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Gadd45β is important for perpetuating cognate and inflammatory signals in T cells

Nature Immunology volume 5, pages 38–44 (2004)Cite this article

Abstract

Gadd45β (growth arrest and DNA damage–inducible, β) is involved in cell cycle arrest, apoptosis, signal transduction and cell survival. In T cells, Gadd45b was rapidly induced by T cell receptor (TCR) and inflammatory signals. Deficiency of Gadd45β in CD4+ T cells impaired their responses to TCR stimulation or inflammatory cytokines. ERK, p38 and JNK activation were all substantially suppressed in Gadd45β-deficient CD4+ T cells. Cytokine production by Gadd45β-deficient CD4+ T cells was also impaired. Furthermore, Gadd45β mediated inflammatory cytokine production by dendritic cells, and Gadd45β-deficient mice showed an impaired T helper type 1 response during Listeria monocytogenes infection. Gadd45β is therefore a critical feedback regulator that perpetuates both cognate and inflammatory signals.

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Figure 1: Gadd45b message is induced by TCR stimulation and enhanced by costimulation.
Figure 2: Gadd45β gene targeting strategy and results.
Figure 3: Gadd45β modulates TCR-induced MAP kinase activation and IL-2 production.
Figure 4: Gadd45β enhances TCR-induced MAP kinase activation and prolonged p38 activation.
Figure 5: Gadd45β is important for TCR-induced effector cytokine production in TH1, TH0 and TH2 cells.
Figure 6: Gadd45β mediates sustained p38 activation by IL-12 plus IL-18.
Figure 7: Gadd45β is important for in vivo generation of TH1 cells.
Figure 8: Gadd45β and Gadd45γ are important for innate immune responses.

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References

  1. Liebermann, D.A. & Hoffman, B. Myeloid differentiation (MyD) primary response genes in hematopoiesis. Oncogene 21, 3391–3402 (2002).

    Article  CAS  Google Scholar 

  2. Hollander, M.C. & Fornace, A.J. Jr. Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45α. Oncogene 21, 6228–6233 (2002).

    Article  CAS  Google Scholar 

  3. Chakravarty, D. et al. Three GADD45 isoforms contribute to hypertonic stress phenotype of murine renal inner medullary cells. Am. J. Physiol. Renal Physiol. 283, F1020–1029 (2002).

    Article  Google Scholar 

  4. Vairapandi, M., Balliet, A.G., Hoffman, B. & Liebermann, D.A. GADD45β and GADD45γ are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J. Cell Physiol. 192, 327–338 (2002).

    Article  CAS  Google Scholar 

  5. Yang, J., Zhu, H., Murphy, T.L., Ouyang, W. & Murphy, K.M. IL-18-stimulated GADD45β required in cytokine-induced, but not TCR-induced, IFN-γ production. Nat. Immunol. 2, 157–164 (2001).

    Article  CAS  Google Scholar 

  6. Lu, B. et al. GADD45γ mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity 14, 583–590 (2001).

    Article  CAS  Google Scholar 

  7. De Smaele, E. et al. Induction of gadd45b by NF-κB downregulates pro-apoptotic JNK signalling. Nature 414, 308–313 (2001).

    Article  CAS  Google Scholar 

  8. Takekawa, M. et al. Smad-dependent GADD45b expression mediates delayed activation of p38 MAP kinase by TGF-β. Embo J. 21, 6473–6482 (2002).

    Article  CAS  Google Scholar 

  9. Hoffmeyer, A., Piekorz, R., Moriggl, R. & Ihle, J.N. Gadd45γ is dispensable for normal mouse development and T-cell proliferation. Mol. Cell. Biol. 21, 3137–43 (2001).

    Article  CAS  Google Scholar 

  10. Zhang, W. et al. CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control. Oncogene 18, 4899–4907 (1999).

    Article  CAS  Google Scholar 

  11. Lang, R., Patel, D., Morris, J.J., Rutschman, R.L. & Murray, P.J. Shaping gene expression in activated and resting primary macrophages by IL-10. J. Immunol. 169, 2253–2263 (2002).

