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Limitin: An interferon-like cytokine that preferentially influences B-lymphocyte precursors

Nature Medicine volume 6, pages 659–666 (2000)Cite this article

Abstract

We have identified an interferon-like cytokine, limitin, on the basis of its ability to arrest the growth of or kill lympho–hematopoietic cells. Limitin strongly inhibited B lymphopoiesis in vitro and in vivo but had little influence on either myelopoiesis or erythropoiesis. Because limitin uses the interferon α/β receptors and induces interferon regulatory factor-1, it may represent a previously unknown type I interferon prototype. However, preferential B-lineage growth inhibition and activation of Janus kinase 2 in a myelomonocytic leukemia line have not been described for previously known interferons.

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Figure 1: Sequence and expression of limitin.
Figure 2: Limitin induces apoptosis in BC7.12 cells and G0/G1 arrest or G1 prolongation in WEHI3 cells.
Figure 3: Limitin selectively inhibits the proliferation of normal lympho–hematopoietic progenitors.
Figure 4: Effects of limitin on LTBMCs.
Figure 5: In vivo effects of limitin.
Figure 6: Limitin uses the IFN-α/β receptors.
Figure 7: Signal transduction pathway used by limitin.

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References

  1. Kincade, P.W. et al. Cell interaction molecules utilized in bone marrow. Cell Adhes. Commun. 6, 211–215 (1998).

    Article  CAS  Google Scholar 

  2. Oritani, K. & Kincade, P.W. Lymphopoiesis and matrix glycoprotein SC1/ECM2. Leuk. Lymphoma 32, 1–7 (1998).

    Article  CAS  Google Scholar 

  3. Morrison, S.J., Shah, N.M. & Anderson, D.J. Regulatory mechanisms in stem cell biology. Cell 88, 287–298 (1997).

    Article  CAS  Google Scholar 

  4. Burrows, P.D. & Cooper, M.D. B cell development and differentiation. Curr. Opin. Immunol. 9, 239–344 (1997).

    Article  CAS  Google Scholar 

  5. Lyman, S.D. & Jacobsen, S.E.W. c-kit ligand and flt3 ligand: Stem/progenitor cell factors with overlapping yet distinct activities. Blood 91, 1101–1134 (1998).

    CAS  Google Scholar 

  6. Whetton, A.D. & Spooncer, E. Role of cytokines and extracellular matrix in the regulation of haemopoietic stem cells. Curr. Opin. Cell Biol. 10, 721–726 (1998).

    Article  CAS  Google Scholar 

  7. Wang, J., Lin, Q., Langston, H. & Cooper, M.D. Resident bone marrow macrophages produce type I interferons that can selectively inhibit interleukin-7-driven growth of B lineage cells. Immunity 3, 475–484 (1995).

    Article  CAS  Google Scholar 

  8. VerFaillie, C.M. Chemokines as inhibitors of hematopoietic progenitors. J. Lab. Clin. Med. 127, 148–150 (1996).

    Article  CAS  Google Scholar 

  9. Graham, G.J. & Wright, E.G. Haemopoietic stem cells: their heterogeneity and regulation. Int. J. Exp. Path. 78, 197–218 (1997).

    Article  CAS  Google Scholar 

  10. Cohen, P.L. & Eisenberg, R.A. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu. Rev. Immunol. 9, 243–269 (1991).

    Article  CAS  Google Scholar 

  11. Pietrangeli, C.E., Hayashi, S-I. & Kincade, P.W. Stromal cell lines which support lymphocyte growth: Characterization, sensitivity to radiation and responsiveness to growth factors. Eur. J. Immunol. 18, 863–872 (1988).

    Article  CAS  Google Scholar 

  12. Gimble, J.M. et al. Response of bone marrow stromal cells to adipogenic antagonists. Mol. Cell. Biol. 9, 4587–4595 (1989).

    Article  CAS  Google Scholar 

  13. Kelly, K.A., Tanaka, S., Baron, R. & Gimble, J.M. Murine bone marrow stromally derived BMS2 adipocytes support differentiation and function of osteoclast-like cells in vitro. Endocrinology 139, 2092–2101 (1998).

    Article  CAS  Google Scholar 

  14. Kincade, P.W., Medina, K., Pietrangeli, C.E., Hayashi, S-I. & Naemen, A.E. Stromal cell lines which support lymphocyte growth II. Characteristics of a suppressive subclone. Adv. Exp. Med. Biol. 292, 227–234 (1991).

    Article  CAS  Google Scholar 

  15. Oritani, K. et al. Both Stat3-activation and Stat3-independent BCL2 down-regulation are important for IL-6-induced apoptosis of 1A9-M cells. Blood 93, 1346–1354 (1999).

    CAS  PubMed  Google Scholar 

  16. Shaw, G.D. et al. Structure and expression of cloned murine IFN-αgenes. Nucleic Acids Res. 11, 555–573 (1983).

    Article  CAS  Google Scholar 

  17. Higashi, Y. et al. Structure and expression of a cloned cDNA for mouse interferon-β. J. Biol. Chem. 258, 9522–9529 (1983).

