Advertisement

Neural Regulation of Hematopoiesis by the Tachykinins

Implications for a “Fine Tuned” Hematopoietic Regulation
  • Pranela Rameshwar
  • Pedro Gascón

Abstract

The neuromodulators/neurotransmitters, substance P (SP) and neurokinin-A (NK-A) belong to the tachykinin family. Both peptides are widely distributed in the central and peripheral nervous systems. Although lymphoid organs such as the bone marrow (BM) are innervated by peptidergic fibers, non-neural sources for these peptides are possible. Specific cells (endothelial, macrophages and eosinophils) produce SP. In addition, we have found that cytokines induce SP-immunoreactivity (SP-IR) in BM stroma. Although both peptides interact with each of the three cloned NK- receptors (NK-1R, NK-2R, NK-3R), SP and NK-A exhibit preferences for NK-1R and NK-2R respectively. SP and NK-A interact with the G-protein coupled NK-like receptors on hematopoietic cells (CD34+, stroma) to regulate hematopoiesis. Our data indicate the presence of NK-1 and NK-2 like receptors, as well as subtypes of these receptors in BM cells. We have reported that SP stimulates in vitro hematopoiesis (erythroid and myeloid). Compared to SP, NK-A is less stimulatory to erythroid and inhibits myeloid colonies. The regulatory effects by the tachykinins are partly determined by the particular type of NK-Rs being stimulated. NK-1R appears to mediate a stimulatory response whereas, NK-2R inhibits hematopoiesis. Most of the effects by the tachykinins are indirect through the induction of growth factors. We have shown that SP induces IL-1, IL-3, IL-6, GM-CSF and c-kit ligand in BM cells and NK-A induces MlP-1α and TGF-ß. Our data indicate that the stroma is involved in most of the tachykinin-mediated effects through the induction of cytokines which in turn regulate the induction, expression and binding affinities of NK-R on BM cells. These studies suggest that the tachykinins can mediate a network of regulatory interactions among BM cells and, that this can lead to “fine-tuned” hematopoiesis. The results also provide evidence that in addition to being neuro-transmitters/-modulators, the tackykinins may be a link of a putative neurohematopoietic axis.

