• Kiyoshi Migita, Tomohiro Koga, Atsumasa Komori, Takafumi Torigoshi, Yumi Maeda, Yasumori Izumi, Junji Sato, Yuka Jiuchi, Taiichiro Miyashita, Satoshi Yamasaki, Atsushi Kawakami, Minoru Nakamura, Satoru Motokawa, and Hiromi Ishibashi.
• Department of Rheumatology and Clinical Research Center, Nagasaki Medical Center, Omura, Nagasaki, Japan. migita@nmc.hosp.go.jp
• J Rheumatol. 2011 Nov 1; 38 (11): 2309-17.

ObjectiveInhibition 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).MethodsIL-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.ResultsIL-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.ConclusionOur 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.

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