title: TGF-beta/Smad signaling inhibits IFN-gamma and TNF-alpha-induced TARC (CCL17) production in HaCaT cells.
abstract: BACKGROUND
  A Th2 chemokine, thymus and activation regulated chemokine (TARC/CCL17), produced by keratinocytes, is implicated in the development of atopic dermatitis by recruiting CLA(+)CCR4(+) lymphocytes into lesional skin and its expression was induced by proinflammatory cytokines such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). However, it remains unknown how TARC expression is negatively regulated in keratinocytes.
  
  
  OBJECTIVE
  We sought to determine whether transforming growth factor-beta 1 (TGF-beta 1) regulated TARC expression in keratinocytes.
  
  
  METHODS
  The effect of TGF-beta 1 on mRNA and protein expression of IFN-gamma and TNF-alpha-induced TARC in a human keratinocyte cell line, HaCaT cells, was evaluated by using RT-PCR and ELISA. Adenovector-mediated gene transfer was used to determine the effect of Smad proteins on TARC expression in HaCaT cells.
  
  
  RESULTS
  TGF-beta 1 inhibited mRNA and protein expression of IFN-gamma and TNF-alpha-induced TARC in HaCaT cells. The inhibitory effect of TGF-beta 1 on the TARC expression was suppressed by overexpression of Smad7, a major inhibitory regulator of Smad pathway for transforming growth factor-beta (TGF-beta) signaling, but not by PD98059, an inhibitor for ERK/mitogen-activated protein kinase (MAPK) pathway. In addition, overexpression of Smad2 or Smad3, major signal transducing Smads, was sufficient to inhibite the IFN-gamma and TNF-alpha-induced TARC production in HaCaT cells.
  
  
  CONCLUSIONS
  TGF-beta1 inhibited IFN-gamma and TNF-alpha-induced TARC production in HaCaT cells via Smad2/3, suggesting that modulation of TGF-beta/Smad signaling pathway may be beneficial for the treatment of atopic dermatitis.
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sumiyoshi
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Nakao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Setoguchi
authors.forename: Ryoji
authors.initials: R
authors.lastname: Tsuboi
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D002460:Cell Line; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C106230:CCL17 protein, human; D054414:Chemokine CCL17; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma