Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas-mediated apoptosis in T cells: implications for rheumatoid arthritis.
Delayed Fas-mediated apoptosis in T cells is associated with inflammatory diseases including rheumatoid arthritis (RA). CD3(+) T cells in RA synovia expressed high amounts of phospho-p38 MAPK. Exposure to RA synovial fluid or soluble collagen, a degradation product of extracellular matrix abundant in RA synovium, induced the phosphorylation of p38 MAPK in Jurkat T cells accompanied by resistance against Fas-mediated apoptosis. Blocking beta1 integrin by antibody diminished this effect. In addition, ectopic expression of auto-activated beta1 integrin variant in T cells profoundly induced the phosphorylation of p38 MAPK. Suppression of p38 MAPK sensitized T cells to Fas-mediated apoptosis and increased caspase-8 and caspase-3 cleavage. A physical interaction of p38 MAPK and caspase-8 was demonstrated by using confocal microscopic imaging and co-immunoprecipitation assay. RA synovial fluid markedly increased the formation of phospho-p38 MAPK/caspase-8 complex in Jurkat T cells. In conclusion, abnormal activation of p38 MAPK to prevent Fas-mediated apoptosis may represent a common survival mechanism of RA synovial T cells contributing to the persistent inflammation of affected synovium.
Lin
Yu-Ping
YP
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
Su
Chung-Chen
CC
Huang
Jyun-Yuan
JY
Lin
Huan-Chin
HC
Cheng
Yu-Jung
YJ
Liu
Ming-Fei
MF
Yang
Bei-Chang
BC
D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D053148:Caspase 3 / Q000276:immunology; D053181:Caspase 8 / Q000276:immunology; D003094:Collagen / Q000276:immunology; D006801:Humans; D019012:Integrin beta1 / Q000276:immunology*; D019169:Jurkat Cells; D010766:Phosphorylation / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*
C491901:FAS protein, human; D019012:Integrin beta1; D019014:fas Receptor; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8