Jy. Sung et al., Methotrexate suppresses the interleukin-6 induced generation of reactive oxygen species in the synoviocytes of rheumatoid arthritis, IMMUNOPHARM, 47(1), 2000, pp. 35-44
Various cytokines and reactive oxygen species (ROS) play a fundamental role
in the inflammatory and immunologic processes of rheumatoid arthritis (RA)
. Methotrexate (MTX) is one of the disease-modifying anti-rheumatic drugs a
nd its effect may be partly due to the modulation of immunologic or inflamm
atory reactions by some cytokines. In the present study, we investigated th
e effects of MTX on the gene expression and synthesis of interleukin-6 (IL-
6), and the proliferative activity and the production of ROS in the fibrobl
ast-like synoviocytes (FLSs) obtained from the patient of RA. The expressio
n or production of IL-6 was induced spontaneously, and augmented by the add
ition of recombinant human IL-6 or recombinant human IL-1 beta and TNF-alph
a in FLSs. These spontaneous and augmented IL-6 expressions or productions
were suppressed by treatment with low-concentration of MTX (1 mu g/ml). Als
o, IL-6 stimulated the proliferation of FLSs, and this IL-6 driven prolifer
ation was inhibited with the treatment of MTX or N-acetylcysteine (NAC, 1 m
M). Furthermore, ROS production in FLSs was increased significantly by IL-6
, and its effect was also abrogated in the presence of MTX or NAC. These re
sults suggest that inflammatory reaction in the synovium of RA patients cou
ld be augmented by the autocrine or other cytokine-induced production of IL
-6 with subsequent generation of ROS in the synoviocytes, and the modulatio
ns of IL-6 synthesis and ROS production may contribute to the therapeutic e
ffects of MTX for RA. (C) 2000 Published by Elsevier Science B.V. All right
s reserved.