https://scholars.lib.ntu.edu.tw/handle/123456789/190537
標題: | Anti-citrullinated Protein Antibodies Activated ERK1/2 and JNK Mitogen-activated Protein Kinases via Binding to Surface-expressed Citrullinated GRP78 on Mononuclear Cells | 作者: | Lu M.-C. Lai N.-S. Yin W.-Y. Yu H.C. Huang H.-B. Tung C.-H. Huang K.-Y. CHIA-LI YU |
關鍵字: | ACPAs;rheumatoid arthritis;MAPK;JNK;ERK;p38;Akt;IKK-alpha | 公開日期: | 2013 | 起(迄)頁: | 558-566 | 來源出版物: | Journal of Clinical Immunology | 摘要: | In a previous study, we found that anti-citrullinated protein antibodies (ACPAs) enhance nuclear factor (NF)-kappa B activity and tumor necrosis factor (TNF)-alpha production by normal human peripheral blood mononuclear cells (PBMCs) and U937 cells via binding to surface-expressed citrullinated glucose-regulated protein 78 (cit-GRP78). However, the downstream signaling pathways remain unclear after binding. In the present study, we firstly measured the effects of different kinase inhibitors on ACPA-mediated TNF-alpha production from normal PBMCs and monocytes. Then, the native and phosphorylated mitogen-activated protein kinases (MAPKs) were detected in ACPA-activated U937 cells by Western blotting. We also explored the role of the phosphoinositide 3-kinase (PI3K)-Akt pathway in activating I kappa B kinase alpha (IKK-alpha) in ACPA-stimulated U937 cells. Finally, we measured the amount of cit-GRP78 from PBMC membrane extracts in RA patients and controls. We found that MAPK and Akt inhibitors, but not PI3K inhibitor, remarkably suppressed ACPA-mediated TNF-alpha production. Interestingly, ACPAs selectively activated extracellular signal-regulated kinase 1/2 (ERK1/2) and c-jun N-terminal kinase (JNK), but not p38 MAPK, in U937 cells. This activation was suppressed by cit-GRP78, but not GRP78. The JNK activation further enhanced the phosphorylation of Akt and IKK-alpha. The expression of cit-GRP78 on cell membrane was higher in RA than normal PBMCs. Taken together; these results suggest that through binding to surface, over-expressed cit-GRP78 on RA PBMCs, ACPAs selectively activate ERK1/2 and JNK signaling pathways to enhance IKK-alpha phosphorylation, which leads to the activation of NF-kappa B and the production of TNF-alpha |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/259421 | DOI: | 10.1007/s10875-012-9841-6 |
顯示於: | 醫學系 |
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