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

根据Betts等人关于诱导人SAA2基因的报道，C/EBPβ和NF-κB转录因子参与了IL-6和IL-1的协同激活。我们建立了SAA亚型实时定量RT-PCR检测，以估计细胞因子刺激后SAA亚型的mRNA表达。我们证明IL-6是协同诱导SAA基因在IL-6，Il-1β和TNF-α之间所必需的，并且IL-6阻断（抗il - 6r抗体）而不是TNF-α或Il-1阻断完全抑制SAA1和SAA2基因在三重刺激中的协同诱导。我们的研究结果表明，IL-6在IL-6、IL-1和TNF-α协同激活人SAA基因中起关键作用。此外，我们认为JAK/STAT3途径通过MAP激酶途径比C/EBPβ发挥更重要的作用。接下来，我们提供证据证明STAT3在SAA表达的细胞因子驱动中起重要作用，尽管人类SAA基因的启动子中没有典型的STAT3应答元件（RE）。STAT3和NF-κB p65首先在IL-1和IL-6（IL-1+6）刺激下形成复合物，然后STAT3在SAA基因启动子NF-κB RE的3'位点与未达成一致的序列相互作用。此外，p300与STAT3的共表达显著增强了SAA的转录活性。与STAT3、NF-κB p65和p300形成复合物是IL-1+6刺激协同诱导SAA基因的必要条件。我们的发现有望帮助理解炎症状态。

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.