Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The STAT3 isoforms α and β have unique and specific functions

Abstract

Signal transducer and activator of transcription 3 (STAT3) is the main mediator of interleukin 6 (IL-6)-type cytokine signaling. It exists in two isoforms: the full-length STAT3α and the truncated STAT3β, generally thought to act as a dominant negative factor. To assess their relative functions, we ablated the expression of either isoform by gene targeting. We show here that in vivo STAT3β is not a dominant negative factor. Its expression can rescue the embryonic lethality of a STAT3-null mutation and it can by itself induce the expression of specific STAT3 target genes. Nevertheless, STAT3α has nonredundant roles such as modulation of cellular responses to IL-6 and mediation of IL-10 function in macrophages.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation and confirmation of STAT3α and STAT3β deficiency in mice.
Figure 2: STAT3 protein phosphorylation and DNA-binding activity in the livers of LPS-treated Stat3Δβ/Δβ mice or Stat3+/+ littermates.
Figure 3: STAT3 protein phosphorylation, DNA-binding activity and induction of acute-phase mRNA in the livers of LPS-treated AlbCre+Stat3Δα/fl mice and mice of control genotypes.
Figure 4: Macrophage STAT3 protein and production of cytokines in Stat3Δβ/Δβ and Stat3+/+ mice.
Figure 5: Macrophage STAT3 protein and production of cytokines in MxCre+Stat3Δα/fl mice and mice of control genotypes.
Figure 6: Differential expression of a subset of genes in Stat3fl/fl, Stat3Δ/Δ, Stat3Δα/Δα and Stat3Δβ/Δβ MEFs after treatment with IL-6 plus soluble IL-6 receptor.
Figure 7: STAT3-STAT1 activation in Stat3Δ/Δ, Stat3Δα/Δα, Stat3Δβ/Δβ and Stat3fl/fl MEFs.

Similar content being viewed by others

References

  1. Aaronson, D.S. & Horvath, C.M. A road map for those who know JAK-STAT. Science 296, 1653–1655 (2002).

    Article  CAS  Google Scholar 

  2. Horvath, C.M. & Darnell, J.E. The state of the STATs: recent developments in the study of signal transduction to the nucleus. Curr. Opin. Cell Biol. 9, 233–239 (1997).

    Article  CAS  Google Scholar 

  3. Wegenka, U.M., Buschmann, J., Lutticken, C., Heinrich, P.C. & Horn, F. Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol. Cell. Biol. 13, 276–288 (1993).

    Article  CAS  Google Scholar 

  4. Akira, S. et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77, 63–71 (1994).

    Article  CAS  Google Scholar 

  5. Zhong, Z., Wen, Z. & Darnell, J.E., Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264, 95–98 (1994).

    Article  CAS  Google Scholar 

  6. Wegenka, U.M. et al. The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. Mol. Cell. Biol. 14, 3186–3196 (1994).

    Article  CAS  Google Scholar 

  7. Levy, D.E. & Lee, C.K. What does Stat3 do? J. Clin. Invest. 109, 1143–1148 (2002).

    Article  CAS  Google Scholar 

  8. Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. USA 94, 3801–3804 (1997).

    Article  CAS  Google Scholar 

  9. Takeda, K. et al. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J. Immunol. 161, 4652–4660 (1998).

    CAS  PubMed  Google Scholar 

  10. Sano, S. et al. Stat3 in thymic epithelial cells is essential for postnatal maintenance of thymic architecture and thymocyte survival. Immunity 15, 261–273 (2001).

    Article  CAS  Google Scholar 

  11. Cheng, F. et al. A critical role for Stat3 signaling in immune tolerance. Immunity 19, 425–436 (2003).

    Article  CAS  Google Scholar 

  12. Lee, C.K. et al. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 17, 63–72 (2002).

    Article  CAS  Google Scholar 

  13. Alonzi, T. et al. Essential role of the signal transducer and activator of transcription STAT3 in the control of the acute phase response as revealed by inducible gene inactivation in the liver. Mol. Cell. Biol. 21, 1621–1632 (2001).

    Article  CAS  Google Scholar 

  14. Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    Article  CAS  Google Scholar 

  15. Kobayashi, M. et al. Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J. Clin. Invest. 111, 1297–1308 (2003).

    Article  CAS  Google Scholar 

  16. Costa-Pereira, A.P. et al. Mutational switch of an IL-6 response to an interferon-γ-like response. Proc. Natl. Acad. Sci. USA 99, 8043–8047 (2002).

    Article  CAS  Google Scholar 

  17. Caldenhoven, E. et al. STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. J. Biol. Chem. 271, 13221–13227 (1996).

    Article  CAS  Google Scholar 

  18. Schaefer, T.S., Sanders, L.K. & Nathans, D. Cooperative transcriptional activity of Jun and Stat3β, a short form of Stat3. Proc. Natl. Acad. Sci. USA 92, 9097–9101 (1995).

    Article  CAS  Google Scholar 

  19. Yoo, J.Y., Huso, D.L., Nathans, D. & Desiderio, S. Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Cell 108, 331–344 (2002).

    Article  CAS  Google Scholar 

  20. Li, W., Liang, X., Kellendonk, C., Poli, V. & Taub, R. STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration. J. Biol. Chem. 277, 28411–28417 (2002).

    Article  CAS  Google Scholar 

  21. Lang, R. et al. SOCS3 regulates the plasticity of gp130 signaling. Nat. Immunol. 4, 546–550 (2003).

    Article  CAS  Google Scholar 

  22. Croker, B.A. et al. SOCS3 negatively regulates IL-6 signaling in vivo . Nat. Immunol. 4, 540–545 (2003).

    Article  CAS  Google Scholar 

  23. Yasukawa, H. et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunol. 4, 551–556 (2003).

    Article  CAS  Google Scholar 

  24. Park, O.K., Schaefer, L.K., Wang, W. & Schaefer, T.S. Dimer stability as a determinant of differential DNA binding activity of Stat3 isoforms. J. Biol. Chem. 275, 32244–32249 (2000).

