Serum amyloid A inhibits dendritic cell apoptosis to induce glucocorticoid resistance in CD4(+) T cells.
Serum amyloid A inhibits dendritic cell apoptosis to induce glucocorticoid resistance in CD4(+) T cells.
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DOI：
10.1038/cddis.2013.327
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发表时间：
2013-09-05
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
在过敏性哮喘的发生和加重过程中，由呼吸道上皮细胞产生的介质控制肺树突状细胞(DC)的激活、募集和存活，DC向CD4+T细胞递呈抗原。上皮来源的急性时相蛋白，血清淀粉样蛋白A(SAA)，诱导DC成熟和TH17极化。Th17反应与严重形式的过敏性哮喘有关，皮质类固醇控制不佳。我们试图确定SAA是否会在血清饥饿期间提高DC的存活率，从而促进CD4+T细胞中糖皮质激素耐药表型的发展。在SAA存在的情况下，血清饥饿的骨髓来源的树突状细胞(BMDC)可以防止caspase-3的激活，并释放更少的乳酸脱氢酶。与未经处理的血清饥饿的BMDC相比，SAA处理下调了促凋亡分子Bim的mRNA表达，增加了促生存的热休克蛋白70(HSP70)的产生，并诱导了促炎症细胞因子的分泌。血清饥饿48 h的SAA处理的BMDC仍能递呈抗原，并在卵白蛋白存在的情况下诱导OTIICD+T细胞分泌IL-17A、IL-17F、IL-21、IL-22和干扰素γ。即使在地塞米松(Dex)作用下，T细胞也能产生IL-17A、IL-17F、IL-21和干扰素γ，而糖皮质激素抑制了T细胞与未经处理的血清饥饿的骨髓基质细胞共培养的细胞因子的分泌。地塞米松反应基因表达的测定表明，作为糖皮质激素高反应性靶点的CD4+T细胞是SAA刺激BMDC的结果。最后，SAA和抗原吸入引起的过敏性呼吸道疾病对地塞米松治疗无效。我们的结果表明，apo-SAA影响DC，在诱导凋亡的条件下，既延长了DC的存活率，又增加了其炎症潜能。这些发现揭示了SAA增强抗原提呈细胞的CD4+T细胞刺激能力的机制，这些细胞可能积极参与糖皮质激素抵抗性肺部疾病的致病。
Mediators produced by the airway epithelium control the activation, recruitment, and survival of pulmonary dendritic cells (DC) that present antigen to CD4+ T cells during the genesis and exacerbation of allergic asthma. The epithelial-derived acute phase protein, serum amyloid A (SAA), induces DC maturation and TH17 polarization. TH17 responses are associated with severe forms of allergic asthma that are poorly controlled by corticosteroids. We sought to determine whether SAA would enhance the survival of DC during serum starvation and could then contribute to the development of a glucocorticoid-resistant phenotype in CD4+ T cells. Bone marrow-derived dendritic cells (BMDC) that were serum starved in the presence of SAA were protected from activation of caspase-3 and released less lactate dehydrogenase. In comparison with untreated serum-starved BMDC, treatment with SAA downregulated mRNA expression of the pro-apoptotic molecule Bim, increased production of the pro-survival heat shock protein 70 (HSP70), and induced secretion of pro-inflammatory cytokines. SAA-treated BMDC that were serum starved for 48 h remained capable of presenting antigen and induced OTII CD4+ T cells to secrete IL-17A, IL-17F, IL-21, IL-22, and IFNγ in the presence of ovalbumin. IL-17A, IL-17F, IL-21, and IFNγ production occurred even when the CD4+ T cells were treated with dexamethasone (Dex), whereas glucocorticoid treatment abolished cytokine secretion by T cells cocultured with untreated serum-starved BMDC. Measurement of Dex-responsive gene expression demonstrated CD4+ T cells as the target of glucocorticoid hyperresponsiveness manifest as a consequence of BMDC stimulation by SAA. Finally, allergic airway disease induced by SAA and antigen inhalation was unresponsive to Dex treatment. Our results indicate that apo-SAA affects DC to both prolong their viability and increase their inflammatory potential under apoptosis-inducing conditions. These findings reveal mechanisms through which SAA enhances the CD4+ T-cell-stimulating capacity of antigen-presenting cells that may actively participate in the pathogenicity of glucocorticoid-resistant lung disease.
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诱导痰和血浆中热休克蛋白 70 水平升高与哮喘患者的严重程度相关
影响因子：
3.8
作者：
Hou Changchun;Zhao Haijin;Zou Fei
通讯作者：
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影响因子：
8
作者：
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影响因子：
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作者：
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Ohashi, PS
DOI：
10.4049/jimmunol.1100500
发表时间：
2011-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ather JL;Ckless K;Martin R;Foley KL;Suratt BT;Boyson JE;Fitzgerald KA;Flavell RA;Eisenbarth SC;Poynter ME
通讯作者：
Poynter ME
DOI：
10.1007/978-1-60761-720-4_11
发表时间：
2012-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
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作者：
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通讯作者：
Pernis, Alessandra B