期刊
JOURNAL OF CLINICAL IMMUNOLOGY
卷 33, 期 3, 页码 558-566出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10875-012-9841-6
关键词
ACPAs; rheumatoid arthritis; MAPK; JNK; ERK; p38; Akt; IKK-alpha
类别
资金
- National Science Council [NCS100-2314-B-303-009, NSC99-2628-B-002-020-MY3]
- Buddhist Dalin Tzu-Chi General Hospital, Taiwan [DTCRD99-E-02]
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
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