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:

Growth Factor, Cytokines and Cell Signaling

Expression and responsiveness of human interleukin-18 receptor (IL-18R) on hematopoietic cell lines

Abstract

Interleukin-18 (IL-18) is a new inflammatory cytokine sharing biological functions with IL-12. The human IL-18 receptor (IL-18R) was recently identified and was found to be expressed on normal peripheral blood lymphocytes. To further characterize IL-18R, we analyzed IL-18R expression using a series of human hematopoietic cell lines selected from various cell lineages. We found the IL-18R expression on cells of T and B lineages as expected from analysis on normal cells. The IL-18R expression, however, was found not to be restricted to any specific maturation stages of T and B cells. In addition, we detected IL-18R expression in myeloid, monocytoid, erythroid and megakaryocytic cell lines, indicating that normal counterparts of these cell lineages could express IL-18R and participate in in vivo reactions caused by IL-18. Biochemical studies showed that IL-18R proteins exist as heterogeneous molecules ranging from 60 to 110 kDa. Deglycosilation experiments indicated that the heterogeneity could not be explained only by a difference in glycosilation. We also found that tumor necrosis factor-α (TNF-α) modulated the IL-18R expression, which implies an important in vivo effect of TNF-α on IL-18-induced reaction. Analyzing the responsiveness of IL-18R, we found that only KG-1 responded to IL-18 stimulation. This suggests that certain inhibitory mechanisms of IL-18 responsive genes are involved in the all IL-18R-positive cell lines except KG-1.

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

Similar content being viewed by others

References

  1. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K, Akita K, Namba M, Tanabe F, Konishi K, Fukuda S, Kurimoto M . Cloning of a new cytokine that induces IFN-γ production by T cells Nature 1995 378: 88–91

    Article  CAS  PubMed  Google Scholar 

  2. Ushio S, Namba M, Okura T, Hattori K, Nukada Y, Akita K, Tanabe F, Konishi K, Micallef M, Fujii M, Torigoe K, Tanimoto T, Fukuda S, Ikeda M, Okamura H, Kurimoto M . Cloning of the cDNA for human IFN-γ-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein J Immunol 1996 156: 4274–4279

    CAS  PubMed  Google Scholar 

  3. Kohno K, Kataoka J, Ohtsuki T, Suemoto Y, Okamoto I, Usui M, Ikeda M, Kurimoto M . IFN-γ-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12 J Immunol 1997 158: 1541–1550

    CAS  PubMed  Google Scholar 

  4. Dao T, Mehal WZ, Crispe IN . IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells J Immunol 1998 161: 2217–2222

    CAS  PubMed  Google Scholar 

  5. Micallef MJ, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Tanimoto T, Torigoe K, Fujii M, Ikeda M, Fukuda S, Kurimoto M . Interferon-γ-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-γ production Eur J Immunol 1996 26: 1647–1651

    Article  CAS  PubMed  Google Scholar 

  6. Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K, Akira S . Defective NK cell activity and Th1 response in IL-18-deficient mice Immunity 1998 8: 383–390

    Article  CAS  PubMed  Google Scholar 

  7. Rothe H, Jenkins NA, Copeland NG, Kolb H . Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2 J Clin Invest 1997 99: 469–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Olee T, Hashimoto S, Quach J, Lotz M . IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses J Immunol 1999 162: 1096–1100

    CAS  PubMed  Google Scholar 

  9. Bohn E, Sing A, Zumbihl R, Bielfeldt C, Okamura H, Kurimoto M, Heesemann J, Autenrieth IB . IL-18 (IFN-γ-inducing factor) regulates early cytokine production in, and promotes resolution of, bacterial infection in mice J Immunol 1998 160: 299–307

    CAS  PubMed  Google Scholar 

  10. Kawakami K, Qureshi MH, Zhang T, Okamura H, Kurimoto M, Saito A . IL-18 protects mice against pulmonary and disseminated infection with Cryptococcus neoformans by inducing IFN-γ production J Immunol 1997 159: 5528–5534

    CAS  PubMed  Google Scholar 

  11. Mastroeni P, Clare S, Khan S, Harrison JA, Hormaeche CE, Okamura H, Kurimoto M, Dougan G . Interleukin 18 contributes to host resistance and γ interferon production in mice infected with virulent Salmonella typhimurium Infect Immun 1999 67: 478–483

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Taniguchi M, Nagaoka K, Ushio S, Nukada Y, Okura T, Mori T, Yamauchi H, Ohta T, Ikegami H, Kurimoto M . Establishment of the cells useful for murine interleukin-18 bioassay by introducing murine interleukin-18 receptor cDNA into human myelomonocytic KG-1 cells J Immunol Meth 1998 217: 97–102

    Article  CAS  Google Scholar 

  13. Torigoe K, Ushio S, Okura T, Kobayashi S, Taniai M, Kunikata T, Murakami T, Sanou O, Kojima H, Fujii M, Ohta T, Ikeda M, Ikegami H, Kurimoto M . Purification and characterization of the human interleukin-18 receptor J Biol Chem 1997 272: 25737–25742

    Article  CAS  PubMed  Google Scholar 

  14. Hoshino K, Tsutsui H, Kawai T, Takeda K, Nakanishi K, Takeda Y, Akira S . Generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 bunding protein J Immunol 1999 162: 5041–5044

    CAS  PubMed  Google Scholar 

  15. Kunikata T, Torigoe K, Ushio S, Okura T, Ushio C, Yamauchi H, Ikeda M, Ikegami H, Kurimoto M . Constitutive and induced IL-18 receptor expression by various peripheral blood cell subsets as determined by anti-hIL-18R monoclonal antibody Cell Immunol 1998 189: 135–143

