RT Journal Article
SR Electronic
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
FD The Journal of Rheumatology
SP 2309
OP 2317
DO 10.3899/jrheum.101362
VO 38
IS 11
A1 KIYOSHI MIGITA
A1 TOMOHIRO KOGA
A1 ATSUMASA KOMORI
A1 TAKAFUMI TORIGOSHI
A1 YUMI MAEDA
A1 YASUMORI IZUMI
A1 JUNJI SATO
A1 YUKA JIUCHI
A1 TAIICHIRO MIYASHITA
A1 SATOSHI YAMASAKI
A1 ATSUSHI KAWAKAMI
A1 MINORU NAKAMURA
A1 SATORU MOTOKAWA
A1 HIROMI ISHIBASHI
YR 2011
UL http://www.jrheum.org/content/38/11/2309.abstract
AB 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.