Clinical Reviews in Allergy & Immunology

, Volume 28, Issue 3, pp 249–256

Role of IL-6 in the neural stem cell differentiation


In the developing brain neurons, astrocytes, and oligodendrocytes are differentiated from common multipotent progenitors called neural stem cells. We have examined the effect of cytokines on mouse neuroepithelial cells that are known to contain neural stem cells. Cytokines belonging to the interleukin (IL)-6 family and those classified into the bone morphogenetic protein (BMP) family act in synergy on neuroepithelial cells to induce astrocyte differentiation. Cooperation of these two types of cytokines is explained by the formulation of a complex between their respective downstream transcription factors (signal tranducer and activator of transcription [STAT]-3 and Smad1), bridged by a transcriptional coactivator (p300). Whereas BMPs family cytokines are involved in astrocyte differentiation, they inhibit neuronal differentiation. This appears to change the fate of neural progenitor cells from neurogenesis to astrocytogenesis. Interestingly, during brain development, neuronal differentiation starts at a very early stage and continues throughout development, whereas astrocytes appear just before term. We have shown that astrocyte differentiation is largely dependent on IL-6 family cytokine-mediated STAT3 activation and that there exists a STAT3 binding element in the promoter region of the gene for the astrocyte marker glial fibrillary acidic protein. A cytosine residue in this element is highly methylated in neuroepithelial cells in a midgestational stage but becomes demethylated in accordance with brain development. Because this methylation inhibits STAT3 binding, we suggest that DNA methylation is a critical determinant in the developmental stage-dependent regulation of astrocytogeneis. In conclusion, fate of neural stem cells during development is regulated by cell-intrinsic programs, such as epigenetic modification (including DNA methylation), and signaling crosstalk of cell-external mediators (including IL-6 family cytokines).

Index Entries

Bone morphogenetic protein cytokine differentiation epigenetic regulation interleukin-6 neural stem cell transcription factor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Temple, S. (2001), Nature 414, 112–117.PubMedCrossRefGoogle Scholar
  2. 2.
    Reynolds, B. A., Tetzlaff, W., and Weiss, S. (1992), J. Neurosci. 12, 4565–4574.PubMedGoogle Scholar
  3. 3.
    Uchida, N., Buck, D. W., He, D., et al. (2000), Proc. Natl. Acad. Sci. U. S. A. 97, 14,720–14,725.CrossRefGoogle Scholar
  4. 4.
    Roy, N. S., Benraiss, A., Wang, S., et al. (2000), J. Neurosci. Res. 59, 321–331.PubMedCrossRefGoogle Scholar
  5. 5.
    Kawaguchi, A., Miyata, T., Sawamoto, K., et al. (2001), Mol. Cell Neurosci. 17, 259–273.PubMedCrossRefGoogle Scholar
  6. 6.
    Bonni, A., Sun, Y., Nadal-Vicens, M., et al. (1997), Science 278, 477–483.PubMedCrossRefGoogle Scholar
  7. 7.
    Nakashima, K., Yanagisawa, M., Arakawa, H., et al. (1999), Science 284, 479–482.PubMedCrossRefGoogle Scholar
  8. 8.
    Yanagisawa, M., Nakashima, K., Takizawa, T., Ochiai, W., Arakawa, H., and Taga, T. (2001), FEBS Lett. 489, 139–143.PubMedCrossRefGoogle Scholar
  9. 9.
    Ochiai, W., Yanagisawa, M., Takizawa, T., Nakashima, K., and Taga, T. (2001), Cytokine 14, 264–271.PubMedCrossRefGoogle Scholar
  10. 10.
    Uemura, A., Takizawa, T., Ochiai, W., Yanagisawa, M., Nakashima, K., and Taga, T. (2002), Cytokine 18, 1–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Nakashima, K., Wiese, S., Yanagisawa, M., et al. (1999), J. Neurosci. 19, 5429–5434.PubMedGoogle Scholar
  12. 12.
    Massague, J. and Chen, Y. G. (2000), Genes Dev. 14, 627–644.PubMedGoogle Scholar
  13. 13.
    Gross, R. E., Mehler, M. F., Mabie, P. C., Zang, Z., Santschi, L., and Kessler, J. A. (1996), Neuron 17, 595–606.PubMedCrossRefGoogle Scholar
  14. 14.
    Nakashima, K., Yanagisawa, M., Arakawa, H., and Taga, T. (1999), FEBS Lett. 457, 43–46.PubMedCrossRefGoogle Scholar
  15. 15.
    Nakashima, K., Takizawa, T., Ochiai, W., et al. (2001), Proc. Natl. Acad. Sci. USA 98, 5868–5873.PubMedCrossRefGoogle Scholar
  16. 16.
    Yanagisawa, M., Takizawa, T., Ochiai, W., Uemura, A., Nakashima, K., and Taga, T. (2001), Neurosci. Res. 41, 391–396.PubMedCrossRefGoogle Scholar
  17. 17.
    Kageyama, R. and Nakanishi, S. (1997), Curr. Opin. Genet. Dev. 7, 659–665.PubMedCrossRefGoogle Scholar
  18. 18.
    Lee, J. E. (1997), Curr. Opin, Neurobiol. 7, 13–20.CrossRefGoogle Scholar
  19. 19.
    Massari, M. E. and Murre, C. (2000), Mol. Cell. Biol. 20, 429–440.PubMedCrossRefGoogle Scholar
  20. 20.
    Akazawa, C., Sasai, Y., Nakanishi, S., and Kageyama, R. (1992), J. Biol. Chem. 267, 21,879–21,885.Google Scholar
  21. 21.
    Ohtsuka, T., Ishibashi, M., Gradwohl, G., Nakanishi, S., Guillemot, F., and Kageyama, R. (1999), EMBO J. 18, 2196–2207.PubMedCrossRefGoogle Scholar
  22. 22.
    Sasai, Y., Kageyama, R., Tagawa, Y., Shigemoto, R., and Nakanishi, S. (1992), Genes Dev. 6, 2620–2634.PubMedCrossRefGoogle Scholar
  23. 23.
    Benezra, R., Davis, R. L., Lockshon, D., Turner, D. L., and Weintraub, H. (1990), Cell 61, 49–59.PubMedCrossRefGoogle Scholar
  24. 24.
    Hirota, H., Kiyama, H., Kishimoto, T., and Taga, T. (1996), J. Exp. Med. 183, 2627–2634.PubMedCrossRefGoogle Scholar
  25. 25.
    Takizawa, T., Nakashima, K., Namihira, M., et al. (2001), Dev. Cell 1, 749–758.PubMedCrossRefGoogle Scholar
  26. 26.
    Namihira, M., Nakashima, K., and Taga, T. (2004), FEBS Lett. 572, 184–188.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  1. 1.Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, and 21st Century Center-of-Excellence Program “Cell Fate Regulation Research and Education Unit”Kumamoto UniversityKumamotoJapan

Personalised recommendations