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Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts.
Aomatsu, Tomoki; Imaeda, Hirotsugu; Takahashi, Kenichiro; Fujimoto, Takehide; Kasumi, Eiji; Yoden, Atsushi; Tamai, Hiroshi; Fujiyama, Yoshihide; Andoh, Akira.
Afiliação
  • Aomatsu T; Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu 520-2192, Japan.
Int J Mol Med ; 30(5): 1152-8, 2012 Nov.
Article em En | MEDLINE | ID: mdl-22895606
ABSTRACT
In order to investigate the molecular mechanisms underlying the immunosuppressive effects of tacrolimus (FK506) on intestinal inflammation, we examined whether FK506 effects cytokine/chemokine secretion in human colonic myofibroblasts. Human colonic myofibroblasts were isolated from normal human colonic tissue. The mRNA and protein expression for human CCL2 and CXCL10 were analyzed by real-time PCR and ELISA, respectively. p38 MAP kinase activation was evaluated by western blotting. Tacrolimus (1 µM) suppressed tumor necrosis factor (TNF)-α-induced CCL2 and CXCL10 mRNA expression, but did not modulate TNF-α-induced interleukin (IL)-6 or CXCL8 mRNA expression. Dose-dependent, inhibitory effects of tacrolimus on CCL2 and CXCL10 expression were observed at the mRNA and protein levels. Significant inhibitory effects of tacrolimus were observed at concentrations as low as 0.5 µM for CCL2 and 0.1 µM for CXCL10, respectively. TNF-α-induced CCL2 and CXCL10 expression depended on p38 MAP kinase activation, and tacrolimus strongly inhibited the TNF-α-induced phosphorylation of p38 MAP kinase. Tacrolimus did not affect interferon (IFN)-γ-induced signaling transducer and activator of transcription (STAT)-1 phosphorylation, nor did it modulate CXCL10 mRNA and protein expression. In conclusion, tacrolimus suppressed CCL2 and CXCL10 expression in human colonic myofibroblasts. These inhibitory effects of tacrolimus may play key roles in the therapeutic effects of colonic inflammation in inflammatory bowel disease (IBD) patients.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ativação Transcricional / Fator de Necrose Tumoral alfa / Tacrolimo / Quimiocina CCL2 / Proteínas Quinases p38 Ativadas por Mitógeno / Quimiocina CXCL10 / Miofibroblastos / Imunossupressores Limite: Humans Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ativação Transcricional / Fator de Necrose Tumoral alfa / Tacrolimo / Quimiocina CCL2 / Proteínas Quinases p38 Ativadas por Mitógeno / Quimiocina CXCL10 / Miofibroblastos / Imunossupressores Limite: Humans Idioma: En Ano de publicação: 2012 Tipo de documento: Article