The roles of pro-inflammatory cytokines on induction of acute phase proteins in inflammatory diseases

点击翻译按钮获取中文摘要

According to the report by Betts et al. on induction of human SAA2 gene, the transcription factors of C/EBPβ and NF-κB are involved in the synergistic activation by IL-6 and IL-1. We established a SAA isoform real-time quantitative RT-PCR assay to estimate the mRNA expression of each of the SAA isoforms after cytokine stimulation. We demonstrate that IL-6 were necessary for the synergistic induction of SAA genes among IL-6,Il-1β and TNF-α and that IL-6 blockade (anti-IL-6R antibody) but not TNF-α or Il-1 blockade completely inhibits the synergistic induction of SAA1 and SAA2 genes in the triple stimulation. Our results indicate that IL-6 plays a critical role in the synergistic activation of human SAA gene by IL-6,IL-1 and TNF-α. Furthermore, we suggest that JAK/STAT3 pathway plays an important role than C/EBPβ through MAP kinase pathway.Next we provide evidence STAT3 plays an essential role in the cytokine-driven of SAA expression, although the human SAA gene has no typical STAT3 response element(RE) in its promoters. STAT3 and NF-κB p65 first form a complex following IL-1 and IL-6(IL-1+6) stimulation, and STAT3 then interacts with no-consensus sequences at a 3'-site of the NF-κB RE of the SAA gene promoter. Moreover, co-expression of p300 with STAT3 dramatically enhanced the transcriptional activity of SAA. The formation of a complex with STAT3,NF-κB p65, and p300 is 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.