Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. STKE, 13 February 2001
Vol. 2001, Issue 69, p. tw2
[DOI: 10.1126/stke.2001.69.tw2]

EDITORS' CHOICE

Immunology IL-18, GADD45β, and IFN-{gamma}

T cells can activate the expression of interferon-{gamma} (IFN-{gamma}) by T cell receptor (TCR)-dependent and TCR-independent means. TCR-independent activation of IFN-{gamma} occurs through the synergistic actions of the cytokines interleukin (IL)-12 and IL-18 and requires new protein synthesis. Yang et al. have identified an important factor required for synergistic activation of IFN-{gamma} production. Yang et al. identified GADD45β as a gene whose expression was modestly increased in T cells by IL-18 treatment, but greatly increased by simultaneous IL-12 and IL-18 treatment. T cells constitutively expressing GADD45β did not produce high levels of IFN-{gamma}, unless treated with IL-12 and IL-18, indicating that GADD45β is not sufficient to cause cytokine-mediated IFN-{gamma} production. Nevertheless, several experiments support a role for GADD45β in promoting IFN-{gamma} production. GADD45β can bind to and activate mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase kinase 4 (MEKK4), an upstream activator of the p38 MAPK. Yang et al. demonstrated that overexpression of GADD45β led to sustained activation of p38 They also showed that treatment of resting T cells with IL-12 and IL-18 was sufficient to activate endogenous p38, presumably through the activation of endogenous GADD45β. Expression of MEKK4 mutants lacking the kinase domain inhibited cytokine- but not TCR-dependent IFN-{gamma} production. Also, a p38-specific inhibitor blocked the production of IFN-{gamma} by IL-12 and IL-18. Although cyclosporin A can inhibit TCR-dependent signaling and IFN-{gamma} production, the experiments by Yang et al. indicate that GADD45β may be a new target for therapeutic intervention in diseases associated with IFN-{gamma} production. A News & Views article by Nakanishi provides a very helpful introduction to the intricacies of cytokine regulation.

J. Yang, H. Zhu, T. L. Murphy, W. Ouyang, K. M. Murphy, IL-18-stimulated GADD45β required in cytokine-induced, but not TCR-induced, IFN-{gamma} production. Nature Immunol. 2, 157-164 (2001). [Online Journal]

K. Nakanishi, Innate and acquired activation pathways in T cells. Nature Immunol. 2, 140-142 (2001). [Online Journal]

Citation: IL-18, GADD45β, and IFN-{gamma}. Sci. STKE 2001, tw2 (2001).


To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882