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Spontaneous and cytokine regulated c-fos gene expression in rheumatoid synovial cells: resistance to cytokine stimulation when the c-fos gene is overexpressed

  • K Shimizu
  • H Kawasaki
  • T Morisawa
  • M Nakamura
  • E Yamamoto
  • N Yoshikawa
  • M Doita
  • K Shiozawa
  • S Yonehara
  • K Chihara
  • S Shiozawa
Publication Date
Aug 01, 2000
  • Biology


OBJECTIVE—To study the effect of cytokines on the transactivation of the c-fos gene in relation to the contribution of overexpression of c-fos/AP-1 in rheumatoid joint destruction.
METHODS—The promoter region (−447 to +109) of the human c-fos gene was integrated upstream of the chloramphenicol acetyltransferase (CAT) reporter gene, and the effect of cytokines on the expression of the c-fos gene was studied in the rheumatoid synovial cells of early (3-4) or late (14-18) passages, in the presence or absence of cytokines, by the transient transfection assay.
RESULTS—Expression of c-fos gene was enhanced by tumour necrosis factor α (TNFα) and interleukin 6 (IL6) in the synovial cells of early passage, whereas it was not enhanced in the synovial cells of late passage. The c-fos gene expression was also enhanced by 13-O-tetradecanoyl phorbol-13-acetate (TPA) in early passage but was somewhat suppressed in the late passage. It was found that the c-fos gene and c-Fos protein were both increased in the synovial cells of late passage. Similarly, c-fos gene expression was also not increased by TPA or cytokine stimulation in the stable c-fos transformants (fos-pH8) or H-ras transformed NIH3T3 cells (NIH H-ras cells) that constitutively expressed c-fos genes.
CONCLUSIONS—Although TNFα and IL6 augmented c-fos gene expression of rheumatoid synovial cells, transactivation of c-fos gene became resistant against cytokine stimulation under prolonged expression of c-fos gene, which may impart a tumour-like characteristic to rheumatoid synovial cells.

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