Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

HIV and Cytokines

Biological significance of the expression of HIV-related chemokine coreceptors (CCR5 and CXCR4) and their ligands by human hematopoietic cell lines

Abstract

The aim of this study was to learn more about the role of the HIV-related chemokine–chemokine receptor axes in human hematopoiesis. To address this issue we phenotyped 35 selected hematopoietic cell lines for the expression of CD4, CXCR4 and CCR5. We next evaluated the functionality of these chemokine receptors by calcium flux and chemotaxis assays, and by the ability of SDF-1, MIP-1α, MIP-1β and RANTES to influence the growth of the cells expressing CXCR4 and/or CCR5. Lastly, we examined whether human hematopoietic cell lines may secrete some HIV-related chemokines, and whether endogenously secreted chemokines might interfere with the infectability of hematopoietic cells by X4 and R5 HIV strains. These results demonstrate that: (1) HIV-related receptors are widely expressed on human hematopoietic cell lines; (2) stimulation of CXCR4 by SDF-1 induces calcium flux and chemotaxis in several hematopoietic cell lines more efficiently than stimulation of CCR5 by receptor-specific β-chemokines; (3) chemokines do not regulate proliferation of the hematopoietic cells; and finally (4) infectability of the hematopoietic cells by HIV-1 may be auto-modulated by endogenously secreted chemokines. These data shed more light on the role of HIV-related chemokine–chemokine receptors axes in human hematopoiesis and interaction of hematopoietic cells with HIV.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Fauci AS . Host factors and the pathogenesis of HIV-induced disease Nature 1996 384: 529–534

    Article  CAS  Google Scholar 

  2. Hoxie JA . Hematologic manifestations of AIDS. In: Hoffman R, Benz EJ, Shatill SJ, Furie B, Cohen HJ, Silberstein LE (eds) Hematology Basic Principles and Practice Churchill Livingstone: New York 1995 2171–2200

    Google Scholar 

  3. Moses A, Nelson J, Bagby GC . The influence of human immunodeficiency virus-1 on hematopoiesis Blood 1998 91: 1479–1495

    CAS  PubMed  Google Scholar 

  4. Lee B, Doranz BJ, Ratajczak MZ, Doms RW . An intricate web: chemokine receptors, HIV-1 and hematopoiesis Stem Cells 1998 16: 79–88

    Article  CAS  Google Scholar 

  5. Cairns JS, D'Souza MP . Chemokines and HIV-1 second receptors: the therapeutic connection Nature Med 1998 4: 563–568

    Article  CAS  Google Scholar 

  6. Rollins BJ . Chemokines Blood 1997 90: 909–928

    CAS  PubMed  Google Scholar 

  7. Lee B, Ratajczak J, Doms RW, Gewirtz AM, Ratajczak MZ . Coreceptor/chemokine receptor expression on human hematopoietic cells: biological implications for HIV-1 infection Blood 1999 93: 1145–1156

    CAS  PubMed  Google Scholar 

  8. Gutkind JS . The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades J Biol Chem 1998 273: 1839–1842

    Article  CAS  Google Scholar 

  9. Majka M, Ratajczak J, Kowalska MA, Ratajczak MZ . Binding of stromal derived factor-1a (SDF-1a) to CXCR4 chemokine receptor in normal human megakaryoblasts but not in platelets induces phosphorylation of mitogen-activated protein kinase p42/44 (MAPK), ELK-1 transcription factor and serine/threonine kinase AKT Eur J Haematol 2000 64: 164–172

    Article  CAS  Google Scholar 

  10. Dohlman HG, Thorner J . RGS proteins and signaling by heterotrimeric G proteins J Biol Chem 1997 272: 3871–3874

    Article  CAS  Google Scholar 

  11. Lefkowitz PJ . G protein-coupled receptors. III. New roles for receptor kinases and b-arrestins in receptor signaling and desensitization J Biol Chem 1998 273: 18677–18680

