title: The role of α-defensin-1 and related signal transduction mechanisms in the production of IL-6, IL-8 and MMPs in rheumatoid fibroblast-like synoviocytes.
abstract: OBJECTIVE
  To investigate the effect of α-defensin-1 on the expression of IL-6, IL-8 and MMPs as well as the signal transduction mechanisms responsible for their expression in RA fibroblast-like synoviocytes (FLS).
  
  
  METHODS
  The concentrations of α-defensin-1 in SF were measured by ELISA. In RA FLS, mRNA expression of IL-6, IL-8 and MMPs and activation of signalling molecules were examined by real-time PCR, western blotting and electrophoretic mobility shift assay.
  
  
  RESULTS
  Concentrations of SF α-defensin-1 were significantly increased in RA patients compared with OA patients. The levels of mRNA expression of IL-6, IL-8, MMP-1 and MMP-3 were significantly increased in RA FLS treated with α-defensin-1 compared with controls. Furthermore, α-defensin-1 activated JNK and ERK in RA FLS, respectively. Treatment of RA FLS with ERK or JNK inhibitors prior to α-defensin-1 treatment resulted in reduced expression of IL-6, IL-8, MMP-1, and MMP-3 compared with controls. Remarkably, treatment of RA FLS with an ERK inhibitor prior to α-defensin-1 stimulation significantly reduced production of IL-6 and MMP-1 by approximately 71% and 98% compared with controls, respectively. The JNK inhibitor significantly suppressed α-defensin-1-induced MMP-1 production by approximately 73% compared with controls. Finally, there was a significant induction of NF-κB DNA binding activity in response to α-defensin-1.
  
  
  CONCLUSIONS
  Our results suggest that α-defensin-1 may play a role in RA pathogenesis by regulating the production of MMPs as well as IL-6 and IL-8. These processes were dependent on the regulation of the JNK and/or ERK and NF-κB pathways.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.
authors.forename: Joong Kyong
authors.initials: JK
authors.lastname: Ahn
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Bae
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Hwang
authors.forename: Jaejoon
authors.initials: J
authors.lastname: Lee
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Koh
authors.forename: Hoon-Suk
authors.initials: HS
authors.lastname: Cha
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000187:drug effects / Q000276:immunology; D008297:Male; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D013583:Synovial Membrane / Q000166:cytology; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D023084:alpha-Defensins; D020782:Matrix Metalloproteinases
keywords: IL-6; MMP-1; RA; fibroblast-like synoviocytes; neutrophil; α-defensin-1