    Article  CAS  Google Scholar 

  12. Fan, W., Richter, G., Cereseto, A., Beadling, C. & Smith, K.A. Cytokine response gene 6 induces p21 and regulates both cell growth and arrest. Oncogene 18, 6573–6582 (1999).

    Article  CAS  Google Scholar 

  13. Fornace, A.J. Jr., Jackman, J., Hollander, M.C., Hoffman-Liebermann, B. & Liebermann, D.A. Genotoxic-stress-response genes and growth-arrest genes. gadd, MyD, and other genes induced by treatments eliciting growth arrest. Ann. NY Acad. Sci. 663, 139–153 (1992).

    Article  CAS  Google Scholar 

  14. Hollander, M.C. et al. Genomic instability in Gadd45α-deficient mice. Nat. Genet. 23, 176–184 (1999).

    Article  CAS  Google Scholar 

  15. Kearsey, J.M., Coates, P.J., Prescott, A.R., Warbrick, E. & Hall, P.A. Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene 11, 1675–83 (1995).

    CAS  PubMed  Google Scholar 

  16. Takekawa, M. & Saito, H. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95, 521–530 (1998).

    Article  CAS  Google Scholar 

  17. Vairapandi, M., Balliet, A., Fornace, A.J. Jr., Hoffman, B. & Liebermann, D.A. The differentiation primary response gene MyD118, related to GADD45, encodes for a nuclear protein which interacts with PCNA and p21WAF1/CIP1. Oncogene 12, 2579–2594 (1996).

    CAS  PubMed  Google Scholar 

  18. Zhan, Q. et al. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18, 2892–2900 (1999).

    Article  CAS  Google Scholar 

  19. Smith, M.L. et al. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266, 1376–1380 (1994).

    Article  CAS  Google Scholar 

  20. Harkin, D.P. et al. Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97, 575–586 (1999).

    Article  CAS  Google Scholar 

  21. Hildesheim, J. et al. Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53. Cancer Res. 62, 7305–7315 (2002).

    CAS  PubMed  Google Scholar 

  22. Takekawa, M., Posas, F. & Saito, H. A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO J. 16, 4973–4982 (1997).

    Article  CAS  Google Scholar 

  23. Gerwins, P., Blank, J.L. & Johnson, G.L. Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J. Biol. Chem. 272, 8288–8295 (1997).

    Article  CAS  Google Scholar 

  24. Azam, N., Vairapandi, M., Zhang, W., Hoffman, B. & Liebermann, D.A. Interaction of CR6 (GADD45γ) with proliferating cell nuclear antigen impedes negative growth control. J. Biol. Chem. 276, 2766–2774 (2001).

    Article  CAS  Google Scholar 

  25. Zhao, H. et al. The central region of Gadd45 is required for its interaction with p21/WAF1. Exp. Cell Res. 258, 92–100 (2000).

    Article  CAS  Google Scholar 

  26. Yi, Y.W. et al. Gadd45 family proteins are coactivators of nuclear hormone receptors. Biochem. Biophys. Res. Commun. 272, 193–198 (2000).

    Article  CAS  Google Scholar 

  27. Kovalsky, O., Lung, F.D., Roller, P.P. & Fornace, A.J. Jr. Oligomerization of human Gadd45a protein. J. Biol. Chem. 276, 39330–39339 (2001).

    Article  CAS  Google Scholar 

  28. Vairapandi, M., Azam, N., Balliet, A.G., Hoffman, B. & Liebermann, D.A. Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 and Gadd45-mediated negative growth control. J. Biol. Chem. 275, 16810–16819 (2000).

    Article  CAS  Google Scholar 

  29. Weiss, L. et al. Regulation of c-Jun NH2-terminal kinase (Jnk) gene expression during T cell activation. J. Exp. Med. 191, 139–146 (2000).

