Essential role of STAT3 in cytokine-driven NF-kappaB-mediated serum amyloid A gene expression.
Serum amyloid A (SAA) is a sensitive marker of acute-phase responses and known as a precursor protein of amyloid fibril in amyloid A (AA) (secondary) amyloidosis. Since the serum SAA level is also closely related to activity of chronic inflammatory disease and coronary artery disease, it is important to clarify the exact induction mechanism of SAA from the clinical point of view. Here we provide evidence that STAT3 plays an essential role in cytokine-driven SAA expression, although the human SAA gene shows no typical STAT3 response element (RE) in its promoters. STAT3 and nuclear factor kappaB (NF-kappaB) p65 first form a complex following interleukin (IL)-1 and IL-6 (IL-1+6) stimulation, after which STAT3 interacts with nonconsensus sequences at a 3' site of the SAA gene promoter's NF-kappaB RE. Moreover, co-expression of p300 with STAT3 dramatically enhances the transcriptional activity of SAA. The formation of a complex with STAT3, NF-kappaB p65, and p300 is thus essential for the synergistic induction of the SAA gene by IL-1+6 stimulation. Our findings are expected to aid the understanding of the inflammatory status of AA amyloidosis to aid development of a therapeutic strategy for this disease by means of normalization of serum SAA levels.
Hagihara
Keisuke
K
Molecular Medicine, Osaka University Graduate School of Medicine, Osaka University, 2-1 Yamada-Oka, Suita, Osaka 565-0871, Japan.
Nishikawa
Teppei
T
Sugamata
Yasuhiro
Y
Song
Jian
J
Isobe
Tomoyasu
T
Taga
Tetsuya
T
Yoshizaki
Kazuyuki
K
D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011993:Recombinant Fusion Proteins; D020218:Response Elements / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein