Direct suppression of human synovial cell proliferation in vitro by salazosulfapyridine and bucillamine.
OBJECTIVE
The mechanism of disease modifying antirheumatic drugs (DMARD) is incompletely understood. We investigated in vitro the effect of DMARD such as bucillamine (Buc), salazosulfapyridine (SASP), and D-penicillamine (D-Pen) on the proliferation of human synovial cells in patients with rheumatoid arthritis (RA).


METHODS
We evaluated the inhibitory effect of DMARD on [3H]-thymidine incorporation and cytokine production in synovial cells from patients with RA. Moreover, the expression of cytokine and protooncogene mRNA in synovial cells was determined by reverse transcription polymerase chain reaction methods.


RESULTS
The proliferation of synovial cells and interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) production of synovial cells were significantly inhibited by Buc and SASP in the concentration range of 1 to 100 microM in a dose dependent manner. In contrast D-Pen had no apparent effect at the same concentrations. Subsequently, the inhibitory effects of these compounds on transcriptional regulation of IL-1 beta, IL-6, and c-fos, which are well known to play an important role in synovial cell proliferation, were clarified. Overexpression of c-fos mRNA was inhibited by Buc and SASP. Moreover, the combination of low dose Buc and SASP inhibited synovial cell growth and transcriptional regulation of these mRNA.


CONCLUSIONS
DMARD may have a direct inhibitory effect on rheumatoid synovial cell proliferation without the involvement of other cellular factors, which may be a mechanism of clinical remission induced by DMARD in patients with RA.
Aono
H
H
Division of Rheumatology and Immunology, St. Marianna University School of Medicine, Kawasaki, Japan.
Hasunuma
T
T
Fujisawa
K
K
Nakajima
T
T
Yamamoto
K
K
Mita
S
S
Nishioka
K
K
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004338:Drug Combinations; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis; D008954:Models, Biological; D008969:Molecular Sequence Data; D012460:Sulfasalazine / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D004338:Drug Combinations; D007378:Interleukins; D012460:Sulfasalazine; D003545:Cysteine; C026535:bucillamine