title: Tacrolimus (FK506) inhibits interleukin-1β-induced angiopoietin-1, Tie-2 receptor, and vascular endothelial growth factor through down-regulation of JNK and p38 pathway in human rheumatoid fibroblast-like synoviocytes.
abstract: OBJECTIVE
  This study aimed to identify the regulatory effect of tacrolimus on the interleukin-1β (IL-1β)-induced expressions of angiopoietin-1 (Ang-1), Tie-2 receptor (Tie-2), and vascular endothelial growth factor (VEGF) in human rheumatoid fibroblast-like synoviocytes (FLS) and to determine the regulatory mechanism in the mitogen-activated protein kinases (MAPKs) signaling pathway.
  
  
  METHODS
  IL-1β-induced Ang-1, Tie-2, and VEGF expressions with and without tacrolimus were measured in cultured FLS using real time-polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining. The effect of tacrolimus on the regulation of Ang-1, Tie-2 and VEGF expressions through the MAPK signaling pathway was identified by Western blotting and immunofluorescence staining.
  
  
  RESULTS
  IL-1β appeared to induce marked expressions of Ang-1, Tie-2, and VEGF in cultured FLS. Tacrolimus significantly inhibited Ang-1, Tie-2, and VEGF mRNA and protein in cultured FLS treated with 10 ng/ml IL-1β. In addition, expressions of these angiogenic molecules were shown to involve all three of the studied MAPK signaling pathways, including ERK, JNK, and p38. However, the inhibitory effects of tacrolimus on Ang-1, Tie-2, and VEGF proteins were regulated by blocking the phosphorylations of JNK and p38 MAPK, but not that of ERK.
  
  
  CONCLUSIONS
  This study demonstrates that tacrolimus inhibits the expressions of Ang-1, Tie-2, and VEGF by blocking the activations of the IL-1β-mediated JNK and p38 MAPK pathways in human FLS. This suggests that tacrolimus contributes to the suppression of angiogenesis in the pathogenesis of RA.
authors.affiliation: Department of Internal Medicine, Arthritis and Autoimmunity Research Center, Catholic University of Daegu School of Medicine, 3056-6 Daemyung 4-Dong, Namgu, Daegu 705-718, Republic of Korea.
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Choe
authors.forename: Seung-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Kim
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology*; D016559:Tacrolimus / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D016559:Tacrolimus