Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
AA amyloidosis is a serious complication of chronic inflammatory and infectious diseases resulting from the deposition of amyloid A protein. Serum amyloid A (SAA), a precursor molecule of AA protein produced in hepatocyte, is deposited in various organs as amyloid fibril during the development of AA amyloidosis. Proinflammatory cytokines, especially IL-6, play a key role in SAA production
1. The expression of SAA mRNA in hepatoma-derived cells treated by cytokines (IL-6, IL-1, TNF-a) with or without their inhibitors was examined by quantitative real-time PCR. Luciferase assay, EMSA and Chip assay were also used for analysis of SAA transcription mechanism
2. Clinical effects of IL-6 blockade on amyloidosis-related parameters including serum SAA, urinal protein and RA disease activity were evaluated in AA amyloidosis patients with RA. Scores of amyloid deposits in gastro-duodenal mucosal biopsy specimens were examined by histopathological staining and protein quantitative ELISA.
1. Our results proved that IL-6 plays a critical role in cytokine-driven SAA expression through STAT3 activation. TNF-a/IL-1 complementally contributes to the synergistic induction of the triple-cytokines-induced SAA gene through NF-kB activation. We further found that a novel STAT3 non-consensus TFBS at the immediate downstream of the NF-κB RE in the SAA1 promoter region that is required for NF-κB p65 and STAT3 to activate SAA1 transcription. In addition, the synergistic induction of SAA expression by cytokines combination was completely inhibited by tocilizumab but not by TNF-a or IL-1 inhibitor.
2. 23 AA amyloidosis with RA patients treated with tocilizumab showed significant improvements in disease activity, and reductions in serum SAA and urinal protein levels, and these effects were more pronounced in the tocilizumab group than in the TNF-a inhibitors group at 12 months after initiation of the treatment. Meanwhile, histological scores of AA deposition observed in gastroduodental biopsy specimens treated with tocilizumab showed significantly decrease in the area and concentration of amyloid deposits after the treatment.
Although activated NF-kB by IL-1 and TNF-a is also involved hepcidin production during inflammation, IL-6-activated STAT3 plays a key role in SAA regulation. Our clinical results with IL-6 blockage therapy suggest that the pathogenic cascade causing AA amyloidosis started from SAA induction by IL-6, so that IL-6 blockage constitute a promising molecular targeting therapy for AA amyloidosis.
Chugai Pamaceuicl Co.,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mechanism-of-effectiveness-of-il-6-blockade-for-reduction-of-saa-production-and-amyloid-a-deposition-in-aa-amyloidosis-patients-with-ra/