, Volume 7, Issue 3, pp 271–276 | Cite as

Role of the CC Chemokine receptor 9/TECK interaction in apoptosis

  • B.-S. Youn
  • K.-Y. Yu
  • J. Oh
  • J. Lee
  • T.-H. Lee
  • H. E. Broxmeyer


Chemokine receptors are members of the G protein coupled receptor (GPCR) supergene family whose expression is highly restricted to hematopoietic cells. Although the primary role of chemokine and chemokine receptor interaction is believed to be regulation of chemotaxis of leukocytes, subsequent information clearly suggests that multiple immune regulatory functions are attributed to chemokine receptor signaling. We recently showed that activation of the CC chemokine 9 receptor (CCR9), a thymus-specific chemokine receptor, led to potent cFLIPL-independent resistance to cycloheximide-induced apoptosis and modest resistance to Fas-mediated apoptosis possibly via activation of multiple signaling components involving Akt and glycogen synthase kinase 3β. The fact that these two apoptotic signals involve activation of similar arrays of death execution machinery such as caspase-8, caspase-9, or caspase-3, suggests that chemokine receptor signaling may provide a wide range of antiapoptotic activities to hematopoietic cells under certain biological conditions. GPCR is a large family of cell surface receptors, many of which are critically involved in hormonal and behavioral control. Recent observations also suggest that GPCR signaling plays a pivotal role in immune cell activation. Heterotrimeric G protein is an integral part of GPCR signaling. Thus, dissection of signaling components involved in the CCR9-mediated antiapoptosis could be a framework for cell survival mechanisms and may provide options for therapeutic interventions for neurdegenerative diseases or T cell malfunctioning.

