Functional activation of proline-rich tyrosine kinase2 (PYK2) in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.
Functional activation of proline-rich tyrosine kinase2 (PYK2) in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.
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DOI：
10.1186/1471-2474-10-141
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发表时间：
2009-11-17
影响因子：
2.3
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Wang M;Sun H;Zhang W;Zhang Y
系统性红斑狼疮（SLE）是一种典型的系统性自身免疫性疾病，其特征是T细胞和多克隆活化的B细胞产生自身抗体。自身反应性T和B细胞的活化在该疾病的发病机制中起关键作用。粘着斑激酶（FAK）在发病机制中的作用已被提出。富含脯氨酸的酪氨酸激酶2（PYK 2）在结构上与FAK相关，然而PYK 2在SLE中的功能激活尚不清楚。在本研究中，我们发现PYK 2在SLE患者的外周血单个核细胞（PBMC）中显著增加和活化。此外，我们发现PYK 2蛋白参与了CD 40 L和CTLA 4表达的上调以及PBMC增殖。采用免疫印迹法和免疫细胞化学法检测48例SLE患者、32例类风湿关节炎（RA）患者和24例健康人外周血单个核细胞（PBMC）中PYK 2的表达和活化。另一组患者分离的PBMC经PMA或TyrA 9刺激后，流式细胞术检测共刺激分子CD 40 L和CTLA 4的表达，[3 H]-胸苷掺入法（CPM）检测PBMC增殖。与RA患者和健康供体相比，SLE患者的PBMC表达更多的总PYK 2蛋白及其活化/磷酸化形式。SLE患者外周血单个核细胞中PYK 2活化蛋白的增加与肾炎的发生有关，与血清补体水平呈负相关。在活动性SLE患者中，PBMC中PYK 2的活化伴随着细胞增殖的增加和共刺激分子CD 40 L和CTLA 4的诱导表达。我们的研究结果表明，磷酸化PYK 2在SLE PBMC中可以诱导CD 40 L和CTLA 4的表达，从而促进细胞增殖。PYK 2信号通路增强自身反应性淋巴细胞的活化，在SLE的发病机制中起重要作用。
Systemic lupus erythematosus (SLE) is a representative systemic autoimmune disease characterized by activated T cells and polyclonally activated B cells that produce autoantibodies. Activation of autoreactive T and B cells plays a pivotal role in the pathogenesis of this disease. A role of focal adhesion kinase (FAK) in the pathogenesis has been suggested. Proline-rich tyrosine kinase2 (PYK2) is structurally related to FAK, however, the functional activation of PYK2 in SLE remains unclear. In the present study, we showed that PYK2 is significantly increased and activated in peripheral blood mononuclear cells (PBMCs) of patients with SLE. In addition, we showed the involvement of PYK2 proteins in the up-regulation of CD40L and CTLA4 expression and PBMC proliferation. Freshly isolated PBMCs from 48 SLE patients, 32 patients with rheumatoid arthritis(RA) and 24 healthy individuals were analyzed for the expression and activation of PYK2 by western-blotting and immunocytochemistry. The other isolated PBMCs from patients with this condition were cultured and stimulated with PMA or TyrA9, and then the expression of costimulatory molecules CD40L and CTLA4 was evaluated using flow cytometry, PBMCs proliferation was determined with [3H]-thymidine incorporation (CPM). Compared with RA patients and healthy donors, PBMCs from SLE patients expressed more of both the total PYK2 protein and its activated/phosphorylated form. The increase of activated PYK2 protein in SLE PBMCs was correlated with the complication of nephritis and inversly associated the level of serum complements. In active SLE patients, activation of PYK2 in PBMCs is accompanying the increased cell proliferation and the induced expression of costimulatory molecules CD40L and CTLA4. Our findings indicate that phosphorylated PYK2 in SLE PBMCs may induce the expression of CD40L and CTLA4, and subsequently the cell proliferation. PYK2 signaling enhances the autoreactive lymphocyte activation and plays an important role in the pathogenesis of SLE.
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