    Article  CAS  PubMed  Google Scholar 

  16. Tomura M, Maruo S, Mu J, Zhou XY, Ahn HJ, Hamaoka T, Okamura H, Nakanishi K, Clark S, Kurimoto M, Fujiwara H . Differential capacities of CD4+, CD8+, and CD4−CD8− T cell subsets to express IL-18 receptor and produce IFN-γ in response to IL-18 J Immunol 1998 160: 3759–3765

    CAS  PubMed  Google Scholar 

  17. Xu D, Chan WL, Leung BP, Hunter D, Schulz K, Carter RW, McInnes IB, Robinson JH, Liew FY . Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells J Exp Med 1998 188: 1485–1492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yoshimoto T, Okamura H, Tagawa YI, Iwakura Y, Nakanishi K . Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-γ production from activated B cells Proc Natl Acad Sci USA 1997 94: 3948–3953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Munder M, Mallo M, Eichmann K, Modolell M . Murine macrophages secrete interferon γ upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation J Exp Med 1998 187: 2103–2108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Osaki T, Peron JM, Cai Q, Okamura H, Robbins PD, Kurimoto M, Lotze MT, Tahara H . IFN-γ-inducing factor/IL-18 administration mediates IFN-γ and IL-12-independent antitumor effects J Immunol 1998 160: 1742–1749

    CAS  PubMed  Google Scholar 

  21. Coughlin CM, Salhany KE, Wysocka M, Aruga E, Kurzawa H, Chang AE, Hunter CA, Fox JC, Trinchieri G, Lee WMF . Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis J Clin Invest 1998 101: 1441–1452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang T, Kawakami K, Qureshi MH, Okamura H, Kurimoto M, Saito A . Interleukin-12 (IL-12) and IL-18 synergistically induce the fungicidal activity of murine peritoneal exudate cells against Cryptococcus neoformans through production of γ interferon by natural killer cells Infect Immun 1997 65: 3594–3599

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Hofstra CL, Van Ark I, Hofman G, Kool M, Nijkamp FP, Van Oosterhout AJ . Prevention of Th2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels J Immunol 1998 161: 5054–5060

    CAS  PubMed  Google Scholar 

  24. Ahn HJ, Maruo S, Tomura M, Mu J, Hamaoka T, Nakanishi K, Clark S, Kurimoto M, Okamura H, Fujiwara H . A mechanism underlying synergy between IL-12 and IFN-γ-inducing factor in enhanced production of IFN-γ J Immunol 1997 159: 2125–2131

    CAS  PubMed  Google Scholar 

  25. Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K . IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-γ production J Immunol 1998 161: 3400–3407

    CAS  PubMed  Google Scholar 

  26. Fischer P, Nacheva E, Mason DY, Sherrington PD, Hoyle C, Hayhoe FG, Karpas A . A Ki-1 (CD30)-positive human cell line (Karpas 299) established from a high-grade non-Hodgkin's lymphoma, showing a 2;5 translocation and rearrangement of the T-cell receptor beta-chain gene Blood 1988 72: 234–240

    CAS  PubMed  Google Scholar 

  27. Maeda M, Shimizu A, Ikuta K, Okamoto H, Kashihara M, Uchiyama T, Honjo T, Yodoi J . Origin of human T-lymphotrophic virus I-positive T cell lines in adult T cell leukemia. Analysis of T cell receptor gene rearrangement J Exp Med 1985 162: 2169–2174

    Article  CAS  PubMed  Google Scholar 

  28. Sagawa K, Koga T, Sasaguri Y, Sadamori N, Nagai K . A novel adult T cell leukemia-derived cell line (SALT-3) susceptible to human immunodeficiency virus type 1 infection Kurume Med J 1995 42: 149–160

    Article  CAS  PubMed  Google Scholar 

  29. Otsuki T, Nakazawa N, Taniwaki M, Yamada O, Sakaguchi H, Wada H, Yawata Y, Ueki A . Establishment of a new human myeloma cell line, KMS-18, having t(4;14)(p16.3;q32.3) derived from a case phenotypically transformed from Ig A-lambda to BJP-lambda, and associated with hyperammonemia Int J Oncol 1998 12: 545–552

    CAS  PubMed  Google Scholar 

  30. Nakamura S, Imanishi J, Minowada J . R1–20, a novel monoclonal antibody reacting with a molecule distinct from integrin family, induces homotypic cell aggregation J Immunol 1992 149: 30–37

    CAS  PubMed  Google Scholar 

  31. Konishi K, Tanabe F, Taniguchi M, Yamauchi H, Tanimoto T, Ikeda M, Orita K, Kurimoto M . A simple and sensitive bioassay for the detection of human interleukin-18/interferon-γ-inducing factor using human myelomonocytic KG-1 cells J Immunol Meth 1997 209: 187–191

    Article  CAS  Google Scholar 

  32. Born TL, Thomassen E, Bird TA, Sims JE . Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling J Biol Chem 1998 273: 29445–29450

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs Hans G Drexler (DSMZ-German Collection of Microorganisms and Cell Cultures), Michiyuki Maeda (Kyoto University), Eiji Tatsumi (Kobe University), Kimitaka Sagawa (Kurume University), Jun Okamura (Kyushu Cancer Center) and Takemi Otsuki (Kawasaki Medical School) for providing some of the leukemia cell lines used in this study. We also thank Dr Mark Micallef for helpful discussion and Ms Keleher for editing the manuscript.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakamura, S., Otani, T., Okura, R. et al. Expression and responsiveness of human interleukin-18 receptor (IL-18R) on hematopoietic cell lines. Leukemia 14, 1052–1059 (2000). https://doi.org/10.1038/sj.leu.2401789

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401789

Keywords

This article is cited by

Search

Quick links