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The Journal of Immunology, 2002, 168: 1146-1153.
Copyright © 2002 by The American Association of Immunologists

Synergy of IL-12 and IL-18 for IFN-{gamma} Gene Expression: IL-12-Induced STAT4 Contributes to IFN-{gamma} Promoter Activation by Up-Regulating the Binding Activity of IL-18-Induced Activator Protein 11

Masakiyo Nakahira*, Hyun-Jong Ahn*, Woong-Ryeon Park*, Ping Gao*, Michio Tomura*, Cheung-Seog Park*, Toshiyuki Hamaoka*, Tsunetaka Ohta{dagger}, Masashi Kurimoto{dagger} and Hiromi Fujiwara2,*

* Department of Oncology, Osaka University Graduate School of Medicine, Osaka, Japan; and {dagger} Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan

IL-12 and IL-18 synergistically enhance IFN-{gamma} mRNA transcription by activating STAT4 and AP-1, respectively. However, it is still unknown how STAT4/AP-1 elicit IFN-{gamma} promoter activation. Using an IL-12/IL-18-responsive T cell clone, we investigated the mechanisms underlying synergistic enhancement of IFN-{gamma} mRNA expression induced by these two cytokines. Synergy was observed in a reporter gene assay using an IFN-{gamma} promoter fragment that binds AP-1, but not STAT4. An increase in c-Jun, a component of AP-1, in the nuclear compartment was elicited by stimulation with either IL-12 or IL-18, but accumulation of serine-phosphorylated c-Jun was induced only by IL-18 capable of activating c-Jun N-terminal kinase. The binding of AP-1 to the relevant promoter sequence depended on the presence of STAT4. STAT4 bound with c-Jun, and a phosphorylated c-Jun-STAT4 complex most efficiently interacted with the AP-1-relevant promoter sequence. Enhanced cobinding of STAT4 and c-Jun to the AP-1 sequence was also observed when activated lymph node T cells were exposed to IL-12 plus IL-18. These results show that STAT4 up-regulates AP-1-mediated IFN-{gamma} promoter activation without directly binding to the promoter sequence, providing a mechanistic explanation for IL-12/IL-18-induced synergistic enhancement of IFN-{gamma} gene expression.




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