title: Inhibition of TNF-induced IL-6 by the TWEAK-Fn14 interaction in rheumatoid arthritis fibroblast like synoviocytes.
abstract: OBJECTIVE
  TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, has been shown to increase cytokine production by rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). In this study, we determined the effect of interaction between TWEAK and its receptor fibroblast growth factor-inducible-14 (Fn14) on cytokine expression in RAFLS.
  
  
  METHODS
  RAFLS were obtained from surgical synovial specimens and used at passage 5-10. Cytokine protein and mRNA expression were measured with ELISA and real time-PCR, respectively. Apoptotic cells were detected by TUNEL assay. RelB activation was detected by Western blot analysis.
  
  
  RESULTS
  TWEAK inhibited IL-6 production from total synovial cells from RA. TWEAK weakly induced FLS IL-6 and IL-8, but in contrast TWEAK dose-dependently inhibited IL-6 and IL-8 production by TNFα-activated FLS. TWEAK did not induce apoptosis in FLS but inhibited proliferation of TNFα-activated FLS. TWEAK induced RelB activation and suppressed IL-6 mRNA expression in TNFα-activated FLS and both of these phenomenon were abolished by inhibition of new protein synthesis with cycloheximide.
  
  
  CONCLUSIONS
  TWEAK has a previously unsuspected inhibitory effect on cytokine production by TNFα-activated RAFLS. This observation suggests that the effects of TWEAK on cytokine expression varies with the pro-inflammatory context, and that in TNFα-activated states such as RA TWEAK may have a net inhibitory effect.
authors: Department of Medicine and Clinical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. jyamanajyamana@yahoo.co.jp
authors: Jiro
authors: J
authors: Yamana
authors: Eric F
authors: EF
authors: Morand
authors: Tsuno
authors: T
authors: Manabu
authors: Katsue
authors: K
authors: Sunahori
authors: Kouji
authors: K
authors: Takasugi
authors: Hirofumi
authors: H
authors: Makino
authors: Masahiro
authors: M
authors: Yamamura
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000074049:Cytokine TWEAK; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D000074050:TWEAK Receptor; D051841:Transcription Factor RelB / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000074049:Cytokine TWEAK; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D000074050:TWEAK Receptor; D051841:Transcription Factor RelB; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C497593:RELB protein, human; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human