    CAS  PubMed  Google Scholar 

  18. Hauptmann, R. & Swetly, P. A novel class of human type I interferons. Nucleic Acids Res. 13, 4739–4749 (1985).

    Article  CAS  Google Scholar 

  19. Leaman, D.W. & Roberts, R.M. Genes for the trophoblast interferons in sheep, goat, and musk ox and distribution of related genes among mammals. J. Interferon Res. 12, 1–11 (1992).

    Article  CAS  Google Scholar 

  20. Whitlock, C.A., Robertson, D. & Witte, O.N. Murine B cell lymphopoiesis in long term culture. J. Immunol. Methods 6, 7353–7569 (1984).

    Google Scholar 

  21. Muller, U. et al. Functional role of type I and type II interferons in antiviral defence. Science 264, 1918–1921 (1994).

    Article  CAS  Google Scholar 

  22. Ihle, J.N. STATs: Signal transducers and activators of transcription. Cell 84, 331–334 (1996).

    Article  CAS  Google Scholar 

  23. Domanski, P. & Colamonici, O.R. The type-I interferon receptor. The long and short of it. Cytokine Growth Factor Rev. 7, 143–151. (1996).

    Article  CAS  Google Scholar 

  24. Zav'Yalov, V.P. & Zav'Yalov, G.A. Interferons alpha/beta and their receptors: place in the hierarchy of cytokines. APMIS 105, 161–186 (1997).

    Article  CAS  Google Scholar 

  25. Haque, S.J. & Williams, B.G. Signal transduction in the interferon system. Semin. Oncol. 25, 14–22 (1998).

    CAS  PubMed  Google Scholar 

  26. Velazquez, L., Felous, M., Stark, G.R. & Pellegrini, S. A protein tyrosine kinase in the interferonα/β signaling pathway. Cell 70, 313–322 (1992).

    Article  CAS  Google Scholar 

  27. Muller, M. et al. The protein tyrosine kinase JAK1 complements defects in interferon-α/β and -γ signal transduction. Nature 366, 129–135 (1993).

    Article  CAS  Google Scholar 

  28. Colamonici, O. et al. Direct binding to and tyrosine phosphorylation of the α subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol. Cell. Biol. 14, 8133–8142 (1994).

    Article  CAS  Google Scholar 

  29. Novick, D., Cohen, B. & Rubinstein, M. The human interferon alpha/beta receptor: Characterization and molecular cloning. Cell 77, 391–400 (1994).

    Article  CAS  Google Scholar 

  30. Rani, S.M.R. et al. Characterization of β-R1, a gene that is selectively induced by interferon-beta (IFN-β) compared with IFN-α. J. Biol. Chem. 271, 22878–22884 (1996).

    Article  CAS  Google Scholar 

  31. Platanias, L.C., Uddin, S., Domanski, P. & Colamonici, O.R. Differences in interferon α and β signaling. Interferon β selectively induces the interaction of the α and βL subunits of the type I interferon receptor. J. Biol. Chem. 271, 23630–23633 (1996).

    Article  CAS  Google Scholar 

  32. Abramovich, C. et al. Differential tyrosine phosphorylation of the IFNAR chain of the type I interferon receptor and an associated surface protein in response to IFN alpha and IFN beta. EMBO J. 13, 5871–5877 (1994).

    Article  CAS  Google Scholar 

  33. Borghesi, L.A., Smithson, G. & Kincade, P.W. Stromal cell modulation of negative regulatory signals that influence apoptosis and proliferation of B lineage lymphocytes. J. Immunol. 159, 4171–4179 (1997).

    CAS  PubMed  Google Scholar 

  34. Mazur, E.M., Richtsmeier, W.J. & South, K. Alpha-interferon: differential suppression of colony growth from human erythroid, myeloid, and megakaryocytic hematopoietic progenitor cells. J. Interferon Res. 6, 199–206 (1986).

    Article  CAS  Google Scholar 

  35. Grawunder, U., Melchers, F. & Rolink, A. Interferon- arrests proliferation and causes apoptosis in stromal cell/interleukin-7-dependent normal murine pre-B cell lines and clones in vitro, but does not induce differentiation to surface immunoglobulin-positive B cells. Eur. J. Immunol. 23, 544–551 (1993).

    Article  CAS  Google Scholar 

  36. Gimble, J.M., Medina, K., Hudson, J., Robinson, M. & Kincade, P.W. Modulation of lymphohematopoiesis in long-term cultures by gamma interferon: direct and indirect action on lymphoid and stromal cells. Exp. Hematol. 21, 224–230 (1993).

    CAS  PubMed  Google Scholar 

  37. Broxmeyer, H.E. Suppressor cytokines and regulation of myelopoiesis. Biology and possible clinical uses. Am. J. Pediatr. Hematol. Oncol. 14, 22–30 (1992).

    Article  CAS  Google Scholar 

  38. Lee, G., Ellingsworth, L.R., Gillis, S., Wall, R. & Kincade, P.W. β transforming growth factors are potential regulators of B lymphopoiesis. J. Exp. Med. 166, 1290–1299 (1987).

