Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Apr 26;91(9):3739–3743. doi: 10.1073/pnas.91.9.3739

Mast cells synthesize, store, and release nerve growth factor.

A Leon 1, A Buriani 1, R Dal Toso 1, M Fabris 1, S Romanello 1, L Aloe 1, R Levi-Montalcini 1
PMCID: PMC43657  PMID: 8170980

Abstract

Mast cells and nerve growth factor (NGF) have both been reported to be involved in neuroimmune interactions and tissue inflammation. In many peripheral tissues, mast cells interact with the innervating fibers. Changes in the behaviors of both of these elements occur after tissue injury/inflammation. As such conditions are typically associated with rapid mast cell activation and NGF accumulation in inflammatory exudates, we hypothesized that mast cells may be capable of producing NGF. Here we report that (i) NGF mRNA is expressed in adult rat peritoneal mast cells; (ii) anti-NGF antibodies clearly stain vesicular compartments of purified mast cells and mast cells in histological sections of adult rodent mesenchymal tissues; and (iii) medium conditioned by peritoneal mast cells contains biologically active NGF. Mast cells thus represent a newly recognized source of NGF. The known actions of NGF on peripheral nerve fibers and immune cells suggest that mast cell-derived NGF may control adaptive/reactive responses of the nervous and immune systems toward noxious tissue perturbations. Conversely, alterations in normal mast cell behaviors may provoke maladaptive neuroimmune tissue responses whose consequences could have profound implications in inflammatory disease states, including those of an autoimmune nature.

