R49
  62. Martin H, Olander B, Norman M. Reactive hyperemia and interleukin 6, interleukin 8, and tumor necrosis factor-alpha in the diagnosis of early-onset neonatal sepsis. Pediatrics. 2001;108:E61
  63. Fraunberger P, Wang Y, Holler E, et al. Prognostic value of interleukin 6, procalcitonin, and C-reactive protein levels in intensive care unit patients during first increase of fever. Shock. 2006;26:10–12
  64. Turnbull IR, Javadi P, Buchman TG, Hotchkiss RS, Karl IE, Coopersmith CM. Antibiotics improve survival in sepsis independent of injury severity but do not change mortality in mice with markedly elevated interleukin 6 levels. Shock. 2004;21:121–125
  65. Remick DG, Bolgos G, Copeland S, Siddiqui J. Role of interleukin-6 in mortality from and physiologic response to sepsis. Infect Immun. 2005;73:2751–2757
  66. Gennari R, Alexander JW. Anti-interleukin-6 antibody treatment improves survival during gut-derived sepsis in a time-dependent manner by enhancing host defense. Crit Care Med. 1995;23:1945–1953
  67. Riedemann NC, Neff TA, Guo RF, et al. Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J Immunol. 2003;170:503–507
  68. Biffl WL, Moore EE, Moore FA, Barnett CC, Silliman CC, Peterson VM. Interleukin-6 stimulates neutrophil production of platelet-activating factor. J Leukoc Biol. 1996;59:569–574
  69. Ottonello L, Frumento G, Arduino N, et al. Differential regulation of spontaneous and immune complex-induced neutrophil apoptosis by proinflammatory cytokines. Role of oxidants, Bax and caspase-3. J Leukoc Biol. 2002;72:125–132
  70. Suwa T, Hogg JC, English D, Van Eeden SF. Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow. Am J Physiol Heart Circ Physiol. 2000;279:H2954–H2960
  71. Erzurum SC, Downey GP, Doherty DE, Schwab B, Elson EL, Worthen GS. Mechanisms of lipopolysaccharide-induced neutrophil retention. Relative contributions of adhesive and cellular mechanical properties. J Immunol. 1992;149:154–162
  72. Worthen GS, Schwab B, Elson EL, Downey GP. Mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries. Science. 1989;245:183–186
  73. Andonegui G, Bonder CS, Green F, et al. Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J Clin Invest. 2003;111:1011–1020
  74. Aldridge AJ. Role of the neutrophil in septic shock and the adult respiratory distress syndrome. Eur J Surg. 2002;168:204–214
  75. Holman RG, Maier RV. Superoxide production by neutrophils in a model of adult respiratory distress syndrome. Arch Surg. 1988;123:1491–1495
  76. Smedly LA, Tonnesen MG, Sandhaus RA, et al. Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase. J Clin Invest. 1986;77:1233–1243
  77. Rothe J, Lesslauer W, Lotscher H, et al. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature. 1993;364:798–802
  78. Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med. 1996;184:1397–1411
  79. Deitch EA. Animal models of sepsis and shock: a review and lessons learned. Shock. 1998;9:1–11
  80. Khadaroo RG, He R, Parodo J, et al. The role of the Src family of tyrosine kinases after oxidant-induced lung injury in vivo. Surgery. 2004;136:483–488
  81. Oberholzer A, Oberholzer C, Bahjat KS, et al. Increased survival in sepsis by in vivo adenovirus-induced expression of IL-10 in dendritic cells. J Immunol. 2002;168:3412–3418
  82. Oberholzer C, Oberholzer A, Bahjat FR, et al. Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis. Proc Natl Acad Sci U S A. 2001;98:11503–11508
  83. Scumpia PO, Moldawer LL. Biology of interleukin-10 and its regulatory roles in sepsis syndromes. Crit Care Med. 2005;33:S468–S471
  84. Wu CL, Lin LY, Yang JS, Chan MC, Hsueh CM. Attenuation of lipopolysaccharide-induced acute lung injury by treatment with IL-10. Respirology. 2009;14:511–521
  85. Lowell CA, Berton G. Resistance to endotoxic shock and reduced neutrophil migration in mice deficient for the Src-family kinases Hck and Fgr. Proc Natl Acad Sci U S A. 1998;95:7580–7584

PII: S0301-472X(09)00387-7

doi: 10.1016/j.exphem.2009.09.007

Experimental Hematology
Volume 37, Issue 12 , Pages 1435-1444 , December 2009