Akt chemokine receptor G protein coupled receptor GSK-3β heterotrimeric G proteins 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Broxmeyer HE Role of cytokines in hematopoiesis. In: Oppenheim JJ, Rossio JL, Gering AJH, eds. Clinical Aspects of Cytokines: Role in Pathogenesis, Diagnosis and Therapy. New York: Oxford University Press, 1993: 201–206.Google Scholar
  2. 2.
    Broxmeyer HE, et al Comparative analysis of the suppressive effects of the human macrophage inflammatory protein family of cytokines (chemokines) on poliferation of human myeloid progenitor cells. J Immunol 1993; 150: 3448–3458.Google Scholar
  3. 3.
    Baggioloini M, Dewald B, Moser B Human chemokines: An update. Annu Rev Immunol 1997; 15: 675–705.Google Scholar
  4. 4.
    Zlotnik A, Yoshie O Chemokines: A new classification system and their role in immunity. Immunity 2000; 12: 121–127.Google Scholar
  5. 5.
    Rossi D, Zlotnik, A The biology of chemokines and their receptors. Ann Rev Immunol 2000; 18: 217–242.Google Scholar
  6. 6.
    Youn B-S, Mantel C, Broxmeyer HE Chemokines, chemokine receptors and hematopoiesis. Immunol Rev 2000; 177: 150–174.Google Scholar
  7. 7.
    Kranenburg O, Moolenaar WH Ras-MAP kinase signaling by lysophosphatidic acid and other G protein-coupled receptor agonists. Oncogene 2001; 20: 1540–1546.Google Scholar
  8. 8.
    Inglese J, Koch WJ, Touhara K, Lefkowitz RJ Gβγ interactions with PH domains and Ras-MAPK signaling pathways. Trends Biochem Sci 1995; 20: 151–156.Google Scholar
  9. 9.
    Ganju RK, Brubaker SA, Meyer J, et al The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J Biol Chem 1998; 273: 23169–23175.Google Scholar
  10. 10.
    Nagasawa T, Kikutani, Kishimoto T Molecular cloning and structure of a pre-B cell growth stimulating factor. Proc Natl Acad Sci USA 1994; 91: 2305–2309.Google Scholar
  11. 11.
    Nagasawa T, et al Defects of B lympoiesis and bone marrow meylopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635–638.Google Scholar
  12. 12.
    Hodohara K, Fujii N, Yamamoto N, Kaushansky K Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoitin to enhance the development of megakaryocytic progenitor cells (CFU-MK). Blood 2000; 95: 769–775.Google Scholar
  13. 13.
    Lataillade, et al Chemokine SDF-1 enhances circulating CD34+ cell proliferation in synergy with cytokines: Possible role in progenitor survival. Blood 2000; 95: 756–768.Google Scholar
  14. 14.
    Han, et al Platelet factor 4 and other CXC chemokines support the survival of normal hematopoietic cells and reduce the chemosensitivity of cells to cytotoxic agents. Blood 1997; 89: 2328–2335.Google Scholar
  15. 15.
    Scheuerer B, et al The CXC chemokine platelet factor 4 promotes survival and induce monocyte differentiation into macrophages. Blood 2000; 95: 1158–1166.Google Scholar
  16. 16.
    Youn BS, Kim CH, Smith FO, Broxmeyer HE TECK, an efficacious chemoattractant for human thymocytes, uses GPR–9–6/CCR9 as a specific receptor. Blood 1999; 94: 2533–2536.Google Scholar
  17. 17.
    Zaballos A, Gutierrez J, Varona R, Ardavin, Marquez G Identification of the orphan chemokine receptor GPR–9–6 as CCR9, the receptor for the chemokine TECK. J Immunol 1999; 162: 5671–5675.Google Scholar
  18. 18.
    Zabel BA, et al Human G protein-coupled receptor GPR–9–6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokinemediated chemotaxis.J Exp Med 1999; 190: 1241–1256.Google Scholar
  19. 19.
    Kim CH, Pelus LM, White JR, Broxmeyer HE Differential chemotactic behavior of developing T cells in response to thymic chemokines. Blood 1998; 91: 4434–4443.Google Scholar
  20. 20.
    Wurbel, et al Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T-and B-cell development and a reduction in T-cell receptor γ δ + gut intraepithelial lymphocytes. Blood 2001; 98: 2626–2632.Google Scholar
  21. 21.
    Youn B-S, Kim YJ, Mantel C, Yu K-Y, Broxmeyer HE Blocking of c-FLIPL-independent cycloheximide-induced apoptosis or Fas-mediated apoptosis by the CC chemokine receptor 9/TECK interaction. Blood 2001; 98: 925–933.Google Scholar
  22. 22.
    Rommel C, Clarke BA, Zimmermann S, et al Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 1999; 286: 1738–1741.Google Scholar
  23. 23.
    Tang D, Lahti JM, Grenet J, Kidd VJ Cycloheximide-induced T-cell death is mediated by a Fas-associated death domaindependent mechanism. J Biol Chem 1999; 274: 7245–7252.Google Scholar
  24. 24.
    Wajant H, Hass E, Schwenzer R, et al Inhibition of death receptor-mediated gene induction by a cycloheximide-sensitive factor occurs at the level of or upstream of Fas-associated death domain protein (FADD). J Biol Chem 2000; 275: 24357–24366.Google Scholar
  25. 25.
    Willems F, Amarauoi Z, Vanderheyde N, et al Expression of c-FLIPL and resistance to CD95-mediated apoptosis of monocytes-derived dendritic cells: Inhibition by bisidolylmaleimide. Blood 2000; 95: 3478–3842.Google Scholar
  26. 26.
    Flesch IE, Stober D, Schirmbeck R, Reimann J Monocyte inflammatory protein-1 alpha facilitates priming of CD8(+) T cell response to exogenous viral antigen. Int Immunol 2000; 12: 1365–1370Google Scholar
  27. 27.
    Arai H, Charo IF Differential regulation of G-proteinmediated signaling by chemokine receptors. J Biol Chem 1996; 271: 21814–21819.Google Scholar
  28. 28.
