IFN-γ Up-Regulates IL-18 Gene Expression Via IFN Consensus Sequence-Binding Protein and Activator Protein-1 Elements in Macrophages

Abstract

Constitutive IL-18 expression is detected from many different cells, including macrophages, keratinocytes, and osteoblasts. It has been known that IL-18 gene expression is regulated by two different promoters (p1 promoter and p2 promoter). When RAW 264.7 macrophages were treated with IFN-γ, IL-18 gene expression was increased in a dose- and time-dependent manner. IFN-γ activated the inducible promoter 1, but not the constitutive promoter 2. Mutagenesis studies indicated that an IFN consensus sequence-binding protein (ICSBP) binding site between −39 and −22 was critical for the IFN-γ inducibility. EMSA using an ICSBP oligonucleotide probe showed that IFN-γ treatment increased the formation of DNA-binding complex, which was supershifted with anti-IFN regulatory factor-1 Ab and anti-ICSBP Ab. Another element, an AP-1 site between −1120 and −1083, was important. EMSA using an AP-1-specific oligonucleotide demonstrated that IFN-γ or LPS treatment increased the AP-1-binding activity. The addition of anti-c-Jun Ab or anti-c-Fos Ab to IFN-γ- or LPS-treated nuclear extracts resulted in the reduction of AP-1 complex or the formation of a supershifted complex. Taken together, these results indicate that IFN-γ increased IL-18 gene expression via ICSBP and AP-1 elements.

Neutrophil Proteinase 3-Mediated Induction of Bioactive IL-18 Secretion by Human Oral Epithelial Cells

“…3A), indicating the requirement of an additional signaling pathway to TLR4/ MyD88 for the active IL-18 induction. It is also reported that IFN-␥ and LPS up-regulate IL-18 gene expression via IFN consensus sequence-binding protein and AP-1 elements in macrophages (41), which may be the mechanism of the IFN-␥ and LPS effects in this study. In support of this, the expression of 24-kDa proIL-18 protein was not reduced in the lysate of the cells treated with LPS and PR3 after IFN-␥ priming, even though 18-kDa IL-18 was markedly generated in the cell lysate and supernatant by the treatment (Fig.…”

Complex Formation of the Interferon (IFN) Consensus Sequence-binding Protein with IRF-1 Is Essential for Murine Macrophage IFN-γ-induced iNOS Gene Expression

“…Accumulated evidence indicates that ICSBP and PU.1 activate transcription through Ets-IRF DNA elements and related elements in IFN-␥-stimulated macrophages, as reported for IL-1␤ and the respiratory oxidase gene gp91 phox (44 -46). ICSBP and PU.1 may also have a role in enhancing expression of the toll-like receptor 4 and IL-18 through a similar element (47,48). This activation seems to involve other factors, notably the co-activator/histone acetylase cAMP-response element-binding protein-binding protein/p300, with which PU.1 has been shown to interact (49).…”

Overexpression of Interleukin-18 Aggravates Cardiac Fibrosis and Diastolic Dysfunction in Fructose-Fed Rats

“…In addition, the inhibitory effect of heat shock on IL-18 expression is related to the interference of the JNK/AP-1 signaling pathway (24). Recent studies revealed that AP-1 is involved in regulating the expression of IL-18 (25), suggesting that the JNK/AP-1 signaling pathway could have a critical role in mediating the production of IL-18. In the present study, we have shown a direct effect of IL-18 on cardiac fibrosis.…”