Full text

PDF
3739

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aloe L., De Simone R. NGF primed spleen cells injected in brain of developing rats differentiate into mast cells. Int J Dev Neurosci. 1989;7(6):565–573. doi: 10.1016/0736-5748(89)90015-4. [DOI] [PubMed] [Google Scholar]
  2. Aloe L., Leon A., Levi-Montalcini R. A proposed autacoid mechanism controlling mastocyte behaviour. Agents Actions. 1993;39(Spec No):C145–C147. doi: 10.1007/BF01972748. [DOI] [PubMed] [Google Scholar]
  3. Aloe L., Levi-Montalcini R. Mast cells increase in tissues of neonatal rats injected with the nerve growth factor. Brain Res. 1977 Sep 16;133(2):358–366. doi: 10.1016/0006-8993(77)90772-7. [DOI] [PubMed] [Google Scholar]
  4. Aloe L., Tuveri M. A., Carcassi U., Levi-Montalcini R. Nerve growth factor in the synovial fluid of patients with chronic arthritis. Arthritis Rheum. 1992 Mar;35(3):351–355. doi: 10.1002/art.1780350315. [DOI] [PubMed] [Google Scholar]
  5. Bienenstock J., Tomioka M., Matsuda H., Stead R. H., Quinonez G., Simon G. T., Coughlin M. D., Denburg J. A. The role of mast cells in inflammatory processes: evidence for nerve/mast cell interactions. Int Arch Allergy Appl Immunol. 1987;82(3-4):238–243. doi: 10.1159/000234197. [DOI] [PubMed] [Google Scholar]
  6. Bischoff S. C., Dahinden C. A. Effect of nerve growth factor on the release of inflammatory mediators by mature human basophils. Blood. 1992 May 15;79(10):2662–2669. [PubMed] [Google Scholar]
  7. Blennerhassett M. G., Tomioka M., Bienenstock J. Formation of contacts between mast cells and sympathetic neurons in vitro. Cell Tissue Res. 1991 Jul;265(1):121–128. doi: 10.1007/BF00318146. [DOI] [PubMed] [Google Scholar]
  8. Bracci-Laudiero L., Aloe L., Levi-Montalcini R., Galeazzi M., Schilter D., Scully J. L., Otten U. Increased levels of NGF in sera of systemic lupus erythematosus patients. Neuroreport. 1993 May;4(5):563–565. doi: 10.1097/00001756-199305000-00025. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Davies A. M., Bandtlow C., Heumann R., Korsching S., Rohrer H., Thoenen H. Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor. 1987 Mar 26-Apr 1Nature. 326(6111):353–358. doi: 10.1038/326353a0. [DOI] [PubMed] [Google Scholar]
  11. Diamond J., Coughlin M., Macintyre L., Holmes M., Visheau B. Evidence that endogenous beta nerve growth factor is responsible for the collateral sprouting, but not the regeneration, of nociceptive axons in adult rats. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6596–6600. doi: 10.1073/pnas.84.18.6596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Donaldson L. F., Harmar A. J., McQueen D. S., Seckl J. R. Increased expression of preprotachykinin, calcitonin gene-related peptide, but not vasoactive intestinal peptide messenger RNA in dorsal root ganglia during the development of adjuvant monoarthritis in the rat. Brain Res Mol Brain Res. 1992 Nov;16(1-2):143–149. doi: 10.1016/0169-328x(92)90204-o. [DOI] [PubMed] [Google Scholar]
  13. Donnerer J., Schuligoi R., Stein C. Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo. Neuroscience. 1992 Aug;49(3):693–698. doi: 10.1016/0306-4522(92)90237-v. [DOI] [PubMed] [Google Scholar]
  14. Dubner R., Ruda M. A. Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci. 1992 Mar;15(3):96–103. doi: 10.1016/0166-2236(92)90019-5. [DOI] [PubMed] [Google Scholar]
  15. Dvorak A. M., Silen W. Differentiation between Crohn's disease and other inflammatory conditions by electron microscopy. Ann Surg. 1985 Jan;201(1):53–63. [PMC free article] [PubMed] [Google Scholar]
  16. Friedman W. J., Lärkfors L., Ayer-LeLievre C., Ebendal T., Olson L., Persson H. Regulation of beta-nerve growth factor expression by inflammatory mediators in hippocampal cultures. J Neurosci Res. 1990 Nov;27(3):374–382. doi: 10.1002/jnr.490270316. [DOI] [PubMed] [Google Scholar]
  17. Galli S. J., Dvorak A. M., Dvorak H. F. Basophils and mast cells: morphologic insights into their biology, secretory patterns, and function. Prog Allergy. 1984;34:1–141. [PubMed] [Google Scholar]
  18. Garry M. G., Hargreaves K. M. Enhanced release of immunoreactive CGRP and substance P from spinal dorsal horn slices occurs during carrageenan inflammation. Brain Res. 1992 Jun 5;582(1):139–142. doi: 10.1016/0006-8993(92)90328-7. [DOI] [PubMed] [Google Scholar]