    Yusta B, Boushey RP, Drucker DJ The glucagons-like peptide-2 receptor mediates direct inhibition of cellular apoptosis via a camp-dependent protein kinase-independent pathway. J Biol Chem 2000; 275: 35345–35352.Google Scholar
  29. 29.
    Leloup C, Michaelson DM, Fisher A, Hartmann T, Beyreeuther K, Stein R M1 muscarinic receptor block caspase activation by phosphoinositide 3-kinase-and MAPK/ERK-independent pathways. Cell Death Differ 2000; 7: 825–833.Google Scholar
  30. 30.
    Gu C, Ma YC, Benjamin J, Chao MV, Huang XY Apoptotic signaling through the beta-adrenergic receptor. A new Gs effector pathway. J Biol Chem 2000; 275: 20726–20733.Google Scholar
  31. 31.
    Turner PR, Mefford S, Christakos S, Nissenson RA Apoptosis mediated by activation of the G protein-coupled receptor for parathyroid hormone (PTH)/PTH-related protein (PTHrP). Mol Endocrinol 2000; 14: 241–254.Google Scholar
  32. 32.
    Davis RJ Signal transduction by the JNK group of MAP kinases. Cell 2000; 103: 239–252.Google Scholar
  33. 33.
    Tournier, et al Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 2000; 288: 870–874.Google Scholar
  34. 34.
    Tobiume K, et al ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO 2001; 2: 222–228.Google Scholar
  35. 35.
    Park, et al Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. J Biol Chem 2002; 277: 2573–2578.Google Scholar
  36. 36.
    Neptune ER, Bourne HR Receptors induce chemotaxis by releasing the βδ subunit of Gi, not by activating Gq or Gs. Proc Natl Acad Sci USA 1997; 94: 14489–14494.Google Scholar
  37. 37.
    Lopez-Ilasaca M, Crespo P, Giuseppe Pellici P, Gutkind JS, Wetzker R Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI3-kinase γ. Science 1997; 275: 394–397.Google Scholar
  38. 38.
    Dudek H, Datta SR, Franke TF, et al Regulation of neuronal survival by the serine-threonie protein kinase Akt. Science 1997; 275: 661–665.Google Scholar
  39. 39.
    Datta SR, Brunet A, Greenberg ME Cellular survival: A play in three Akts. Genes Dev 1999; 13: 2905–2927.Google Scholar
  40. 40.
    Tilton B, Andjelkovic M, Didichenko SA, Hemmings BA, Thelen M G-protein-coupled receptors and Fc gammareceptors mediate activation of Akt/protein kinase B in human phagocytes. J Biol Chem 1997; 272: 28096–28101.Google Scholar
  41. 41.
    Sotsios Y, Whittaker GC, Westwick J, Ward SG The CXC chemokine stromal cell-derived factor activates a Gi-coupled phosphoinositide 3-kinase in T lymphocytes. J Immunol 1999; 163: 5954–5963.Google Scholar
  42. 42.
    Coffer PJ, Schweizer RC, Dubois GR, Maikoe T, Lammers JW, Koenderman L Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5. Blood 1998; 91: 2547–2557.Google Scholar
  43. 43.
    Datta SR, Brunet A, Greenberg ME Cellular survival: A play in three Akts. Genes Dev 1999; 13: 2905–2927.Google Scholar
  44. 44.
    Frame S, Cohen P GSK3 takes center stage more than 20 years after its discovery. Biochem J 2001; 359: 1–16.Google Scholar
  45. 45.
    Frame S, Cohen P, Biodni RM A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell 2001; 7: 1321–1327.Google Scholar
  46. 46.
    Pap M, Cooper GM Role of glycogen synthase kinase-3 in the phosphatidylinocitol 3-kinase/Akt cell survival pathway. J Biol Chem 1998; 273: 19929–19932.Google Scholar
  47. 47.
    Hetman M, Cavanaugh JE, Kimelman D, Xia Z Role of glycogen synthase kinase-3 in neuronal apoptosis induced by trophic withdrawal. J Neurosci 2000; 20: 2567–2574.Google Scholar
  48. 48.
    Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000; 14: 2501–2514.Google Scholar
  49. 49.
    Chen, et al Wnt-1 signaling inhibits apoptosis by activating β-catenin/T cell factor-mediated transcription. J Cell Biol 2001; 152: 87–96.Google Scholar
  50. 50.
    Eisenman RN Deconstructing myc. Genes Dev 2001; 15: 2023–2030.Google Scholar
  51. 51.
    Maiese K, Vincent AM Group I metabotropic receptors downregulate nitric oxide induced caspase-3 activity in rat hippocampal neurons. Neurosci Lett 1999; 264: 17–20.Google Scholar
  52. 52.
    Dorsam G, Voice J, Kong Y, Goetzl EJ Vasoactive intestinal peptide mediation of development and functions of T lymphocytes. Ann NY Acad Sci 2000; 921: 79–91.Google Scholar
  53. 53.
    Wilkin F, Duhant X, Bruyns C, Suarez-Huerta N, Boeynaems J-M, Robaye B The P2Y11 receptor mediates the ATPindependent maturation of human monocyte-derived dendritic cells. J Immunol 2001; 166: 7172–7177.Google Scholar
  54. 54.
    Tilley SL, Coffman TM, Koller BH Mixed messages: Modulation of inflammation and immune responses by prostagrandins and thromboxanes. J Clin Invest 2001; 108: 15–23.Google Scholar
  55. 55.
    Le, et al Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 2001; 14: 561–571.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • B.-S. Youn
    • 1
  • K.-Y. Yu
    • 1
  • J. Oh
    • 2
  • J. Lee
    • 1
  • T.-H. Lee
    • 3
  • H. E. Broxmeyer
    • 4
    • 5
  1. 1.KOMED Institute for Life Science, Graduate School of BiotechnologyKorea UniversitySeoulKorea
  2. 2.Department of Anatomy, School of MedicineWonkwang UniversityIksanKorea
  3. 3.Formulae Pharmacology Department, Oriental Medical SchoolKyungwon UniversityKorea
  4. 4.The Walther Oncology CenterIndiana University School of MedicineIndianapolis
  5. 5.the Walther Cancer InstituteIndianapolisUSA

Personalised recommendations