IL-18, GADD45β, and IFN-γ

Science's STKE  13 Feb 2001:
Vol. 2001, Issue 69, pp. tw2
DOI: 10.1126/stke.2001.69.tw2

T cells can activate the expression of interferon-γ (IFN-γ) by T cell receptor (TCR)-dependent and TCR-independent means. TCR-independent activation of IFN-γ 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-γ 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-γ, unless treated with IL-12 and IL-18, indicating that GADD45β is not sufficient to cause cytokine-mediated IFN-γ production. Nevertheless, several experiments support a role for GADD45β in promoting IFN-γ 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-γ production. Also, a p38-specific inhibitor blocked the production of IFN-γ by IL-12 and IL-18. Although cyclosporin A can inhibit TCR-dependent signaling and IFN-γ production, the experiments by Yang et al. indicate that GADD45β may be a new target for therapeutic intervention in diseases associated with IFN-γ 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-γ 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]