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. 1994 Mar 15;13(6):1350–1356. doi: 10.1002/j.1460-2075.1994.tb06388.x

STF-IL-4: a novel IL-4-induced signal transducing factor.

C Schindler 1, H Kashleva 1, A Pernis 1, R Pine 1, P Rothman 1
PMCID: PMC394951  PMID: 8137819

Abstract

The mechanism by which interleukin-4 (IL-4) regulates the expression of particular genes is unknown. We have determined that IL-4 induces a DNA binding factor (termed STF-IL-4) which has a strong affinity for an IFN-gamma activation site (GAS). Interestingly, STF-IL-4 also binds to the IL-4 responsive promoter for the Ig heavy chain germline epsilon transcript. The IL-4 dependent activation of STF-IL-4 is rapid, does not require protein synthesis and results in the sequential appearance of binding activity first in the cytoplasm and then later in the nucleus. Activation of STF-IL-4 is sensitive to tyrosine kinase inhibitors and the active factor is tyrosine phosphorylated. This pattern of activation is similar to the activation of interferon-induced transcription factors. STF-IL-4 appears to be a new member of a growing family of cytokine-induced transcriptional regulators.

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Selected References

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

  1. Alt F. W., Rosenberg N., Casanova R. J., Thomas E., Baltimore D. Immunoglobulin heavy-chain expression and class switching in a murine leukaemia cell line. Nature. 1982 Mar 25;296(5855):325–331. doi: 10.1038/296325a0. [DOI] [PubMed] [Google Scholar]
  2. Berton M. T., Uhr J. W., Vitetta E. S. Synthesis of germ-line gamma 1 immunoglobulin heavy-chain transcripts in resting B cells: induction by interleukin 4 and inhibition by interferon gamma. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2829–2833. doi: 10.1073/pnas.86.8.2829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bonni A., Frank D. A., Schindler C., Greenberg M. E. Characterization of a pathway for ciliary neurotrophic factor signaling to the nucleus. Science. 1993 Dec 3;262(5139):1575–1579. doi: 10.1126/science.7504325. [DOI] [PubMed] [Google Scholar]
  4. Coffman R. L., Lebman D. A., Rothman P. Mechanism and regulation of immunoglobulin isotype switching. Adv Immunol. 1993;54:229–270. doi: 10.1016/s0065-2776(08)60536-2. [DOI] [PubMed] [Google Scholar]
  5. Cosman D. The hematopoietin receptor superfamily. Cytokine. 1993 Mar;5(2):95–106. doi: 10.1016/1043-4666(93)90047-9. [DOI] [PubMed] [Google Scholar]
  6. Defrance T., Aubry J. P., Rousset F., Vanbervliet B., Bonnefoy J. Y., Arai N., Takebe Y., Yokota T., Lee F., Arai K. Human recombinant interleukin 4 induces Fc epsilon receptors (CD23) on normal human B lymphocytes. J Exp Med. 1987 Jun 1;165(6):1459–1467. doi: 10.1084/jem.165.6.1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eilers A., Seegert D., Schindler C., Baccarini M., Decker T. The response of gamma interferon activation factor is under developmental control in cells of the macrophage lineage. Mol Cell Biol. 1993 Jun;13(6):3245–3254. doi: 10.1128/mcb.13.6.3245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Esser C., Radbruch A. Rapid induction of transcription of unrearranged S gamma 1 switch regions in activated murine B cells by interleukin 4. EMBO J. 1989 Feb;8(2):483–488. doi: 10.1002/j.1460-2075.1989.tb03401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Glimcher L. H., Hamano T., Asofsky R., Herber-Katz E., Hedrick S., Schwartz R. H., Paul W. E. I region-restricted antigen presentation by B cell-B lymphoma hybridomas. Nature. 1982 Jul 15;298(5871):283–284. doi: 10.1038/298283a0. [DOI] [PubMed] [Google Scholar]
  10. Glimcher L. H., Kara C. J. Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol. 1992;10:13–49. doi: 10.1146/annurev.iy.10.040192.000305. [DOI] [PubMed] [Google Scholar]
