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Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis

Nature Immunology volume 1, pages 392–397 (2000)Cite this article

Abstract

We report here the molecular cloning of a newly identified preprotachykinin gene, Pptc, which specifies the sequence for a new preprotachykinin protein and bioactive peptide designated hemokinin 1 (HK-1). PPT-C mRNA was detected primarily in hematopoietic cells in contrast to the previously described Ppta and Pptb genes, which are predominantly expressed in neuronal tissues. HK-1 has several biological activities that are similar to the most studied tachykinin, substance P, such as induction of plasma extravasation and mast cell degranulation. However, HK-1 also has properties that are indicative of a critical role in mouse B cell development. HK-1 stimulated the proliferation of interleukin 7–expanded B cell precursors, whereas substance P had no effect. HK-1, but not substance P, promoted the survival of freshly isolated bone marrow B lineage cells or cultured, lipopolysaccharide-stimulated pre-B cells. N-acetyl-l-trytophan-3,5-bistrifluromethyl benzyl ester, a tachykinin receptor antagonist, increased apoptosis of these cells and in vivo administration of this antagonist led to specific reductions of the B220lowCD43− population (the pre-B cell compartment) in the bone marrow and the IgMhighIgDlow population (the newly generated B cells) in the spleen. Thus, HK-1 may be an autocrine factor that is important for the survival of B cell precursors at a critical phase of development.

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Figure 1: Sequences of PPT-C and HK-1.
Figure 2: Expression of the Pptc gene.
Figure 3: Decreased expression of PPT-C in, and protective effect of HK-1 on,70Z/3 following LPS stimulation.
Figure 4: Enhanced survival and proliferation of primary B lineage cells by HK-1.
Figure 5: FACS analysis of bone marrow and spleen cells from tachykinin antagonist–treated mice.

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References

  1. Bertaccini, G. Active polypeptides of non-mammalian origin. Pharmacol. Rev. 28, 127–177 (1976).

    CAS  PubMed  Google Scholar 

  2. Erspamer, V. The tachykinin peptide family. Trends Neurosci. 4, 267–269 (1981).

    Article  CAS  Google Scholar 

  3. von Euler, U. S. & Gaddum, J. H. An unidentified depressor in certain tissue extracts. J. Physiol. 72 , 74–87 (1931).

    Article  Google Scholar 

  4. Chang, M. M., Leeman, S. E. & Niall H. D. Amino acid sequence of substance P. Nature 232, 86–87 ( 1971).

    Article  CAS  Google Scholar 

  5. Kimura, S., Okada, M., Sugita, Y., Kanazawa, I. & Muneketa, E. Novel neuropeptides, neurokinin α and β, isolated from porcine spinal cord. Proc. Jpn. Acad. B 59, 101–104 (1983).

    Article  CAS  Google Scholar 

  6. Kangawa, K., Minamino, N., Fukuda, A. & Matsuo, H. Neuromedin K: a novel mammalian tachykinin identified in porcine spinal cord. Biochem. Biophys. Res. Commun. 114, 533– 540 (1983).

    Article  CAS  Google Scholar 

  7. Nawa, H., Doteuchi, M., Igano, K., Inouye, K. & Nakanishi, S. Substance K, a novel mammalian tachykinin that differs from substance P in its pharmacological profiles. Life Sci. 34, 1153–1160 (1984).

    Article  CAS  Google Scholar 

  8. Douglass, J., Civelli, O. & Herbert, E. Polyprotein gene expression: generation of diversity of neuroendocrine peptides. Annu. Rev. Biochem. 53, 665–715 (1984).

    Article  CAS  Google Scholar 

  9. Harris, R. B. Processing of prehormone precursor proteins. Arch. Biochem. Biophys. 275, 315–333 ( 1989).

    Article  CAS  Google Scholar 

  10. Nawa, H., Hirose, T., Takashima, H., Inayama, S. & Nakanishi, S. Nucleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor. Nature 306, 32–36 ( 1983).