    Article  CAS  Google Scholar 

  39. Dorskind, K. IL-1 inhibits B cell differentiation in long term bone marrow cultures. J. Immunol. 141, 531–538 (1988).

    Google Scholar 

  40. Hirayama, F., Clark, S.C. & Ogawa, M. Negative regulation of early B lymphopoiesis by interleukin 3 and interleukin 1α. Proc. Natl. Acad. Sci. USA 91, 469–473 (1994).

    Article  CAS  Google Scholar 

  41. Medina, K. & Kincade, P.W. Pregnancy related steroids are potential negative regulators of B lymphopoiesis. Proc. Natl. Acad. Sci. USA 91, 5382–5386 (1994).

    Article  CAS  Google Scholar 

  42. Medina, K.L., Smithson, G. & Kincade, P.W. Suppression of B lymphopoiesis during normal pregnancy. J. Exp. Med. 178, 1507–1515 (1995).

    Article  Google Scholar 

  43. Smithson, G., Medina, K., Ponting, I. & Kincade, P.W. Estrogen suppresses stromal celldependent lymphopoiesis in culture. J. Immunol. 155, 3409–3417 (1995).

    CAS  PubMed  Google Scholar 

  44. Shimozato, T. & Kincade P.W. Indirect suppression of IL-7-responsive B cell precursors by vasoactive intestinal peptide. J. Immunol. 158, 5178–5184 (1997).

    CAS  PubMed  Google Scholar 

  45. Lengyel, P. Tumor-suppressor genes: new about the interferon connection. Proc. Natl. Acad. Sci. USA 90, 5893–5895 (1993).

    Article  CAS  Google Scholar 

  46. Taniguchi, T., Harada, H. & Lamphier, M. Regulation of the interferon system and cell growth by the IRF transcription factors. J. Cancer Res. Clin. Oncol. 121, 516–520 (1995).

    Article  CAS  Google Scholar 

  47. Nguyen, H., Hiscott, J. & Pitha, P.M. The growing family of interferon regulatory factors. Cytokine Growth Factor Rev. 8, 293–312 (1997).

    Article  CAS  Google Scholar 

  48. Tamura, T. et al. An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes. Nature 376, 596–599 (1995).

    Article  CAS  Google Scholar 

  49. Kirchoff, S. et al. IRF-1 induced cell growth inhibition and interferon induction requires the activity of the protein kinase PKR. Oncogene 11, 439–445 (1995).

    Google Scholar 

  50. Kimura, T. et al. Involvement of the IRF-1 transcription factor in antiviral responses to interferons. Science 264, 1921–1924 (1994).

    Article  CAS  Google Scholar 

  51. Itri, L.M. The interferon. Cancer 70, 940–945 (1992).

    CAS  PubMed  Google Scholar 

  52. Weiss, K. Safety profile of interferon-αtherapy. Semin. Oncolo. 25, 9–13 (1998).

    CAS  Google Scholar 

  53. Oritani, K. & Kincade, P.W. Identification of stromal cell products that interact with pre-B cells. J. Cell Biol. 134, 771–782 (1996).

    Article  CAS  Google Scholar 

  54. Yokota, T. et al. Growth-supporting activities of fibronectin on hematopoietic stem/progenitor cells in vitro and in vivo: structural requirement for fibronectin activities of CS1 and cell-binding domains. Blood 91, 3263–3272 (1998).

    CAS  PubMed  Google Scholar 

  55. Dexter, T.M. & Testa, N.G. Differentiation and proliferation of hemopoietic cells in culture. Methods Cell Biol. 14, 387–405 (1976).

    Article  CAS  Google Scholar 

  56. Tomiyama, Y. et al. The Arg-Gly-Asp (RGD) recognition site of platelet glycoprotein Iib-IIIa on nonactivated platelets is accessible to high-affinity macromolecules. Blood 79, 2303–2312 (1992).

    CAS  PubMed  Google Scholar 

  57. Matsumura, I. et al. Thrombopoietin-induced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21WAF1/Cip1 by STAT5. Mol. Cell. Biol. 17, 2933–2943 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by grants from the Yamanouchi Foundation for Research on Metabolic Disorders, the Kowa Life Science Foundation, the Ministry of Education, Science and Culture of Japan and the Japan Society for the Promotion of Science as well as grants AI-33085 and AI-20069 from the National Institutes of Health.

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  1. Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita City, 565-0871, Osaka, Japan

    Kenji Oritani, Yoshiaki Tomiyama, Jun Ishikawa, Yu Okajima, Megumu Ogawa, Takahumi Yokota, Keisuke Aoyama, Isao Takahashi & Yuji Matsuzawa

  2. Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, 73104, Oklahoma, USA

    Kay L. Medina & Paul W. Kincade

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Oritani, K., Medina, K., Tomiyama, Y. et al. Limitin: An interferon-like cytokine that preferentially influences B-lymphocyte precursors. Nat Med 6, 659–666 (2000). https://doi.org/10.1038/76233

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