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IL-18–stimulated GADD45β required in cytokine-induced, but not TCR-induced, IFN-γ production

Nature Immunology volume 2, pages 157–164 (2001)Cite this article

Abstract

Interleukin-12 (IL-12) and IL-18 induce synergistic transcription of interferon γ (IFN-γ) that is T cell receptor (TCR)-independent, not inhibited by cyclosporin A and requires new protein synthesis. To characterize this pathway, we screened for genes that are induced in IL-12– and IL-18–treated T helper type 1 cells. GADD45β, which activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase kinase 4 (MEKK4), was induced by IL-18 and augmented by IL-12. GADD45β expression in naïve CD4+ T cells activated p38 MAPK and selectively increased cytokine-induced, but not TCR-induced, IFN-γ production. Kinase-inactive MEKK4 and inhibition of the p38 MAPK pathway both selectively inhibit cytokine-induced, but not TCR-induced, IFN-γ production. Thus, the synergy between IL-12 and IL-18 may involve GADD45β induction, which can maintain the MEKK4 and p38 MAPK activation that is necessary for cytokine-induced, but not TCR-induced, IFN-γ production.

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Figure 1: IL-18–dependent protein synthesis is required for cytokine-induced IFN-γ transcription.
Figure 2: IL-12 + IL-18 induces expression of GADD45β and GADD45γ mRNA in TH1 cells.
Figure 3: GADD45β selectively augments cytokine-induced, but not TCR-induced, IFN-γ.
Figure 4: GADD45β induces constitutive p38 MAPK phosphorylation in CD4+ T cells.
Figure 5: Dominant-negative MEKK4 selectively inhibits cytokine-induced, but not TCR-induced, IFN-γ.
Figure 6: Selective requirement of p38 MAPK for cytokine-induced, but not TCR-induced, IFN-γ production.
Figure 7: Model of IL-18 and IL-12 signaling for induction of IFN-γ

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Acknowledgements

We thank J. D. Farrar for careful reading of the manuscript. Supported by grants from the NIH.

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  1. Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, 63110, MO, USA

    Jianfei Yang, Hong Zhu, Theresa L. Murphy, Wenjun Ouyang & Kenneth M. Murphy

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Correspondence to Kenneth M. Murphy.

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Yang, J., Zhu, H., Murphy, T. et al. IL-18–stimulated GADD45β required in cytokine-induced, but not TCR-induced, IFN-γ production. Nat Immunol 2, 157–164 (2001). https://doi.org/10.1038/84264

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