    Article  CAS  Google Scholar 

  11. Kotani, H., Hoshimaru, M., Nawa, H. & Nakanishi, S. Structure and gene organization of bovine neuromedin K precursor. Proc. Natl Acad. Sci. USA 83, 7074–7078 (1986).

    Article  CAS  Google Scholar 

  12. Regoli, D., Boudon, A. & Fauchere, L. -L. Receptors and antagonists for substance P and related peptides. Pharmacol. Rev. 46, 551– 599 (1994).

    CAS  PubMed  Google Scholar 

  13. Cao, Y. Q. et al. I. Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392, 390 –394 (1998).

    Article  CAS  Google Scholar 

  14. Zimmer, A. et al. Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc. Natl Acad. Aci. USA 95, 2630 –2635 (1998).

    Article  CAS  Google Scholar 

  15. De Felipe, C. et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392, 394–397 (1998).

    Article  CAS  Google Scholar 

  16. Bozic, C. R., Lu, B., Hopken, U. E., Gerard, C. & Gerard, N. P. Neurogenic amplification of immune complex inflammation . Science 273, 1722–1725 (1996).

    Article  CAS  Google Scholar 

  17. Castagliuolo, I. et al. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile-induced enteritis. J. Clin. Invest. 101 , 1547–1550 (1998).

    Article  CAS  Google Scholar 

  18. Bhatia, M. et al. Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. Proc. Natl Acad. Sci. USA 95, 4760–4765 (1998).

    Article  CAS  Google Scholar 

  19. Rameshwar, P., Ganea, D. & Gascon, P. In vitro stimulatory effect of substance P on hematopoiesis . Blood 81, 391–398 (1993).

    CAS  PubMed  Google Scholar 

  20. Rameshwar, P. & Gascon, P. Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma. Blood 88, 98–106 (1996).

    CAS  PubMed  Google Scholar 

  21. Rameshwar, P. & Gascon, P. Substance P (SP) mediates production of stem cell factor and interleukin-1 in bone marrow stroma: potential autoregulatory role for these cytokines in SP receptor expression and induction. Blood 86, 482–290 ( 1995).

    CAS  PubMed  Google Scholar 

  22. Manske, J. M., Sullivan, E. L. & Anderson, S. M. Substance P mediated stimulation of cytokine levels in cultured mruine bone marrow stromal cells. Adv. Exp. Med. Biol. 383, 53–64 ( 1995).

    Article  CAS  Google Scholar 

  23. Paige, C. J., Kincade, P. W. & Ralph, P. Murine B cell leukemia line with inducible surface immunoglobulin expression. J. Immunol. 121, 641– 647 (1981).

    Google Scholar 

  24. MacLeod, A. M. et al. N-acyl-l-tryptophan benzyl esters: potent substance P receptor antagonists. J. Med. Chem. 36, 2044–2045 (1993).

    Article  CAS  Google Scholar 

  25. Cascieri, M. A. et al. Characterization of the interaction of N-acyl- l-tryptophan benzyl ester neurokinin antagonists with the human neurokinin-1 receptor. J. Biol. Chem. 269, 6587– 6591 (1994).

    CAS  PubMed  Google Scholar 

  26. Seabrook, G. U. et al. L-733,060, a novel tachykinin NK1 receptor antagonist; effects in [Ca2+]i mobilisation, cardiovascular and dural extravasation assays. Eur. J. Pharmacol. 317, 129–135 (1996).

    Article  CAS  Google Scholar 

  27. ten Botekel, E., Yamagami, T., Andersson J., Rolink, A. G. & Melchers, F. The formation and selection of cells expressing preB cell receptors and B cell receptors. Curr. Top. Microbiol. Immunol. 246, 3–9 (1999).

    Google Scholar 

  28. Pillai, S. The chosen few? Positive selection and the generation of naive B lymphocytes . Immunity 10, 493–502 (1999).