Keywords

Vasoactive Intestinal Peptide Neural Regulation Bone Marrow Microenvironment Bone Marrow Stroma Bone Marrow Cavity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    . Savino W, Dardenne M: Immune-neuroendocrine interactions. Immunol Today16: 318, 1995.PubMedCrossRefGoogle Scholar
  2. 2.
    . Blalock JE: The syntax of immune-neuroendocrine communications. Immunol Today15: 503, 1994.CrossRefGoogle Scholar
  3. 3.
    . Miller ML, McCuskey RS: Innervation of bone marrow in the rabbit. Scand J Haematol10: 17, 1973.PubMedCrossRefGoogle Scholar
  4. 4.
    . Felten LD, Felten YS, Ackerman DK, Bellinger DL, Kelly SM, Carlson SL, Livnat S: Peripheral innervation of lymphoid tissue, in Neuroendocrine-Immune Network (Freier S, ed), CRC, Boca Raton, pp 9, 1990.Google Scholar
  5. 5.
    . Weihe E, Nohr D, Michel S, Müller S, Zentel H-J, Fink T, Krekel J: Molecular anatomy of the neuro-immune connection. Intern J Neurosci 59: 1, 1991.CrossRefGoogle Scholar
  6. 6.
    . Felten SY, Felten DL, Bellinger DL, Olschowka JA: Noradrenergic and peptidergic innervation of lymphoid organs, in Neuroimmunoendocrinology(Blalock JE, ed) Karger, Basel pp 25, 1992.CrossRefGoogle Scholar
  7. 7.
    . Yamazaki K, Allen TD: Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: The “Neuro-Reticular Complex”. Am J Anat 187: 261, 1990.PubMedCrossRefGoogle Scholar
  8. 8.
    . Calvo W: The innervation of the bone marrow in laboratory animals. Am J Anat 123: 315, 1986.CrossRefGoogle Scholar
  9. 9.
    . Maggi CA, Giachetti A, Dey RD, Said SI: Neuropeptides as regulators of airway function: Vasoactive intestinal peptide and the tachykinins. Physiol Rev 75: 277, 1995.PubMedGoogle Scholar
  10. 10.
    . Bulloch K: Neuroanatomy of lymphoid tissue: a review, in Neural Modulation of Immunity. (Guillemin et al, eds.). Raven Press, NY, p 11, 1985.Google Scholar
  11. 11.
    . Pernow B: Substance P. Pharmacol Rev 35: 85, 1983.PubMedGoogle Scholar
  12. 12.
    . Krause JE, Chirgwin JM, Carter MS, Xu ZS, Hershey D: Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A. Proc Natl Acad Sci USA 84: 881, 1987.PubMedCrossRefGoogle Scholar
  13. 13.
    . Khan I, Collins SM: Fourth isoform of preprotachykinin messenger RNA encoding for substance P in the rat intestine. Biochem Biophy Res Commun 202: 796, 1994.CrossRefGoogle Scholar
  14. 14.
    . Gerard NP, Bao L, Ping HX, Gerard C: Molecular aspects of the tachykinin receptors. Regul Pept 43: 21, 1993.PubMedCrossRefGoogle Scholar
  15. 15.
    . Patacchini R, Maggi CA: Tachykinin receptors and receptor subtypes. Arch Int Pharmacodyn 329: 161, 1995.PubMedGoogle Scholar
  16. 16.
    . Kavelaars A, Broeke D, Jeurissen F, Kardux J, Meijer A, Franklin R, Gelfand EW, Heijnen CJ: Activation of human monocytes via a non-neurokinin substance P receptor that is coupled to Gi protein, calcium, phospholipase D, MAP kinase, and IL-6 production. J Immunol153: 3691, 1994.PubMedGoogle Scholar
  17. 17.
    . Payan DG: The role of neuropeptides in inflammation, in Inflammation: Basic principles and clinical correlates(Gallin R et al, eds), Ravel Press, NY, pp 177, 1992.Google Scholar
  18. 18.
    . Bost KL, Pascual DW: Substance P: a late-acting B lymphocyte differentiation cofactor. Am Physiol Soc 31: C537, 1992.Google Scholar
  19. 19.
    . Rameshwar P, Ganea D, Gascón P: In vitrostimulatory effect of substance P on hematopoiesis. Blood 81: 391, 1993.PubMedGoogle Scholar
  20. 20.
    . Rameshwar P, Ganea D, Gascón P: Induction of IL-3 and granulocyte-macrophage colony-stimulating factor by substance P in bone marrow cells is partially mediated through the release of IL-1 and IL-6. J Immunol 152: 4044, 1994.PubMedGoogle Scholar
  21. 21.
    . Rameshwar P, Gascón 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, 1995.PubMedGoogle Scholar
  22. 22.
    . Lotz M, Vaughan JH, Carson DA: Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 241: 1218, 1988.PubMedCrossRefGoogle Scholar
  23. 23.
    . Rameshwar P, Gascón P, Ganea D: Stimulation of interleukin 2 production in murine lymphocytes by substance P and related tachykinins. J Immunol 151: 2484, 1993.PubMedGoogle Scholar
  24. 24.
    . Wagner F, Fink R, Hart R, Dancygier H: Substance P enhances interferon-g production by human peripheral blood mononuclear cells. Regulat Peptides 19: 355, 1987.CrossRefGoogle Scholar
  25. 25.
    . Pascual DW, Bost KL: Substance P production by P388D1 macrophages: a possible autocrine function for this neuropeptide. Immunology 71: 52, 1990.PubMedGoogle Scholar
  26. 26.
    . Rameshwar P, Gascón P: Regulation of substance-P (SP)-like receptors in CD34+ cells by cytokines and neurotrophic factors. FASEB J 1432: A248, 1994.Google Scholar
  27. 27.
    . Rameshwar P, Gascon P: Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma. Blood 88: 98, 1996.PubMedGoogle Scholar
  28. 28.
    . Freidin M, Kessler JA: Cytokine regulation of substance P expression in sympathetic neurons. Proc Natl Acad Sci USA 88: 3200, 1991.PubMedCrossRefGoogle Scholar
  29. 29.
    . Hart RP, Shadiack AM, Jonakait GM: Substance P gene expression is regulated by interleukin-1 in cultured sympathetic ganglia. J Neurosci Res 29: 282, 1991.PubMedCrossRefGoogle Scholar
  30. 30.
    . Curtis R, Krystyna MA, Yuan Z, Harkness PJ, Lindsay RM, DeStefano PS: Retrograde axonal transport of ciliary neurotrophic factor is increased by peripheral nerve injury. Nature 365: 253, 1993.PubMedCrossRefGoogle Scholar
  31. 31.
    . JeanJean AP, Moussaaoui SM, Maloteaux JM, Laduron PM: Interleukin-1ß induces long-term increase of axonally transported opiate receptors and substance P. Neuroscience 68: 151, 1995.PubMedCrossRefGoogle Scholar
  32. 32.
    . Patterson PH, Nawa H. 1993. Neuronal differentiation factors cytokines and synaptic plasticity. Cell 72/Neuron 10 (Suppl): 123.Google Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • Pranela Rameshwar
    • 1
    • 2
  • Pedro Gascón
    • 1
  1. 1.UMDNJ-New Jersey Medical SchoolDepartment of Medicine Division of HematologyNewarkUSA
  2. 2.UMDNJ- New Jersey Medical SchoolNewarkUSA

Personalised recommendations