title: Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas-mediated apoptosis in T cells: implications for rheumatoid arthritis.
abstract: 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.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Lin
authors.forename: Chung-Chen
authors.initials: CC
authors.lastname: Su
authors.forename: Jyun-Yuan
authors.initials: JY
authors.lastname: Huang
authors.forename: Huan-Chin
authors.initials: HC
authors.lastname: Lin
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Cheng
authors.forename: Ming-Fei
authors.initials: MF
authors.lastname: Liu
authors.forename: Bei-Chang
authors.initials: BC
authors.lastname: Yang
mesh_terms: 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*
chemical_list: 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