TGF-beta/Smad signaling inhibits IFN-gamma and TNF-alpha-induced TARC (CCL17) production in HaCaT cells

• Published in: Journal of dermatological science Vol. 31; no. 1; pp. 53 - 58
• Main Authors: Sumiyoshi, Koji, Nakao, Atsuhito, Setoguchi, Yasuhiro, Tsuboi, Ryoji, Okumura, Ko, Ogawa, Hideoki
• Format: Journal Article
• Language: English
• Published: Netherlands 01.02.2003
• Subjects: Cell Line; Chemokine CCL17; Chemokines, CC - antagonists & inhibitors; Chemokines, CC - biosynthesis; DNA-Binding Proteins - metabolism; Humans; Interferon-gamma - pharmacology; Keratinocytes - metabolism; Signal Transduction - physiology; Smad2 Protein; Smad3 Protein; Trans-Activators - metabolism; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0923-1811
• DOI: 10.1016/S0923-1811(02)00141-X

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. We sought to determine whether transforming growth factor-beta 1 (TGF-beta 1) regulated TARC expression in keratinocytes. 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. 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. 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.