Differential effects of the immunosuppressant FK-506 on human α2(I) collagen gene expression and transforming growth factor β signaling in normal and scleroderma fibroblasts

Yoshihide Asano, Hironobu Ihn, Kenichi Yamane, Masatoshi Jinnin, Yoshihiro Mimura, Kunihiko Tamaki

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Objective. To investigate the effects of FK-506 on the expression of the human α2(I) collagen gene and transforming growth factor β (TGFβ) signaling in normal and scleroderma fibroblasts. Methods. The expression levels of type I procollagen protein and α2(I) collagen messenger RNA (mRNA) were analyzed by immunoblotting and Northern blotting, respectively. The promoter activities of α2(I) collagen gene and 3TP-Lux were determined by transient transfection assay. Interaction between TGFβ receptor type I and FK-506 binding protein 12 (FKBP12) was evaluated by immunoprecipitation. Results. FK-506 did not affect the basal expression of type I procollagen protein or α2(I) collagen mRNA, but it significantly reduced the TGFβ1-induced expression of type 1 procollagen protein and α2(I) collagen mRNA in normal fibroblasts. The effect of FK-506 was regulated posttranscriptionally, but not transcriptionally. In scleroderma fibroblasts, FK-506 significantly reduced the expression of type I procollagen protein and α2(I) collagen mRNA through post-transcriptional regulation, but not transcriptional regulation. FK-506 increased the basal activity of the 3TP-Lux promoter, but it did not affect the TGFβ1-induced promoter activity in normal fibroblasts. In contrast, FK-506 did not affect the basal or the TGFβ1-induced 3TP-Lux promoter activity in scleroderma fibroblasts. Furthermore, FKBP12, which protects TGFβ receptor type I from ligand-independenf activation by TGFβ receptor type II, constitutively dissociated from TGFβ receptor type I in scleroderma fibroblasts. Conclusion. FK-506 inhibits α2(I) collagen gene expression by reducing the stability of mRNA without exhibiting its activation effect on TGFβ signaling in scleroderma fibroblasts.

Original languageEnglish
Pages (from-to)1237-1247
Number of pages11
JournalArthritis and Rheumatism
Volume52
Issue number4
DOIs
Publication statusPublished - 2005 Apr
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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