Synergy of IL-12 and IL-18 for IFN-γ gene expression

IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein

Masakiyo Nakahira, Hyun Jong Ahn, Woong Ryeon Park, Ping Gao, Michio Tomura, Cheung Seog Park, Toshiyuki Hamaoka, Tsunetaka Ohta, Masashi Kurimoto, Hiromi Fujiwara

Research output: Contribution to journalArticle

Abstract

IL-12 and IL-18 synergistically enhance IFN-γ mRNA transcription by activating STAT4 and AP-1, respectively. However, it is still unknown how STAT4/AP-1 elicit IFN-γ promoter activation. Using an IL-12/IL-18-responsive T cell clone, we investigated the mechanisms underlying synergistic enhancement of IFN-γ mRNA expression induced by these two cytokines. Synergy was observed in a reporter gene assay using an IFN-γ 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-γ promoter activation without directly binding to the promoter sequence, providing a mechanistic explanation for IL-12/IL-18-induced synergistic enhancement of IFN-γ gene expression.

Original languageEnglish (US)
Pages (from-to)1146-1153
Number of pages8
JournalJournal of Immunology
Volume168
Issue number3
StatePublished - Feb 1 2002
Externally publishedYes

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Interleukin-18
Transcription Factor AP-1
Interleukin-12
Gene Expression
Proteins
T-Lymphocytes
Messenger RNA
JNK Mitogen-Activated Protein Kinases
Reporter Genes
Serine
Up-Regulation
Clone Cells
Lymph Nodes
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

Synergy of IL-12 and IL-18 for IFN-γ gene expression : IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein. / Nakahira, Masakiyo; Ahn, Hyun Jong; Park, Woong Ryeon; Gao, Ping; Tomura, Michio; Park, Cheung Seog; Hamaoka, Toshiyuki; Ohta, Tsunetaka; Kurimoto, Masashi; Fujiwara, Hiromi.

In: Journal of Immunology, Vol. 168, No. 3, 01.02.2002, p. 1146-1153.

Research output: Contribution to journalArticle

Nakahira, M, Ahn, HJ, Park, WR, Gao, P, Tomura, M, Park, CS, Hamaoka, T, Ohta, T, Kurimoto, M & Fujiwara, H 2002, 'Synergy of IL-12 and IL-18 for IFN-γ gene expression: IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein', Journal of Immunology, vol. 168, no. 3, pp. 1146-1153.
Nakahira, Masakiyo ; Ahn, Hyun Jong ; Park, Woong Ryeon ; Gao, Ping ; Tomura, Michio ; Park, Cheung Seog ; Hamaoka, Toshiyuki ; Ohta, Tsunetaka ; Kurimoto, Masashi ; Fujiwara, Hiromi. / Synergy of IL-12 and IL-18 for IFN-γ gene expression : IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein. In: Journal of Immunology. 2002 ; Vol. 168, No. 3. pp. 1146-1153.
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abstract = "IL-12 and IL-18 synergistically enhance IFN-γ mRNA transcription by activating STAT4 and AP-1, respectively. However, it is still unknown how STAT4/AP-1 elicit IFN-γ promoter activation. Using an IL-12/IL-18-responsive T cell clone, we investigated the mechanisms underlying synergistic enhancement of IFN-γ mRNA expression induced by these two cytokines. Synergy was observed in a reporter gene assay using an IFN-γ 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-γ promoter activation without directly binding to the promoter sequence, providing a mechanistic explanation for IL-12/IL-18-induced synergistic enhancement of IFN-γ gene expression.",
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