title: Inhibition of the signalling kinase JAK3 alleviates inflammation in monoarthritic rats.
abstract: OBJECTIVE
  Many cytokines associated with autoimmune disorders and inflammation have been shown to activate the signalling kinase JAK3, implying that JAK3 plays key roles in the pathogenesis of these diseases. Therefore, investigating the alterations of JAK3 activity and the efficacy of selective JAK3 antagonists in animal models of such disorders is essential to a better understanding of the biology of JAK3 and to assess the potential clinical benefits of JAK3 inhibitors.
  
  
  METHODS
  Through high-throughput cell-based screening using the NCI compound library, we identified NSC163088 (berberine chloride) as a novel inhibitor of JAK3. Specificity and efficacy of this compound were investigated in both cellular and animal models.
  
  
  RESULTS
  We show that berberine chloride has selectivity for JAK3 over other JAK kinase members, as well as over other oncogenic kinases such as Src, in various cellular assays. Biochemical and modelling studies strongly suggested that berberine chloride bound directly to the kinase domain of JAK3. Also phospho-JAK3 levels were significantly increased in the synovial tissues of rat joints with acute inflammation, and the treatment of these rats with berberine chloride decreased JAK3 phosphorylation and suppressed the inflammatory responses.
  
  
  CONCLUSIONS
  The up-regulation of JAK3/STATs was closely correlated with acute arthritic inflammation and that inhibition of JAK3 activity by JAK3 antagonists, such as berberine chloride, alleviated the inflammation in vivo.
authors: Department of Pediatrics, New York Medical College, Valhalla, New York, USA.
authors: Byung-Hak
authors: BH
authors: Kim
authors: Myunghwan
authors: M
authors: Kim
authors: Chang-Hong
authors: CH
authors: Yin
authors: Jun-Goo
authors: JG
authors: Jee
authors: Claudio
authors: C
authors: Sandoval
authors: Hyejung
authors: H
authors: Lee
authors: Erika A
authors: EA
authors: Bach
authors: Dae-Hyun
authors: DH
authors: Hahm
authors: Gyeong-Hun
authors: GH
authors: Baeg
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000201:enzymology; D001599:Berberine / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; C494094:Stat5a protein, rat; D001599:Berberine; D053616:Janus Kinase 3