Inhibition of antigen-presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP - Relevance to the treatment of inflammatory arthritis
Inhibition of antigen-presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP - Relevance to the treatment of inflammatory arthritis
复制标题
DOI：
10.1002/art.20134
复制
发表时间：
2004-04-01
影响因子：
--
通讯作者：
Panayi, GS
中科院分区：
文献类型：
--
作者：
Corrigall, VM;Bodman-Smith, MD;Panayi, GS
Objective.应激蛋白和内质网伴侣，免疫球蛋白结合蛋白（BiP），是类风湿关节炎（RA）的自身抗原。然而，应激蛋白可以具有经由细胞表面受体介导的细胞外功能，其可以包括免疫调节功能。我们试图确定无细胞BiP是否存在于RA患者的滑液（SF）中，并进一步研究BiP在体外外周血单核细胞（PBMC）中可能的细胞外增殖和免疫调节特性。通过Western印迹法确定SF中BiP的存在。用外源性重组人BiP刺激PBMC，并在存在和不存在细胞信号传导抑制剂或中和性抗白细胞介素-10（抗IL-10）单克隆抗体的情况下测量细胞因子产生和细胞增殖。酶联免疫吸附测定法测定细胞因子水平，氚化胸苷摄取法测定细胞增殖，流式细胞术测定细胞表面分子表达。PBMCs对BiP的反应是分泌细胞因子的一种非线性分布。虽然BiP刺激肿瘤坏死因子α（TNF α）的早期产生，但诱导的主要细胞因子是IL-10。可溶性TNF受体II和IL-1受体拮抗剂分泌也增加。添加MAPK p38通路抑制剂SB 203580部分抑制IL-10和TNF α的产生，而MAPK ERK-1/2抑制剂PD 98059不影响它们。BiP还抑制PBMC对结核菌素纯化蛋白衍生物的回忆抗原反应。进一步的研究表明，在BiP或IL-10存在下孵育单核细胞下调CD 86和HLA-DR表达。与BiP诱导的持久减少相比，IL-10观察到的效果是短暂的。细胞外BiP可以刺激免疫调节和免疫调节途径，这仅部分是由于IL-10的产生。这些性质可能与治疗诸如RA的疾病有关。
Objective. The stress protein and endoplasmic reticulum chaperone, immunoglobulin binding protein (BiP), is an autoantigen in rheumatoid arthritis (RA). Stress proteins, however, may have extracellular functions, mediated via cell surface receptors, that may include immunomodulatory functions. We sought to determine whether cell-free BiP is present in the synovial fluid (SF) of patients with RA and to further investigate the possible extracellular antiinflammatory and immunomodulatory properties of BiP in peripheral blood mononuclear cells (PBMCs) in vitro.Methods. The presence of BiP in SF was established by Western blotting. PBMCs were stimulated with exogenous recombinant human BiP, and cytokine production and cell proliferation were measured in the presence and absence of cell signaling inhibitors or neutralizing anti-interleukin-10 (anti-IL-10) monoclonal antibody. Cytokine levels were quantified by enzyme-linked immunosorbent assay, cell proliferation by tritiated thymidine uptake, and cell surface molecule expression by flow cytometry.Results. PBMCs responded to BiP with secretion of an antiinflammatory profile of cytokines. Although BiP stimulated the early production of tumor necrosis factor alpha (TNFalpha), the major cytokine induced was IL-10. Soluble TNF receptor II and IL-1 receptor antagonist secretion was also increased. Addition of SB203580, the MAPK p38 pathway inhibitor, partially inhibited the production of IL-10 and TNFa, whereas they were unaffected by the MAPK ERK-1/2 inhibitor PD98059. BiP also inhibited the recall antigen response by PBMCs to tuberculin purified protein derivative. Further investigation showed that incubation of monocytes in the presence of either BiP or IL-10 down-regulated CD86 and HLA-DR expression. The effect observed with IL-10 was transient compared with the long-lasting reduction induced by BiP.Conclusion. Extracellular BiP may stimulate immunomodulatory and antiinflammatory pathways, which are only partly due to the production of IL-10. These properties may be of relevance for the treatment of diseases such as RA.