    Article  CAS  Google Scholar 

  30. Rincon, M. et al. Interferon-γ expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J. 17, 2817–2829 (1998).

    Article  CAS  Google Scholar 

  31. Ladel, C.H., Flesch, I.E., Arnoldi, J. & Kaufmann, S.H. Studies with MHC-deficient knock-out mice reveal impact of both MHC I- and MHC II-dependent T cell responses on Listeria monocytogenes infection. J. Immunol. 153, 3116–3122 (1994).

    CAS  PubMed  Google Scholar 

  32. Hsieh, C.S. et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547–549 (1993).

    Article  CAS  Google Scholar 

  33. Shen, H. et al. Recombinant Listeria monocytogenes as a live vaccine vehicle for the induction of protective anti-viral cell-mediated immunity. Proc. Natl. Acad. Sci. USA 92, 3987–3991 (1995).

    Article  CAS  Google Scholar 

  34. Pan, Z.K., Ikonomidis, G., Lazenby, A., Pardoll, D. & Paterson, Y. A recombinant Listeria monocytogenes vaccine expressing a model tumour antigen protects mice against lethal tumour cell challenge and causes regression of established tumours. Nat. Med. 1, 471–477 (1995).

    Article  CAS  Google Scholar 

  35. Morinobu, A. et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc. Natl. Acad. Sci. USA 99, 12281–12286 (2002).

    Article  CAS  Google Scholar 

  36. Huang, Q. et al. The plasticity of dendritic cell responses to pathogens and their components. Science 294, 870–875 (2001).

    Article  CAS  Google Scholar 

  37. Jin, R. et al. Regulation of the gadd45β promoter by NF-κB. DNA Cell. Biol. 21, 491–503 (2002).

    Article  CAS  Google Scholar 

  38. Wang, X., Gorospe, M. & Holbrook, N.J. Gadd45 is not required for activation of c-Jun N-terminal kinase or p38 during acute stress. J. Biol. Chem. 274, 29599–29602 (1999).

    Article  CAS  Google Scholar 

  39. Shaulian, E. & Karin, M. Stress-induced JNK activation is independent of Gadd45 induction. J. Biol. Chem. 274, 29595–29598 (1999).

    Article  CAS  Google Scholar 

  40. Dong, C., Davis, R.J. & Flavell, R.A. MAP kinases in the immune response. Annu. Rev. Immunol. 20, 55–72 (2002).

    Article  CAS  Google Scholar 

  41. Lu, B. et al. Genome wide analysis reveals key molecular circuitries that control T cell activation and Th1/Th2 differentiation. Proc. Natl. Acad. Sci. USA (in the press).

  42. Kursar, M. et al. Organ-specific CD4+ T cell response during Listeria monocytogenes infection. J. Immunol. 168, 6382–6387 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Eynon for scientific interactions; E. Tran for suggestions and reading the manuscript; L. Evangelisti, J. Miller and J. Stein for technical assistance; G. Chenell for secretarial assistance; and F. Manzo for assistance with manuscript preparation. We also thank Wyeth (formerly Genetics Institute) for the gift of recombinant IL-12. Supported by National Institutes of Health grants (1 P01 AI36529 and 1 K01 AR048854) and the Howard Hughes Medical Institute.

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  1. Binfeng Lu

    Present address: Department of Immunology, University of Pittsburgh School of Medicine, E1047 BST, 200 Lothrop Street, Pittsburgh, Pennsylvania, 15261, USA

Authors and Affiliations

  1. Section of Immunobiology, Yale University School of Medicine, 310 Cedar Street, New Haven, 06520-8011, Connecticut, USA

    Binfeng Lu, Anthony F Ferrandino & Richard A Flavell

  2. Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, 06520-8011, Connecticut, USA

    Richard A Flavell

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Correspondence to Richard A Flavell.

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Lu, B., Ferrandino, A. & Flavell, R. Gadd45β is important for perpetuating cognate and inflammatory signals in T cells. Nat Immunol 5, 38–44 (2004). https://doi.org/10.1038/ni1020

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