    Article  CAS  Google Scholar 

  12. Lu Li, Xiao M, Grigsby S, Wang WX, Wu B, Shen RN, Broxmeyer HE . Comparative effects of suppressive cytokines on isolated single CD34++ stem/progenitor cells from human bone marrow and umbilical cord blood plated with and without serum Exp Hematol 1993 21: 1442–1446

    CAS  PubMed  Google Scholar 

  13. Broxmeyer HE, Sherry B, Cooper S, Lu L, Maze R, Beckmann MP, Cerami A, Ralph P . Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells J Immunol 1993 150: 3448–3458

    CAS  PubMed  Google Scholar 

  14. Mantel C, Kim YJ, Cooper S, Kwon B, Broxmeyer HE . Polymerization of murine macrophage inflammatory protein 1a inactivates its myelosuppressive effects in vitro: the active form is monomer Proc Natl Acad Sci USA 1993 90: 2232–2236

    Article  CAS  Google Scholar 

  15. Su S, Mukaida N, Wang J, Zhang Y, Takami A, Nakao S, Matsushima K . Inhibition of immature erythroid progenitor cell proliferation by macrophage inflammatory protein-1a by interacting mainly with a C–C chemokine receptor, CCR1 Blood 1997 90: 605–611

    CAS  PubMed  Google Scholar 

  16. VanRanst PCF, Snoeck HW, Lardon F, Lenjou M, Nijs G, Weekx SFA, Rodrigus I, Berneman ZN, VanBockstaele DR . TGF-b and MIP-1a exert their main inhibitory activity on very primitive CD34++CD38− cells but show opposite effects on more mature CD34+CD38+ human hematopoietic progenitors Exp Hematol 1996 24: 1509–1515

    CAS  Google Scholar 

  17. Mayani H, Little MT, Dragowska W, Thornbury G, Lansdorp PM . Differential effects of the hematopoietic inhibitors MIP-1a, TGF-b, and TNF-a on cytokine-induced proliferation of subpopulations of CD34+ cells purified from cord blood and fetal liver Exp Hematol 1995 23: 422–427

    CAS  PubMed  Google Scholar 

  18. Drexler HG, Zaborski M, Quentmeier H . Cytokine response profiles of human myeloid factor-dependent leukemia cell lines Leukemia 1997 11: 701–708

    Article  CAS  Google Scholar 

  19. Patel VP, Kreider BL, Li Y, Li H, Leung K, Salcedo T, Nardelli B, Pippalla V, Gentz S, Thotakura R, Parmelee D, Gentz R, Gianni G . Molecular and functional chracterization of two novel human C-C chemokines as inhibitors of two distinct classes of myeloid progenitors J Exp Med 1997 185: 1163–1172

    Article  CAS  Google Scholar 

  20. Cook DN, Beck MA, Coffman TM, Kirby SL, Sheridan JF, Prangell IB, Smithies O . Requirement of MIP-1a for an inflammatory response to viral infection Science 1995 269: 1583–1585

    Article  CAS  Google Scholar 

  21. Dutt P, Wang JF, Groopman JE . Stromal cell-derived factor-1a and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis J Immunol 1998 161: 3652–3658

    CAS  PubMed  Google Scholar 

  22. Keller IR, Bartelmez SH, Sitnicka E, Ruscetti FW, Ortiz M, Gooya JM, Jacobsen SEW . Distinct and overlapping direct effects of macrophage inflammatory protein-1a and transforming growth factor-b on hematopoietic progenitor/stem cell growth Blood 1994 84: 2175–2181

    CAS  PubMed  Google Scholar 

  23. Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC . The chemokine SDF-1 is a chemoatractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood J Exp Med 1997 185: 111–120

    Article  CAS  Google Scholar 

  24. Mohle R, Bautz F, Rafii S, Moore MA, Brugger W, Kanz L . The chemokine receptor CXCR4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1 Blood 1998 91: 4523–4530

    CAS  PubMed  Google Scholar 

  25. Kowalska MA, Ratajczak J, Hoxie J, Brass L, Gewirtz AM, Poncz M, Ratajczak MZ . Platelet and megakaryocytes express the HIV co-receptor CXCR4 on their surface but do not respond to stromal derived factor (SDF)-1 Br J Haematol 1999 104: 220–229

