title: Induction of macrophage migration inhibitory factor in ConA-stimulated rheumatoid arthritis synovial fibroblasts through the P38 map kinase-dependent signaling pathway.
abstract: OBJECTIVE
  This study was undertaken to identify the intracellular signaling pathway involved in induction of macrophage migration inhibitory factor (MIF) in human rheumatoid arthritis (RA) synovial fibroblasts.
  
  
  METHODS
  Human RA synovial fibroblasts were treated with concanavalin A (ConA), various cytokines, and inhibitors of signal transduction molecules. The production of MIF by synovial fibroblasts was measured in culture supernatants by ELISA. The expression of MIF mRNA was determined using reverse transcriptase polymerase chain reaction (RT-PCR) and real-time PCR. Phosphorylation of p38 mitogen-activated protein (MAP) kinase in synovial fibroblasts was confirmed using Western blotting. The expression of MIF and p38 MAP kinase in RA synovium was determined using dual immunohistochemistry.
  
  
  RESULTS
  The production of MIF by RA synovial fibroblasts increased in a dose-dependent manner after ConA stimulation. MIF was also induced by interferon-γ, CD40 ligand, interleukin-15, interleukin-1β, tumor necrosis factor-α, and transforming growth factor-β. The production of MIF by RA synovial fibroblasts was significantly reduced after inhibition of p38 MAP kinase. The expression of MIF and p38 MAP kinase was upregulated in the RA synovium compared with the osteoarthritis synovium.
  
  
  CONCLUSIONS
  These results suggest that MIF production was induced through a p38 MAP-kinase-dependent pathway in RA synovial fibroblasts.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine Seoul, Korea.
authors.forename: Hae-Rim
authors.initials: HR
authors.lastname: Kim
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Kyoung-Woon
authors.initials: KW
authors.lastname: Kim
authors.forename: Hye-Joa
authors.initials: HJ
authors.lastname: Oh
authors.forename: Jin-Sil
authors.initials: JS
authors.lastname: Park
authors.forename: Yang-Mi
authors.initials: YM
authors.lastname: Heo
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Lee
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D017931:DNA Primers; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D003208:Concanavalin A; D048051:p38 Mitogen-Activated Protein Kinases