Defects of mitogen-activated protein kinase in ICOS signaling pathway lead to CD4(+) and CD8(+) T-cell dysfunction in patients with active SLE.
In this study, hypoproliferation and defects of effectors and cytokines in CD4(+) and CD8(+) T-cells via ICOS costimulation were found in active SLE patients, relative to normal individuals and RA patient controls. Exogenous IL-2 can partially reverse those defects. In addition, low level of ERK phosphorylation in ICOS-mediated signaling pathway was discovered in lupus CD4(+) and CD8(+) T-cells. When blocked with ERK-specific chemical inhibitor PD98059, cell proliferation and IL-2 production via ICOS costimulation from both CD4(+) and CD8(+) T-cells will be severely inhibited. These findings confirmed the dysfunction of both CD4(+) and CD8(+) T-cells after ICOS costimulation in lupus patients and most importantly pointed out that impairment of ERK activation might be one of the critical factors involved in ICOS-mediated IL-2 and T-cell hypoproliferation in active SLE.
Department of Experimental Diagnosis, Shanghai Changhai Hospital, Shanghai, PR China.
Cai
C
Gang
Yang
Y
Jiahui
Wang
W
Huaizhou
Cai
C
Qing
Zhao
Z
Dongbao
Shen
S
Qian
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D005419:Flavonoids; C556692:ICOS protein, human; C508609:IL10 protein, human; C508594:IL2 protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2; D016753:Interleukin-10; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one