  11. Hudak S. A., Gollnick S. O., Conrad D. H., Kehry M. R. Murine B-cell stimulatory factor 1 (interleukin 4) increases expression of the Fc receptor for IgE on mouse B cells. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4606–4610. doi: 10.1073/pnas.84.13.4606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Izuhara K., Yang G., Miyajima A., Howard M., Harada N. Structure of the IL4 receptor and signal transduction mechanism of IL4. Res Immunol. 1993 Oct;144(8):584–590. doi: 10.1016/s0923-2494(05)80007-0. [DOI] [PubMed] [Google Scholar]
  13. Justement L., Chen Z., Harris L., Ransom J., Sandoval V., Smith C., Rennick D., Roehm N., Cambier J. BSF1 induces membrane protein phosphorylation but not phosphoinositide metabolism, Ca2+ mobilization, protein kinase C translocation, or membrane depolarization in resting murine B lymphocytes. J Immunol. 1986 Dec 1;137(11):3664–3670. [PubMed] [Google Scholar]
  14. Khan K. D., Shuai K., Lindwall G., Maher S. E., Darnell J. E., Jr, Bothwell A. L. Induction of the Ly-6A/E gene by interferon alpha/beta and gamma requires a DNA element to which a tyrosine-phosphorylated 91-kDa protein binds. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6806–6810. doi: 10.1073/pnas.90.14.6806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klemsz M. J., Justement L. B., Palmer E., Cambier J. C. Induction of c-fos and c-myc expression during B cell activation by IL-4 and immunoglobulin binding ligands. J Immunol. 1989 Aug 1;143(3):1032–1039. [PubMed] [Google Scholar]
  16. Kühn R., Rajewsky K., Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. doi: 10.1126/science.1948049. [DOI] [PubMed] [Google Scholar]
  17. Levy D. E., Kessler D. S., Pine R., Reich N., Darnell J. E., Jr Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 1988 Apr;2(4):383–393. doi: 10.1101/gad.2.4.383. [DOI] [PubMed] [Google Scholar]
  18. Lütticken C., Wegenka U. M., Yuan J., Buschmann J., Schindler C., Ziemiecki A., Harpur A. G., Wilks A. F., Yasukawa K., Taga T. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994 Jan 7;263(5143):89–92. doi: 10.1126/science.8272872. [DOI] [PubMed] [Google Scholar]
  19. McKendry R., John J., Flavell D., Müller M., Kerr I. M., Stark G. R. High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both alpha and gamma interferons. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11455–11459. doi: 10.1073/pnas.88.24.11455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Miyajima A., Kitamura T., Harada N., Yokota T., Arai K. Cytokine receptors and signal transduction. Annu Rev Immunol. 1992;10:295–331. doi: 10.1146/annurev.iy.10.040192.001455. [DOI] [PubMed] [Google Scholar]
  21. Mizuguchi J., Beaven M. A., Ohara J., Paul W. E. BSF-1 action on resting B cells does not require elevation of inositol phospholipid metabolism or increased [Ca2+]i. J Immunol. 1986 Oct 1;137(7):2215–2219. [PubMed] [Google Scholar]
  22. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  23. Noelle R., Krammer P. H., Ohara J., Uhr J. W., Vitetta E. S. Increased expression of Ia antigens on resting B cells: an additional role for B-cell growth factor. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6149–6153. doi: 10.1073/pnas.81.19.6149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Paul W. E., Ohara J. B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol. 1987;5:429–459. doi: 10.1146/annurev.iy.05.040187.002241. [DOI] [PubMed] [Google Scholar]
  25. Pellegrini S., Schindler C. Early events in signalling by interferons. Trends Biochem Sci. 1993 Sep;18(9):338–342. doi: 10.1016/0968-0004(93)90070-4. [DOI] [PubMed] [Google Scholar]
  26. Pine R., Canova A., Schindler C. Tyrosine phosphorylated p91 binds to a single element in the ISGF2/IRF-1 promoter to mediate induction by IFN alpha and IFN gamma, and is likely to autoregulate the p91 gene. EMBO J. 1994 Jan 1;13(1):158–167. doi: 10.1002/j.1460-2075.1994.tb06245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Roehm N. W., Leibson H. J., Zlotnik A., Kappler J., Marrack P., Cambier J. C. Interleukin-induced increase in Ia expression by normal mouse B cells. J Exp Med. 1984 Sep 1;160(3):679–694. doi: 10.1084/jem.160.