Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway
Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway
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DOI：
10.1016/j.jaci.2004.08.005
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发表时间：
2004-11-01
影响因子：
14.2
通讯作者：
Leung, DYM
中科院分区：
文献类型：
--
作者：
Li, LB;Goleva, E;Leung, DYM
背景资料：微生物超抗原诱导人T细胞对皮质类固醇的耐药性。目的：了解导致皮质类固醇耐药T细胞的分子途径是很重要的，因为这种情况下可以复杂化治疗inflammation.Methods：人PBMC对类固醇的反应进行了评估后，刺激与超抗原或抗CD 3在各种激酶抑制剂的存在下，使用增殖试验。糖皮质激素受体α（GCR α）定位是根据细胞内染色确定的。蛋白磷酸化测定通过Western blotting.Results：在目前的研究中，我们发现，PBMC刺激superamigen，但不抗CD 3，诱导皮质类固醇耐药的T细胞。然而，用葡萄球菌肠毒素B（SE B）或抗CD 3刺激的纯化的T细胞对皮质类固醇抑制敏感。这些结果表明，抗原呈递细胞上的信号可能与T细胞受体协同作用，导致类固醇抵抗。阻断CD 40-CD 40配体相互作用对superamigen诱导的皮质类固醇抵抗没有影响。然而，CD 28与T细胞受体活化共刺激诱导的人T细胞的皮质类固醇耐药的剂量依赖性的方式。与抗CD 3刺激相比，超抗原刺激可诱导丝裂原激活的细胞外信号调节激酶（ERK）更快速、持续的磷酸化。用PD 98059和UO 126（特异性丝裂原活化蛋白激酶激酶[MEK]/ERK抑制剂）治疗，而不是p38抑制剂或c-Jun N-末端激酶抑制剂，恢复了对类固醇的反应，如增殖试验所示。此外，纯化的ERK 1和ERK 2能够在体外激酶测定中直接磷酸化重组人GCR α。值得注意的是，超抗原诱导的皮质类固醇抵抗与GCR α核转位的消除相关。这种效果可以逆转治疗与MEK/ERK pathway inhibitors.Conclusions：这些数据是兼容的假设，即超抗原诱导的皮质类固醇激素抵抗涉及Raf-MEK-ERK 1/ERK 2途径的T细胞受体信号转导，从而导致GCR α磷酸化和地塞米松诱导的GCR α核转位的抑制。
Background: Microbial superantigens induce human T-cell resistance to corticosteroids.Objective: Understanding the molecular pathways resulting in corticosteroid-resistant T cells is important because this condition can complicate the treatment of inflammation.Methods: The response of human PBMCs to steroids was assessed by using proliferation assays after stimulation with superantigens or anti-CD3 in the presence of various kinase inhibitors. Glucocorticoid receptor alpha (GCRalpha) localization was defined on the basis of intracellular staining. Protein phosphorylation was measured by means of Western blotting.Results: In the current study we found that PBMCs stimulated with superamigen, but not anti-CD3, induced corticosteroid-resistant T cells. However, the purified T cells stimulated either with staphylococcal enterotoxin B (SEB) or anti-CD3 are susceptible to corticosteroid inhibition. These results imply that signals on antigen-presenting cells might act in concert with the T-cell receptor to cause steroid resistance. Blockade of CD40-CD40 ligand interaction had no effect on superamigen-induced corticosteroid resistance. However, CD28 costimulation with T-cell receptor activation induced corticosteroid resistance of human T cells in a dose-dependent manner. Superantigen stimulation, compared with anti-CD3 stimulation, was found to induce a more rapid and sustained phosphorylation of mitogen-activated extracellular signal-regulated kinase (ERK). Treatment with PD98059 and UO126 (specific mitogen-activated protein kinase kinase [MEK]/ERK inhibitors), but not a p38 inhibitor or a c-Jun N-terminal kinase inhibitor, restored the response to steroids, as indicated by proliferation assays. Furthermore, purified ERK1 and ERK2 were able to phosphorylate recombinant human GCRalpha directly in an in vitro kinase assay. Of note, superantigen-induced corticosteroid resistance was associated with abrogation of GCRalpha nuclear translocation. This effect could be reversed by treatment with MEK/ERK pathway inhibitors.Conclusions: These data are compatible with the hypothesis that superantigen-induced corticosteroid resistance involves the Raf-MEK-ERK1/ERK2 pathway of T-cell receptor signaling, which leads to GCRalpha phosphorylation and inhibition of dexamethasone-induced GCRalpha nuclear translocation.