TY - JOUR
T1 - Synergy of IL-12 and IL-18 for IFN-γ gene expression
T2 - IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein
AU - Nakahira, Masakiyo
AU - Ahn, Hyun Jong
AU - Park, Woong Ryeon
AU - Gao, Ping
AU - Tomura, Michio
AU - Park, Cheung Seog
AU - Hamaoka, Toshiyuki
AU - Ohta, Tsunetaka
AU - Kurimoto, Masashi
AU - Fujiwara, Hiromi
PY - 2002/2/1
Y1 - 2002/2/1
N2 - 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.
AB - 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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U2 - 10.4049/jimmunol.168.3.1146
DO - 10.4049/jimmunol.168.3.1146
M3 - Article
C2 - 11801649
AN - SCOPUS:0036467440
SN - 0022-1767
VL - 168
SP - 1146
EP - 1153
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -