Preferential and persistent activation of the STAT1 pathway in rheumatoid synovial fluid cells.
OBJECTIVE
Inflammatory cytokines such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor-alpha are produced in great quantities in inflamed rheumatoid joints. However, little is known about the pathogenic significance of each cytokine in the proliferative synovitis and destruction of bone and joint. We investigated the role of cytokine receptor signals transduced into cells at the foci of rheumatoid inflammation.


METHODS
Synovial fluid (SF) cells from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were examined for the activation of a group of cytokine receptor signaling molecules, signal transducers and activators of transcription (STAT).


RESULTS
DNA binding of STAT1 in SF cells was observed in 8 out of 14 patients with RA, but in none of the 10 patients with OA studied, and this was prevented by preincubation of these cells with neutralizing anti-IL-6 antibody. IL-6 activated both STAT1 and STAT3 in normal peripheral blood (PB) leukocytes, and preferentially STAT1 in rheumatoid SF cells. Moreover, STAT1 activation in rheumatoid SF cells appeared to be continuous, in contrast to the transient activation in normal PB leukocytes.


CONCLUSIONS
STAT1 and STAT3 are differentially regulated in response to IL-6 in different cell types. The continuous STAT1 activation may be of pathogenic significance in the progression and persistence of RA.
Yokota
A
A
Division of Allergy and Rheumatology, Osaka Prefectural Habikino Hospital, Japan. yokota@hbk.pref.osaka.jp
Narazaki
M
M
Shima
Y
Y
Murata
N
N
Tanaka
T
T
Suemura
M
M
Yoshizaki
K
K
Fujiwara
H
H
Tsuyuguchi
I
I
Kishimoto
T
T
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000503:physiopathology; D001483:Base Sequence; D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000187:drug effects*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010003:Osteoarthritis / Q000378:metabolism* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012016:Reference Values; D050794:STAT1 Transcription Factor; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology; D013582:Synovial Fluid / Q000737:chemistry* / Q000166:cytology; D015534:Trans-Activators / Q000032:analysis* / Q000187:drug effects*
D015415:Biomarkers; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D004247:DNA