    Article  CAS  Google Scholar 

  26. Sanchez X, Cousins-Hodges B, Aguilar T, Gosselink P, Lu Z, Navarro J . Activation of HIV-1coreceptor (CXCR4) mediates myelosuppression J Biol Chem 1997 272: 27529–27531

    Article  CAS  Google Scholar 

  27. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T . Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1 Nature 1996 382: 635–638

    Article  CAS  Google Scholar 

  28. Zou Y, Kottmann AH, Kuroda M, Taniuchi I, Littman DR . Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development Nature 1998 393: 595–599

    Article  CAS  Google Scholar 

  29. Drexler HG, Matsuo Y . Guidelines for the characterization and publication of human malignant hematopoietic cell lines Leukemia 1999 13: 835–842

    Article  CAS  Google Scholar 

  30. Ratajczak J, Marlicz W, Machalinski B, Pertusini E, Czajka R, Ratajczak MZ . An improved serum free system for cloning human ‘pure’ erythroid colonies. The role of the different growth factors and cytokines on BFU-E formation by the bone marrow and cord blood CD34+ cells Folia Histochem Cytobiol 1998 36: 55–60

    CAS  PubMed  Google Scholar 

  31. Ratajczak J, Zhang Q, Pertusini E, Wojczyk B, Wasik M, Ratajczak MZ . The role of insulin (INS) and insulin like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum free conditions – comparison to other cytokines and growth factors Leukemia 1998 12: 371–381

    Article  CAS  Google Scholar 

  32. Majka M, Lee B, Ratajczak J, Pertusini E, Honczarenko M, Kowalska MA, Wasik MA, Gewirtz AM, Ratajczak MZ . Expression and function of HIV-1 co-receptor on human hematopoietic cell lines Blood 1998 92: (Suppl. 1) 166a

    Google Scholar 

  33. Yao XJ, Mouland AJ, Subbramanian RA, Forget J, Rougeau N, Bergeron D, Cohen EA . Vpr stimulates viral expression and induces cell killing in human immunodeficiency virus type-1 dividing Jurkat T cells J Virol 1998 72: 4686–4693

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Cane AM, Chang J, Naif H, Amato T, Cunningham AL, Chong BH . Human immunodeficiency virus-1 infection of megakaryocytic cells Annu Conf Australas Soc HIV Med 1996 8: 39

    Google Scholar 

  35. Zauli G, Catani L, Gribellini D, Rec MC, Milani D, Borgatti P, Bassini A, La Placa M, Capitani S . The CD4 receptor plays essential but distinct roles in HIV-1 infection and induction of apoptosis in primary bone marrow GPIIb/IIIa+ megakaryocytes and the HEL cell line Br J Haematol 1995 91: 290–298

    Article  CAS  Google Scholar 

  36. DiFronzo NL, Pise-Masison CA, Fernandez-Larsson R, Holland CA . Viral determinants of HIV-1 sufficient to extend tropism to macrophages are distinct from the determinants that control the cytopathic phenotype in HL-60 cells AIDS 1997 11: 1681–1688

    Article  CAS  Google Scholar 

  37. Ushijima H, Dairaku M, Honma H, Yamaguchi K, Shimizu H, Tsuchie H, Abe K, Yamamoto A, Hoshino H, Muller WE . Human immunodeficiency virus infection in cells of myeloid-monocytic lineage Microbiol Immunol 1991 35: 487–492

    Article  CAS  Google Scholar 

  38. Shen H, Cheng T, Preffer FI, Dombkowski D, Tomasson MH, Golan DE, Yang O, Hofmann W, Sodroski JG, Luster AD, Scadden AD . Intrinsic human immunodeficiency virus type 1 resistance of hematopoietic stem cells despite coreceptor expression J Virol 1999 73: 728–737

