Spontaneous and cytokine regulated c-fos gene expression in rheumatoid synovial cells: resistance to cytokine stimulation when the c-fos gene is overexpressed.
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 alpha (TNF alpha) 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 TNF alpha 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.
Kobe University School of Medicine, Faculty of Health Science and Department of Medicine, Japan.
K
K
Shimizu
H
H
Kawasaki
T
T
Morisawa
M
M
Nakamura
E
E
Yamamoto
N
N
Yoshikawa
M
M
Doita
K
K
Shiozawa
S
S
Yonehara
K
K
Chihara
S
S
Shiozawa
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D011401:Promoter Regions, Genetic; D013583:Synovial Membrane / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate