Transcriptional Complex Formation of c-Fos, STAT3, and Hepatocyte NF-1α Is Essential for Cytokine-Driven C-Reactive Protein Gene Expression
In: The Journal of Immunology, Jg. 180 (2008-03-01), S. 3492-3501
Online
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Zugriff:
C-reactive protein (CRP) is a sensitive marker and mediator of inflammation, whereas IL-6 blocking therapy can normalize serum levels of CRP in chronic inflammatory diseases. We investigated the precise synergistic induction mechanism of CRP gene expression by IL-1 and IL-6 in Hep3B cells. In the early induction phase, IL-1 inhibited IL-6-mediated CRP gene expression, and NF-κB p65 inhibited the luciferase activity of pGL3-CRP by IL-1 plus IL-6 even in the presence of overexpressed STAT3. In the late induction phase, we focused on JNK and p38 activated by IL-1. SP600125 reduced the expression of the CRP gene induced by IL-1 plus IL-6. Unexpectedly, overexpression of c-Fos dramatically enhanced the luciferase activity by IL-1 and IL-6 even though the CRP gene has no AP-1 response element (RE) in its promoter. The augmentative effect of c-Fos required the presence of STAT3 and 3′-hepatocyte NF-1 (HNF-1) RE, which were eliminated by dominant negative STAT3 and HNF-1α, respectively. SB203580 inhibited the phosphorylation of c-Fos enhanced by IL-1 plus IL-6, and diminished expression of the CRP gene. Immunoprecipitation, Western blot analysis, the Supershift assay using a CRP oligonucleotide containing STAT3 and 3′-HNF-1 RE, and the chromatin immunoprecipitation assay demonstrated that c-Fos/STAT3/HNF-1α forms a complex on the CRP gene promoter. Because human fetus liver cells failed to express c-Fos/STAT3/HNF-1α showed no CRP production, transcriptional complex formation of c-Fos/STAT3/HNF-1α is essential for the synergistic induction of CRP gene expression by IL-1 plus IL-6. Our findings fully explain the clinical results of IL-6 blocking therapy and are expected to contribute to the development of a therapeutic strategy for chronic inflammatory diseases.
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Transcriptional Complex Formation of c-Fos, STAT3, and Hepatocyte NF-1α Is Essential for Cytokine-Driven C-Reactive Protein Gene Expression
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Autor/in / Beteiligte Person: | Naka, Tetsuji ; Tanaka, Toshio ; Isobe, Tomoyasu ; Hagihara, Keisuke ; Song, Jian ; Matsumura, Atsumi ; Serada, Satoshi ; Yoshizaki, Kazuyuki ; Nishikawa, Teppei ; Kawase, Ichiro |
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Zeitschrift: | The Journal of Immunology, Jg. 180 (2008-03-01), S. 3492-3501 |
Veröffentlichung: | The American Association of Immunologists, 2008 |
Medientyp: | unknown |
ISSN: | 1550-6606 (print) ; 0022-1767 (print) |
DOI: | 10.4049/jimmunol.180.5.3492 |
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