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Majka M, Lee B, Honczarenko M, Ratajczak J, Douglas R, Kowalska MA, Silberstein L, Gewirtz AM, Ratajczak MZ . The stromal derived factor-1 (SDF-1) receptor – CXCR4 is expressed on the human erythroid progenitors and SDF-1 is an important chemotactic factor for early human erythroid cells. Comparison to other chemokine receptor–chemokines axes Stem Cells 2000 18: 128–138

    Article  CAS  Google Scholar 

  40. Bonecchi R, Sozzani S, Stine JT, Luini W, D'Amico G, Allavena P, Chantry D, Mantovani A . Divergent effects of interleukin-4 and interferon-g on macrophage-derived chemokine production: an amplification circuit of polarized T helper 2 responses Blood 1998 92: 2668–2671

    CAS  PubMed  Google Scholar 

  41. Farzan M, Mirzabekov T, Kolchinsky P, Wyatt R, Cayabyab M, Gerard NP, Gerard C, Sodorski J, Choe H . Tyrosine sulfatation of the amino terminus of CCR5 facilitates HIV-1 entry Cell 1999 96: 667–676

    Article  CAS  Google Scholar 

  42. Fehinger TA, Herbein G, Yu H, Para MI, Bernstein ZP, O'Brien WA, Caliguri MA . Natural killer cells from HIV-1+ patients produce C–C chemokines and inhibit HIV-1 infection J Immunol 1998 161: 6433–6438

    Google Scholar 

  43. Wagner L, Yang OO, Garcia-Zepeda EA, Ge Y, Kalmas SA, Walker BD, Pasternack MS, Luster AD . β-chemokines are released from HIV-1 specific cytolytic T-cell granules complexed to proteoglycans Nature 1998 391: 908–911

    Article  CAS  Google Scholar 

  44. Oliva A, Ninter AL, Vaccarezza M, Rubbert A, Catanzaro A, Moir S, Monaco J, Ehler L, Mizelli S, Jackson R, Li Y, Romano JW, Fauci AS . Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro J Clin Invest 1998 102: 223–231

    Article  CAS  Google Scholar 

  45. Fehniger TA, Herbein G, Yu H, Para MI, Bernstein ZP, O'Brien WA, Caliguri MA . Natural killer cells from HIV-1+ patients produce CC-chemokines and inhibit HIV-1 infection Blood 1998 92: (Suppl. 1) 544a

    Google Scholar 

  46. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Luso P . Identification of RANTES, MIP-1α, and MIP-1β as the major HIV suppressive factors produced by CD8+ T cells Science 1995 270: 1811–1815

    Article  CAS  Google Scholar 

  47. Saha K, Bentsman G, Chess L, Volsky DJ . Endogenous production of b-chemokines by CD4+, but not CD8+, T-cell clones correlates with the clinical state of human immunodeficiency virus type-1 (HIV-1)-infected individuals and may be responsible for blocking infection with non-syncytium-inducing HIV-1 in vitro J Virol 1998 72: 876–881

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Majka M, Rozmyslowicz T, Lee B, Pietrzkowski Z, Gaulton GN, Silberstein L, Ratajczak MZ . Bone marrow CD34+ cells and megakaryoblasts secrete β-chemokines; implications for infectability by M-tropic human immunodeficiency virus (R5 HIV) J Clin Invest 1999 104: 1739–1749

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This paper was presented as an oral presentation at 41st Annual Meeting of American Society of Hematology, 1999 New Orleans, LA, December 3–7 and published in abstract form Blood 94: 618a, 1999 (abstr. suppl. 1). The authors are indebted to Dr Anna Janowska-Wieczorek from University of Alberta for critical comments. This work was supported by a NIH grant R01 HL61796–01 to MZR and R01 AI4083 to GNG.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Majka, M., Rozmyslowicz, T., Honczarenko, M. et al. Biological significance of the expression of HIV-related chemokine coreceptors (CCR5 and CXCR4) and their ligands by human hematopoietic cell lines. Leukemia 14, 1821–1832 (2000). https://doi.org/10.1038/sj.leu.2401891

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401891

Keywords

This article is cited by

Search

Quick links