    Article  CAS  Google Scholar 

  29. Nussenzweig, M. C. Immune receptor editing: revise and select. Cell 95 , 875–878 (1998).

    Article  CAS  Google Scholar 

  30. Rajewsky, K. Clonal selection and learning in antibody system. Nature 381, 751–758 (1996).

    Article  CAS  Google Scholar 

  31. Fischer, A. & Malissen, B. Natural and engineered disorders of lymphocyte development. Science 280, 237–243 (1998).

    Article  CAS  Google Scholar 

  32. Conley, M. E. & Cooper, M. D. Genetic basis of abnormal B cell development. Curr. Opin. Immunol. 10, 399 –406 (1998).

    Article  CAS  Google Scholar 

  33. von Freeden-Feffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).

    Article  Google Scholar 

  34. Peschon, J. J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994).

    Article  CAS  Google Scholar 

  35. Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2, 223–238 (1995).

    Article  CAS  Google Scholar 

  36. DiSanto, J. P., Muller, W., Guy-Grand, D., Fischer, A. & Rajewsky, K. Lymphoid development in mice with a targeted deletion of the interleukin-2 receptor γ chain. Proc. Natl Acad. Sci. USA 92, 377– 381 (1995).

    Article  CAS  Google Scholar 

  37. Thomis, D. C., Gurniak, C. B., Tivol, E., Sharpe, A. H. & Berg, L. J. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270, 794–797 (1995).

    Article  CAS  Google Scholar 

  38. Nosaka, T. et al. Defective lymphoid development in mice lacking Jak3. Science 270, 800–802 ( 1995).

    Article  CAS  Google Scholar 

  39. Grabstein, K. H. et al. Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody. J. Exp. Med. 178, 257–264 (1993).

    Article  CAS  Google Scholar 

  40. Masu, Y. et al. cDNA cloning of substance K receptor through oocyte expression system. Nature 329, 836– 838 (1987).

    Article  CAS  Google Scholar 

  41. Yokota, Y. et al. Molecular characterization of a functional cDNA for rat substance P receptor. J. Biol. Chem. 264, 17649– 17652 (1989).

    CAS  PubMed  Google Scholar 

  42. Shigemoto, R., Yokota, Y., Tsuchida, K. & Nakanishi, S. Cloning and expression of a rat neuromedin K receptor cDNA. J. Biol. Chem. 265, 623–628 ( 1990).

    CAS  PubMed  Google Scholar 

  43. Lemback, F. & Holzer, P. Substance P as neurogenic mediator of antidromic vasodilatation and neurogenic plasma extravasation. Naunyn Schmiedebergs Arch. Pharmacol. 310, 175– 183 (1979).

    Article  Google Scholar 

  44. Devillier, P., Renoux, M., Giroud, J. P. & Regoli, D. Peptides and histamine release from rat peripheral mast cells. Eur. J. Pharmacol. 117, 89–96 (1985).

    Article  CAS  Google Scholar 

  45. Stoddart, A., Zhang, Y. & Paige, C. J. Molecular cloning of the cDNA encoding a murine sialic acid-specific 9-O-acetylesterase and RNA expression in cells of hematopoietic and nonhematopoietic origin. Nucleic Acids Res. 20, 4003–4008 (1996).

    Article  Google Scholar 

  46. Lu, L. & Osmond, D. G. Apoptosis during B lymphopoiesis in mouse bone marrow. J. Immunol. 158, 5136 –5145 (1997).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by the National Cancer Institute of Canada with funds from the Terry Fox Foundation, and the Canadian Institutes for Health Research.

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  1. Princess Margaret Hospital University Health Network and Department of Medical Biophysics and Immunology University of Toronto, Ontario Cancer Institute, Toronto, M5G 2M9, Ontario, Canada

    Yu Zhang, Liwei Lu, Caren Furlonger, Gillian E. Wu & Christopher J. Paige

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Correspondence to Christopher J. Paige.

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Zhang, Y., Lu, L., Furlonger, C. et al. Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis . Nat Immunol 1, 392–397 (2000). https://doi.org/10.1038/80826

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