title: Influence of Janus kinase inhibition on interleukin 6-mediated induction of acute-phase serum amyloid A in rheumatoid synovium.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Rheumatology and Clinical Research Center, Nagasaki Medical Center, Omura, Nagasaki, Japan. migita@nmc.hosp.go.jp
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Koga
authors.forename: Atsumasa
authors.initials: A
authors.lastname: Komori
authors.forename: Takafumi
authors.initials: T
authors.lastname: Torigoshi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Maeda
authors.forename: Yasumori
authors.initials: Y
authors.lastname: Izumi
authors.forename: Junji
authors.initials: J
authors.lastname: Sato
authors.forename: Yuka
authors.initials: Y
authors.lastname: Jiuchi
authors.forename: Taiichiro
authors.initials: T
authors.lastname: Miyashita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
authors.forename: Minoru
authors.initials: M
authors.lastname: Nakamura
authors.forename: Satoru
authors.initials: S
authors.lastname: Motokawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ishibashi
mesh_terms: D000210:Acute-Phase Reaction / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000187:drug effects; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000187:drug effects; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D010880:Piperidines; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000187:drug effects; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D015850:Interleukin-6; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; C479163:tofacitinib; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053612:Janus Kinases