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rothman P., Chen Y. Y., Lutzker S., Li S. C., Stewart V., Coffman R., Alt F. W. Structure and expression of germ line immunoglobulin heavy-chain epsilon transcripts: interleukin-4 plus lipopolysaccharide-directed switching to C epsilon. Mol Cell Biol. 1990 Apr;10(4):1672–1679. doi: 10.1128/mcb.10.4.1672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rothman P., Li S. C., Gorham B., Glimcher L., Alt F., Boothby M. Identification of a conserved lipopolysaccharide-plus-interleukin-4-responsive element located at the promoter of germ line epsilon transcripts. Mol Cell Biol. 1991 Nov;11(11):5551–5561. doi: 10.1128/mcb.11.11.5551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rothman P., Lutzker S., Cook W., Coffman R., Alt F. W. Mitogen plus interleukin 4 induction of C epsilon transcripts in B lymphoid cells. J Exp Med. 1988 Dec 1;168(6):2385–2389. doi: 10.1084/jem.168.6.2385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sadowski H. B., Gilman M. Z. Cell-free activation of a DNA-binding protein by epidermal growth factor. Nature. 1993 Mar 4;362(6415):79–83. doi: 10.1038/362079a0. [DOI] [PubMed] [Google Scholar]
  32. Sadowski H. B., Shuai K., Darnell J. E., Jr, Gilman M. Z. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science. 1993 Sep 24;261(5129):1739–1744. doi: 10.1126/science.8397445. [DOI] [PubMed] [Google Scholar]
  33. Schindler C., Fu X. Y., Improta T., Aebersold R., Darnell J. E., Jr Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7836–7839. doi: 10.1073/pnas.89.16.7836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schindler C., Shuai K., Prezioso V. R., Darnell J. E., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992 Aug 7;257(5071):809–813. doi: 10.1126/science.1496401. [DOI] [PubMed] [Google Scholar]
  35. Shuai K., Schindler C., Prezioso V. R., Darnell J. E., Jr Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. Science. 1992 Dec 11;258(5089):1808–1812. doi: 10.1126/science.1281555. [DOI] [PubMed] [Google Scholar]
  36. Silvennoinen O., Schindler C., Schlessinger J., Levy D. E. Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation. Science. 1993 Sep 24;261(5129):1736–1739. doi: 10.1126/science.8378775. [DOI] [PubMed] [Google Scholar]
  37. Silvennoinen O., Witthuhn B. A., Quelle F. W., Cleveland J. L., Yi T., Ihle J. N. Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8429–8433. doi: 10.1073/pnas.90.18.8429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sims S. H., Cha Y., Romine M. F., Gao P. Q., Gottlieb K., Deisseroth A. B. A novel interferon-inducible domain: structural and functional analysis of the human interferon regulatory factor 1 gene promoter. Mol Cell Biol. 1993 Jan;13(1):690–702. doi: 10.1128/mcb.13.1.690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Stavnezer J., Radcliffe G., Lin Y. C., Nietupski J., Berggren L., Sitia R., Severinson E. Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7704–7708. doi: 10.1073/pnas.85.20.7704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Strehlow I., Seegert D., Frick C., Bange F. C., Schindler C., Böttger E. C., Decker T. The gene encoding IFP 53/tryptophanyl-tRNA synthetase is regulated by the gamma-interferon activation factor. J Biol Chem. 1993 Aug 5;268(22):16590–16595. [PubMed] [Google Scholar]
  41. Wakao H., Schmitt-Ney M., Groner B. Mammary gland-specific nuclear factor is present in lactating rodent and bovine mammary tissue and composed of a single polypeptide of 89 kDa. J Biol Chem. 1992 Aug 15;267(23):16365–16370. [PubMed] [Google Scholar]
  42. Wang L. M., Keegan A. D., Paul W. E., Heidaran M. A., Gutkind J. S., Pierce J. H. IL-4 activates a distinct signal transduction cascade from IL-3 in factor-dependent myeloid cells. EMBO J. 1992 Dec;11(13):4899–4908. doi: 10.1002/j.1460-2075.1992.tb05596.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wegenka U. M., Buschmann J., Lütticken 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. 1993 Jan;13(1):276–288. doi: 10.1128/mcb.13.1.276. [DOI] [PMC free article] [PubMed] [Google Scholar]

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