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. 1992 Apr 15;89(8):3209–3212. doi: 10.1073/pnas.89.8.3209

Neuromodulatory loop mediated by nerve growth factor and interleukin 6 in thymic stromal cell cultures.

I Screpanti 1, D Meco 1, S Scarpa 1, S Morrone 1, L Frati 1, A Gulino 1, A Modesti 1
PMCID: PMC48835  PMID: 1373490

Abstract

Neural crest cell derivatives have been suggested to be involved in thymus development. We established nonlymphoid thymic stromal cell cultures capable of supporting T-cell differentiation. In these nonlymphoid cell cultures, we identified cells with phenotypic and biochemical markers specific for neuronal cells. Neurofilament mRNA and 68- and 160-kDa neurofilament proteins, as well as 74-kDa synapsin I isoform, were expressed in many of the cultured cells. For example, neurofilament immunoreactivity was detected in 20-30% of the cells. To see whether thymic neuronal-like cells were involved in a neural differentiation pathway, we investigated the effect of nerve growth factor (NGF) and interleukin 6 (IL-6), two known neurotrophic factors. The expression of the above-described neural markers was enhanced by NGF and IL-6, which we report to be produced in an autocrine way by thymic stromal cell cultures. Finally, we found that IL-6 gene expression in these cell cultures was enhanced by NGF. Evidence is thus offered of a neuromodulatory loop within the thymic stromal cell population supported by local production of NGF and IL-6 and involving neural cell elements. Interestingly, IL-6, which is known to be implicated in thymocyte differentiation, also displays a neuromodulatory activity on thymic stromal cells, suggesting a multivalent role for this cytokine within the thymus.