    Article  CAS  Google Scholar 

  25. Schaefer, T.S., Sanders, L.K., Park, O.K. & Nathans, D. Functional differences between Stat3α and Stat3β. Mol. Cell. Biol. 17, 5307–5316 (1997).

    Article  CAS  Google Scholar 

  26. Sasse, J. et al. Mutational analysis of acute-phase response factor/Stat3 activation and dimerization. Mol. Cell. Biol. 17, 4677–4686 (1997).

    Article  CAS  Google Scholar 

  27. Duncan, S.A., Zhong, Z., Wen, Z. & Darnell, J.E., Jr. STAT signaling is active during early mammalian development. Dev. Dyn. 208, 190–198 (1997).

    Article  CAS  Google Scholar 

  28. Paulson, M. et al. Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J. Biol. Chem. 274, 25343–25349 (1999).

    Article  CAS  Google Scholar 

  29. Giraud, S. et al. Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a. J. Biol. Chem. 277, 8004–8011 (2002).

    Article  CAS  Google Scholar 

  30. Ray, S., Sherman, C.T., Lu, M. & Brasier, A.R. Angiotensinogen gene expression is dependent on signal transducer and activator of transcription 3-mediated p300/cAMP response element binding protein-binding protein coactivator recruitment and histone acetyltransferase activity. Mol. Endocrinol. 16, 824–836 (2002).

    Article  CAS  Google Scholar 

  31. Zhang, X., Wrzeszczynska, M.H., Horvath, C.M. & Darnell, J.E., Jr. Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation. Mol. Cell. Biol. 19, 7138–7146 (1999).

    Article  CAS  Google Scholar 

  32. Zhang, X. & Darnell, J.E., Jr. Functional importance of Stat3 tetramerization in activation of the α2-macroglobulin gene. J. Biol. Chem. 276, 33576–33581 (2001).

    Article  CAS  Google Scholar 

  33. Yoo, J.Y., Wang, W., Desiderio, S. & Nathans, D. Synergistic activity of STAT3 and c-Jun at a specific array of DNA elements in the α2-macroglobulin promoter. J. Biol. Chem. 276, 26421–26429 (2001).

    Article  CAS  Google Scholar 

  34. Kile, B.T. et al. The SOCS box: a tale of destruction and degradation. Trends Biochem. Sci. 27, 235–241 (2002).

    Article  CAS  Google Scholar 

  35. Benkhart, E.M., Siedlar, M., Wedel, A., Werner, T. & Ziegler-Heitbrock, H.W. Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression. J. Immunol. 165, 1612–1617 (2000).

    Article  CAS  Google Scholar 

  36. Ziegler-Heitbrock, L. et al. IFN-α induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3. J. Immunol. 171, 285–290 (2003).

    Article  CAS  Google Scholar 

  37. Gu, H., Zou, Y.R. & Rajewsky, K. Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell 73, 1155–1164 (1993).

    Article  CAS  Google Scholar 

  38. Mackiewicz, A. et al. Soluble interleukin 6 receptor is biologically active in vivo . Cytokine 7, 142–149 (1995).

    Article  CAS  Google Scholar 

  39. Doyle, A.G. & Fraser, I.P. in Weir's Handbook of Experimental Immunology 5th edn. (Herzenberg, L.A., Weir, D.M., Herzenberg, L.A. and Blackwell, C.) 154.1–154.8 (Blackwell Science, 1996).

    Google Scholar 

  40. Todaro, G.J. & Green, H. Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J. Cell. Biol. 17, 299–313 (1963).

    Article  CAS  Google Scholar 

  41. Cappelletti, M., Alonzi, T., Fattori, E., Libert, C. & Poli, V. C/EBPb is required for the late phases of acute phase genes induction in the liver and for tumour necrosis factor-α, but not interleukin-6, regulation. Cell Death Differ. 3, 29–35 (1996).

    CAS  PubMed  Google Scholar 

  42. Fattori, E. et al. Defective inflammatory response in interleukin 6-deficient mice. J. Exp. Med. 180, 1243–1250 (1994).

    Article  CAS  Google Scholar 

  43. Aberger, F. et al. Analysis of gene expression using high-density and IFN-γ-specific low-density cDNA arrays. Genomics 77, 50–57 (2001).

    Article  CAS  Google Scholar 

  44. Strobl, B. et al. A completely foreign receptor can mediate an interferon-γ-like response. EMBO J. 20, 5431–5442 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Rose John, H. Baumann, U. Müller-Eberhard and W. Liao for the gifts of plasmids; F. Tronche, W. Müller and K. Rajewsky for providing the AlbCre or MxCre transgenic mice; I. Kerr and A. Costa Pereira for ideas and support for the macroarray analysis; S. Pensa and A. Cimino for help with the expression and histological analyses; and I. Kerr, F. Di Cunto, E. Hirsch, F. Bazzoni and T. Alonzi for critically reading the manuscript. Supported by the Wellcome Trust (V.P. and M.L.S.), the Italian Ministry of Research (MIUR) and the Italian Cancer Research Association (AIRC). D.M. was the recipient of a Marie Curie European Community post-doctoral fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Valeria Poli.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maritano, D., Sugrue, M., Tininini, S. et al. The STAT3 isoforms α and β have unique and specific functions. Nat Immunol 5, 401–409 (2004). https://doi.org/10.1038/ni1052

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1052

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing