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Anti-cytokine therapies have been used for rheumatoid arthritis (RA) and their efficacy has been previously reported. Serum amyloid A (SAA) is an acute phase protein and known as a precursor of amyloid fibril in AA amyloidosis. IL-6 blocking therapy normalized the serum levels of SAA, in RA patients, while anti-TNFα or IL-1 therapy did not. From the clinical point of view, the exact identification of the induction mechanism of SAA is important. We found that IL-6 plays a critical role in the synergistic induction of the SAA gene by combining with proinflammatory cytokines. Moreover, we discovered that STAT3 plays an essential role in cytokine-driven SAA gene expression even though no typical STAT3 response element (RE) is located in its promoters. STAT3 and NF-κB p65 first form a complex following IL-1 and IL-6 stimulation, after which STAT3 interacts with non-consensus sequences at a 3'-site of NF-κB RE on the SAA gene promoter. STAT3 then recruits p300, which coordinates the interaction of NF-κB p65, STAT3 and C/EBPβ in the synergistic induction of the SAA gene. Our findings have a direct bearing on a better understanding of inflammatory status and are expected to contribute to the development of a therapeutic strategy for AA amyloidosis.

Analysis of cytokine-driven serum amyloid A expression based on the clinical results of IL-6 blocking therapy: a new cis-acting mechanism of STAT3