  19. Gold B. G., Mobley W. C., Matheson S. F. Regulation of axonal caliber, neurofilament content, and nuclear localization in mature sensory neurons by nerve growth factor. J Neurosci. 1991 Apr;11(4):943–955. doi: 10.1523/JNEUROSCI.11-04-00943.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gordon J. R., Burd P. R., Galli S. J. Mast cells as a source of multifunctional cytokines. Immunol Today. 1990 Dec;11(12):458–464. doi: 10.1016/0167-5699(90)90176-a. [DOI] [PubMed] [Google Scholar]
  21. Hattori A., Tanaka E., Murase K., Ishida N., Chatani Y., Tsujimoto M., Hayashi K., Kohno M. Tumor necrosis factor stimulates the synthesis and secretion of biologically active nerve growth factor in non-neuronal cells. J Biol Chem. 1993 Feb 5;268(4):2577–2582. [PubMed] [Google Scholar]
  22. Horigome K., Pryor J. C., Bullock E. D., Johnson E. M., Jr Mediator release from mast cells by nerve growth factor. Neurotrophin specificity and receptor mediation. J Biol Chem. 1993 Jul 15;268(20):14881–14887. [PubMed] [Google Scholar]
  23. Johnson D., Krenger W. Interactions of mast cells with the nervous system--recent advances. Neurochem Res. 1992 Sep;17(9):939–951. doi: 10.1007/BF00993271. [DOI] [PubMed] [Google Scholar]
  24. Korsching S. The neurotrophic factor concept: a reexamination. J Neurosci. 1993 Jul;13(7):2739–2748. doi: 10.1523/JNEUROSCI.13-07-02739.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Laudiero L. B., Aloe L., Levi-Montalcini R., Buttinelli C., Schilter D., Gillessen S., Otten U. Multiple sclerosis patients express increased levels of beta-nerve growth factor in cerebrospinal fluid. Neurosci Lett. 1992 Nov 23;147(1):9–12. doi: 10.1016/0304-3940(92)90762-v. [DOI] [PubMed] [Google Scholar]
  26. Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987 Sep 4;237(4819):1154–1162. doi: 10.1126/science.3306916. [DOI] [PubMed] [Google Scholar]
  27. Lewin G. R., Ritter A. M., Mendell L. M. Nerve growth factor-induced hyperalgesia in the neonatal and adult rat. J Neurosci. 1993 May;13(5):2136–2148. doi: 10.1523/JNEUROSCI.13-05-02136.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lindsay R. M., Harmar A. J. Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons. Nature. 1989 Jan 26;337(6205):362–364. doi: 10.1038/337362a0. [DOI] [PubMed] [Google Scholar]
  29. Mallat M., Houlgatte R., Brachet P., Prochiantz A. Lipopolysaccharide-stimulated rat brain macrophages release NGF in vitro. Dev Biol. 1989 May;133(1):309–311. doi: 10.1016/0012-1606(89)90322-9. [DOI] [PubMed] [Google Scholar]
  30. Marshall J. S., Stead R. H., McSharry C., Nielsen L., Bienenstock J. The role of mast cell degranulation products in mast cell hyperplasia. I. Mechanism of action of nerve growth factor. J Immunol. 1990 Mar 1;144(5):1886–1892. [PubMed] [Google Scholar]
  31. Matsuda H., Kannan Y., Ushio H., Kiso Y., Kanemoto T., Suzuki H., Kitamura Y. Nerve growth factor induces development of connective tissue-type mast cells in vitro from murine bone marrow cells. J Exp Med. 1991 Jul 1;174(1):7–14. doi: 10.1084/jem.174.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mayrhofer G. Fixation and staining of granules in mucosal mast cells and intraepithelial lymphocytes in the rat jejunum, with special reference to the relationship between the acid glycosaminoglycans in the two cell types. Histochem J. 1980 Sep;12(5):513–526. doi: 10.1007/BF01011925. [DOI] [PubMed] [Google Scholar]
  33. Mousli M., Bronner C., Bueb J. L., Tschirhart E., Gies J. P., Landry Y. Activation of rat peritoneal mast cells by substance P and mastoparan. J Pharmacol Exp Ther. 1989 Jul;250(1):329–335. [PubMed] [Google Scholar]
  34. Murphy R. A., Acheson A., Hodges R., Haskins J., Richards C., Reklow E., Chlumecky V., Barker P. A., Alderson R. F., Lindsay R. M. Immunological relationships of NGF, BDNF, and NT-3: recognition and functional inhibition by antibodies to NGF. J Neurosci. 1993 Jul;13(7):2853–2862. doi: 10.1523/JNEUROSCI.13-07-02853.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Naukkarinen A., Harvima I., Paukkonen K., Aalto M. L., Horsmanheimo M. Immunohistochemical analysis of sensory nerves and neuropeptides, and their contacts with mast cells in developing and mature psoriatic lesions. Arch Dermatol Res. 1993;285(6):341–346. doi: 10.1007/BF00371834. [DOI] [PubMed] [Google Scholar]