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Selected References

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

  1. Abo T., Balch C. M. A differentiation antigen of human NK and K cells identified by a monoclonal antibody (HNK-1). J Immunol. 1981 Sep;127(3):1024–1029. [PubMed] [Google Scholar]
  2. Anderson D. J., Axel R. A bipotential neuroendocrine precursor whose choice of cell fate is determined by NGF and glucocorticoids. Cell. 1986 Dec 26;47(6):1079–1090. doi: 10.1016/0092-8674(86)90823-8. [DOI] [PubMed] [Google Scholar]
  3. Bockman D. E., Kirby M. L. Dependence of thymus development on derivatives of the neural crest. Science. 1984 Feb 3;223(4635):498–500. doi: 10.1126/science.6606851. [DOI] [PubMed] [Google Scholar]
  4. Chen W. F., Fischer M., Frank G., Zlotnik A. Distinct patterns of lymphokine requirement for the proliferation of various subpopulations of activated thymocytes in a single cell assay. J Immunol. 1989 Sep 1;143(5):1598–1605. [PubMed] [Google Scholar]
  5. De Camilli P., Benfenati F., Valtorta F., Greengard P. The synapsins. Annu Rev Cell Biol. 1990;6:433–460. doi: 10.1146/annurev.cb.06.110190.002245. [DOI] [PubMed] [Google Scholar]
  6. De Camilli P., Cameron R., Greengard P. Synapsin I (protein I), a nerve terminal-specific phosphoprotein. I. Its general distribution in synapses of the central and peripheral nervous system demonstrated by immunofluorescence in frozen and plastic sections. J Cell Biol. 1983 May;96(5):1337–1354. doi: 10.1083/jcb.96.5.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eisenbarth G. S., Shimizu K., Bowring M. A., Wells S. Expression of receptors for tetanus toxin and monoclonal antibody A2B5 by pancreatic islet cells. Proc Natl Acad Sci U S A. 1982 Aug;79(16):5066–5070. doi: 10.1073/pnas.79.16.5066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Felli M. P., Vacca A., Meco D., Screpanti I., Farina A. R., Maroder M., Martinotti S., Petrangeli E., Frati L., Gulino A. Retinoic acid-induced down-regulation of the interleukin-2 promoter via cis-regulatory sequences containing an octamer motif. Mol Cell Biol. 1991 Sep;11(9):4771–4778. doi: 10.1128/mcb.11.9.4771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fink P. J., Bevan M. J. H-2 antigens of the thymus determine lymphocyte specificity. J Exp Med. 1978 Sep 1;148(3):766–775. doi: 10.1084/jem.148.3.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Frei K., Malipiero U. V., Leist T. P., Zinkernagel R. M., Schwab M. E., Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol. 1989 Apr;19(4):689–694. doi: 10.1002/eji.1830190418. [DOI] [PubMed] [Google Scholar]
  11. Geenen V., Defresne M. P., Robert F., Legros J. J., Franchimont P., Boniver J. The neurohormonal thymic microenvironment: immunocytochemical evidence that thymic nurse cells are neuroendocrine cells. Neuroendocrinology. 1988 Apr;47(4):365–368. doi: 10.1159/000124938. [DOI] [PubMed] [Google Scholar]
  12. Gutierrez J. C., Palacios R. Heterogeneity of thymic epithelial cells in promoting T-lymphocyte differentiation in vivo. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):642–646. doi: 10.1073/pnas.88.2.642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hoffman P. N., Lasek R. J. The slow component of axonal transport. Identification of major structural polypeptides of the axon and their generality among mammalian neurons. J Cell Biol. 1975 Aug;66(2):351–366. doi: 10.1083/jcb.66.2.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kruisbeek A. M., Zijlstra J. J., Kröse T. J. Distinct effects of T cell growth factors and thymic epithelial factors on the generation of cytotoxic T lymphocytes by thymocyte subpopulations. J Immunol. 1980 Sep;125(3):995–1002. [PubMed] [Google Scholar]
  15. Le J. M., Fredrickson G., Reis L. F., Diamantstein T., Hirano T., Kishimoto T., Vilcek J. Interleukin 2-dependent and interleukin 2-independent pathways of regulation of thymocyte function by interleukin 6. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8643–8647. doi: 10.1073/pnas.85.22.8643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Le P. T., Lazorick S., Whichard L. P., Yang Y. C., Clark S. C., Haynes B. F., Singer K. H. Human thymic epithelial cells produce IL-6, granulocyte-monocyte-CSF, and leukemia inhibitory factor. J Immunol. 1990 Nov 15;145(10):3310–3315. [PubMed] [Google Scholar]
  17. Levi-Montalcini R. The nerve growth factor: thirty-five years later. EMBO J. 1987 May;6(5):1145–1154. doi: 10.1002/j.1460-2075.1987.tb02347.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lindenbaum M. H., Carbonetto S., Grosveld F., Flavell D., Mushynski W. E. Transcriptional and post-transcriptional effects of nerve growth factor on expression of the three neurofilament subunits in PC-12 cells. J Biol Chem. 1988 Apr 25;263(12):5662–5667. [PubMed] [Google Scholar]
  19. Lotz M., Vaughan J. H., Carson D. A. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science. 1988 Sep 2;241(4870):1218–1221. doi: 10.1126/science.2457950. [DOI] [PubMed] [Google Scholar]
  20. Maisonpierre P. C., Belluscio L., Squinto S., Ip N. Y., Furth M. E., Lindsay R. M., Yancopoulos G. D. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990 Mar 23;247(4949 Pt 1):1446–1451. doi: 10.1126/science.247.4949.1446. [DOI] [PubMed] [Google Scholar]
  21. Payan D. G., Brewster D. R., Goetzl E. J. Specific stimulation of human T lymphocytes by substance P. J Immunol. 1983 Oct;131(4):1613–1615. [PubMed] [Google Scholar]
  22. Romano C., Nichols R. A., Greengard P., Greene L. A. Synapsin I in PC12 cells. I. Characterization of the phosphoprotein and effect of chronic NGF treatment. J Neurosci. 1987 May;7(5):1294–1299. doi: 10.1523/JNEUROSCI.07-05-01294.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Romano C., Nichols R. A., Greengard P. Synapsin I in PC12 cells. II. Evidence for regulation by NGF of phosphorylation at a novel site. J Neurosci. 1987 May;7(5):1300–1306. doi: 10.1523/JNEUROSCI.07-05-01300.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Satoh T., Nakamura S., Taga T., Matsuda T., Hirano T., Kishimoto T., Kaziro Y. Induction of neuronal differentiation in PC12 cells by B-cell stimulatory factor 2/interleukin 6. Mol Cell Biol. 1988 Aug;8(8):3546–3549. doi: 10.1128/mcb.8.8.3546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sztein M. B., Goldstein A. L. Thymic hormones--a clinical update. Springer Semin Immunopathol. 1986;9(1):1–18. doi: 10.1007/BF00201901. [DOI] [PubMed] [Google Scholar]
  26. Söder O., Hellström P. M. The tachykinins neurokinin A and physalaemin stimulate murine thymocyte proliferation. Int Arch Allergy Appl Immunol. 1989;90(1):91–96. doi: 10.1159/000235006. [DOI] [PubMed] [Google Scholar]
  27. Tanabe O., Akira S., Kamiya T., Wong G. G., Hirano T., Kishimoto T. Genomic structure of the murine IL-6 gene. High degree conservation of potential regulatory sequences between mouse and human. J Immunol. 1988 Dec 1;141(11):3875–3881. [PubMed] [Google Scholar]
  28. Tooze J., Hollinshead M., Fuller S. D., Tooze S. A., Huttner W. B. Morphological and biochemical evidence showing neuronal properties in AtT-20 cells and their growth cones. Eur J Cell Biol. 1989 Aug;49(2):259–273. [PubMed] [Google Scholar]
  29. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278. doi: 10.1146/annurev.iy.08.040190.001345. [DOI] [PubMed] [Google Scholar]
  30. Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Klein P. A., Klein J. On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? J Exp Med. 1978 Mar 1;147(3):882–896. doi: 10.1084/jem.147.3.882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zinkernagel R. M., Doherty P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701–702. doi: 10.1038/248701a0. [DOI] [PubMed] [Google Scholar]
  32. van Ewijk W. Immunohistology of lymphoid organs. Curr Opin Immunol. 1989 Jun;1(5):954–965. doi: 10.1016/0952-7915(89)90079-4. [DOI] [PubMed] [Google Scholar]

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