Role of GADD45 beta in the regulation of synovial fluid T cell apoptosis in rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by persistent Th1 cell infiltration and production of inflammatory cytokines in the location of joint lesion. It is known that infiltrated Th1 cells in the synovial fluid (SF) of RA patients are resistant to apoptosis. Here we demonstrate that Th1 cells accumulated in patient SF expressed a high level of GADD45 beta (Growth Arrest and DNA Damage-inducible 45 beta) which further inhibited Th1 cell apoptosis. Interestingly, in vitro culture of T cells with SF from RA patients increased GADD45 beta expression in Th1 cells and inhibited their apoptosis. Silencing of GADD45 beta by RNAi abolished the anti-apoptotic effect of RA SF, which was accompanied by down-regulation of Bcl-2 and up-regulation of Bax. Further analysis showed that TNF-alpha and IL-12 in RA SF could stimulate GADD45 beta expression in Th1 cells and inhibit their apoptosis. Taken together, our results suggest a novel mechanism by which specific cytokines in the RA SF elevate GADD45 beta expression in local Th1 cells and subsequently leading to the enhanced T cell survival.
Du
Fang
F
Shanghai Institute of Immunology, Institute of Medical Sciences, Jiao Tong University School of Medicine, Shanghai, China.
Wang
Li
L
Zhang
Yan
Y
Jiang
Wei
W
Sheng
Huiming
H
Cao
Qi
Q
Wu
Juanjuan
J
Shen
Baihua
B
Shen
Tianwei
T
Zhang
Jingwu Z
JZ
Bao
Chunde
C
Li
Dangsheng
D
Li
Ningli
N
D000328:Adult; D000368:Aged; D000943:Antigens, Differentiation / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002470:Cell Survival; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013582:Synovial Fluid / Q000276:immunology*; D018417:Th1 Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D018664:Interleukin-12; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C086470:GADD45B protein, human; D000097642:GADD45 Proteins