  36. Newson B., Dahlström A., Enerbäck L., Ahlman H. Suggestive evidence for a direct innervation of mucosal mast cells. Neuroscience. 1983 Oct;10(2):565–570. doi: 10.1016/0306-4522(83)90153-7. [DOI] [PubMed] [Google Scholar]
  37. Näher-Noé M., Gnahn H., Grundler A., Klingelhöfer J., Weindl A., Conrad B. Determination of nerve growth factor concentrations in human samples by two-site immunoenzymometric assay and bioassay. Eur J Clin Chem Clin Biochem. 1993 Jun;31(6):375–380. doi: 10.1515/cclm.1993.31.6.375. [DOI] [PubMed] [Google Scholar]
  38. Olsson Y. Mast cells in the nervous system. Int Rev Cytol. 1968;24:27–70. doi: 10.1016/s0074-7696(08)61396-0. [DOI] [PubMed] [Google Scholar]
  39. Otten U., Ehrhard P., Peck R. Nerve growth factor induces growth and differentiation of human B lymphocytes. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10059–10063. doi: 10.1073/pnas.86.24.10059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ratzlaff R. E., Cavanaugh V. J., Miller G. W., Oakes S. G. Evidence of a neurogenic component during IgE-mediated inflammation in mouse skin. J Neuroimmunol. 1992 Nov;41(1):89–96. doi: 10.1016/0165-5728(92)90199-u. [DOI] [PubMed] [Google Scholar]
  41. Scarisbrick I. A., Jones E. G., Isackson P. J. Coexpression of mRNAs for NGF, BDNF, and NT-3 in the cardiovascular system of the pre- and postnatal rat. J Neurosci. 1993 Mar;13(3):875–893. doi: 10.1523/JNEUROSCI.13-03-00875.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Skofitsch G., Savitt J. M., Jacobowitz D. M. Suggestive evidence for a functional unit between mast cells and substance P fibers in the rat diaphragm and mesentery. Histochemistry. 1985;82(1):5–8. doi: 10.1007/BF00502084. [DOI] [PubMed] [Google Scholar]
  43. Stead R. H., Kosecka-Janiszewska U., Oestreicher A. B., Dixon M. F., Bienenstock J. Remodeling of B-50 (GAP-43)- and NSE-immunoreactive mucosal nerves in the intestines of rats infected with Nippostrongylus brasiliensis. J Neurosci. 1991 Dec;11(12):3809–3821. doi: 10.1523/JNEUROSCI.11-12-03809.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Söderström S., Hallbök F., Ibáez C. F., Persson H., Ebendal T. Recombinant human beta-nerve growth factor (NGF): biological activity and properties in an enzyme immunoassay. J Neurosci Res. 1990 Dec;27(4):665–677. doi: 10.1002/jnr.490270427. [DOI] [PubMed] [Google Scholar]
  45. Taiwo Y. O., Levine J. D., Burch R. M., Woo J. E., Mobley W. C. Hyperalgesia induced in the rat by the amino-terminal octapeptide of nerve growth factor. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5144–5148. doi: 10.1073/pnas.88.12.5144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tomioka M., Stead R. H., Nielsen L., Coughlin M. D., Bienenstock J. Nerve growth factor enhances antigen and other secretagogue-induced histamine release from rat peritoneal mast cells in the absence of phosphatidylserine. J Allergy Clin Immunol. 1988 Oct;82(4):599–607. doi: 10.1016/0091-6749(88)90971-2. [DOI] [PubMed] [Google Scholar]
  47. Weskamp G., Otten U. An enzyme-linked immunoassay for nerve growth factor (NGF): a tool for studying regulatory mechanisms involved in NGF production in brain and in peripheral tissues. J Neurochem. 1987 Jun;48(6):1779–1786. doi: 10.1111/j.1471-4159.1987.tb05736.x. [DOI] [PubMed] [Google Scholar]
  48. Whittemore S. R., Friedman P. L., Larhammar D., Persson H., Gonzalez-Carvajal M., Holets V. R. Rat beta-nerve growth factor sequence and site of synthesis in the adult hippocampus. J Neurosci Res. 1988 Aug;20(4):403–410. doi: 10.1002/jnr.490200402. [DOI] [PubMed] [Google Scholar]
  49. Whittemore S. R., Lärkfors L., Ebendal T., Holets V. R., Ericsson A., Persson H. Increased beta-nerve growth factor messenger RNA and protein levels in neonatal rat hippocampus following specific cholinergic lesions. J Neurosci. 1987 Jan;7(1):244–251. doi: 10.1523/JNEUROSCI.07-01-00244.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Young J. D., Liu C. C., Butler G., Cohn Z. A., Galli S. J. Identification, purification, and characterization of a mast cell-associated cytolytic factor related to tumor necrosis factor. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9175–9179. doi: 10.1073/pnas.84.24.9175. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES