TY - JOUR T1 - Influence of Janus Kinase Inhibition on Interleukin 6-mediated Induction of Acute-phase Serum Amyloid A in Rheumatoid Synovium JF - The Journal of Rheumatology JO - J Rheumatol SP - 2309 LP - 2317 DO - 10.3899/jrheum.101362 VL - 38 IS - 11 AU - KIYOSHI MIGITA AU - TOMOHIRO KOGA AU - ATSUMASA KOMORI AU - TAKAFUMI TORIGOSHI AU - YUMI MAEDA AU - YASUMORI IZUMI AU - JUNJI SATO AU - YUKA JIUCHI AU - TAIICHIRO MIYASHITA AU - SATOSHI YAMASAKI AU - ATSUSHI KAWAKAMI AU - MINORU NAKAMURA AU - SATORU MOTOKAWA AU - HIROMI ISHIBASHI Y1 - 2011/11/01 UR - http://www.jrheum.org/content/38/11/2309.abstract N2 - Objective. Inhibition of intracellular signal transduction is considered to be a therapeutic target for chronic inflammation. The new Janus kinase (JAK)3 inhibitor CP690,550 has shown efficacy in the treatment of rheumatoid arthritis (RA). We investigated the influence of JAK/STAT inhibition using CP690,550 on the induction of acute-phase serum amyloid A (SAA), which is triggered by interleukin 6 (IL-6) stimulation in rheumatoid fibroblast-like synoviocytes (RA-FLS). Methods. IL-6-stimulated gene expression of the acute-phase serum amyloid A genes (A-SAA; encoded by SAA1+SAA2) and SAA4 was analyzed by reverse transcriptase-polymerase chain reaction. The intracellular signaling pathway mediating the effects of CP690,550 on IL-6-stimulated JAK/STAT activation was assessed by measuring the phosphorylation levels using Western blots. Results. IL-6 trans-signaling induced A-SAA messenger RNA (mRNA) expression in RA-FLS. By contrast IL-6 stimulation did not affect SAA4 mRNA expression, which is expressed constitutively in RA-FLS. IL-6 stimulation elicited rapid phosphorylation of JAK2 and STAT3, which was blunted by CP690,550. CP690,550 abrogated IL-6-mediated A-SAA mRNA expression in RA-FLS. Similarly, CP690,550 inhibited IL-6-mediated A-SAA mRNA expression in human hepatocytes. Conclusion. Our data indicated that CP690,550 blocked IL-6-induced JAK2/STAT3 activation, as well as the induction of A-SAA. Inhibition of IL-6-mediated proinflammatory signaling pathways by CP690,550 may represent a new antiinflammatory therapeutic strategy for RA and AA amyloidosis. ER -