Session Type: Abstract Submissions (ACR)
Cytokine-induced hepatic serum amyloid A (SAA) is associated with the pathogenesis of AA amylodosis, a fatal disease with deposition of AA amyloid fibril on systemic organs, especially on kidney, thyroid and intestine in chronic inflammatory disease such as rheumatoid arthritis (RA). This study was to provide our recent results on SAA activation by IL-6-induced STAT3 and clinical analysis of IL-6 blocking therapy in AA amyloidosis complicating RA.
STAT3 contributing to transcriptional activation of SAA by forming a complex with NF-kB was analyzed by using the super shift assay, ChIP assay, and DNA affinity choromatography systems. A set of candidates for non-consensus STAT3 binding sites on SAA promoter was identified by using a new mathematics calculation theory. The binding of STAT3 to the non-consensus STAT3 binding sites was also confirmed by means of Luciferas assay and DNA affinity choromatography assay.
We demonstrated that IL-6 activated STAT3 is essential for inducing SAA mRNA expression, and that NF-kB p65 complementally augments SAA mRNA induction by IL-6 stimulation combined with IL-1or TNF-α.We found a non-consensus STAT3 response element (RE) at the 3’-down stream of NF-kB site on SAA promoter region for STAT3 binding. Anti-IL-6 receptor antibody can completely inhibit SAA expression and stat3-NF-kB complex formation induced by IL-6+IL-1+TNF-α.
We identified a non-consensus STAT3 binding site in SAA promoter based on a new statistical analysis method of protein-DNA complex structures, and confirmed that STAT3 binds to the predicted site followed for SAA expression induced by IL-6+IL-1. Our basic results may explain why IL-6 blockade completely inhibit the SAA production in AA amyloidosis patients with RA, and IL-6 is a pivotal cytokine for induction of SAA. Our results also indicated that STAT3 may activate more broad genes during inflammation through non-consensus RE, and IL-6 inhibition may inactivate more broad inflammatory genes.
L. P. Tripathi,
S. N. J. Song,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/basic-and-clinical-significance-of-interleukin-6-il-6-in-aa-amyloidosis-with-ra/