Amplification of cytokine production through synergistic activation of NFAT and AP-1 following stimulation of mast cells with antigen and IL-33.
Amplification of cytokine production through synergistic activation of NFAT and AP-1 following stimulation of mast cells with antigen and IL-33.
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DOI：
10.1002/eji.201040718
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发表时间：
2011-03
影响因子：
5.4
通讯作者：
Beaven, Michael A.
中科院分区：
文献类型：
--
作者：
Andrade, Marcus V.;Iwaki, Shoko;Ropert, Catherine;Gazzinelli, Ricardo T.;Cunha-Melo, Jose R.;Beaven, Michael A.
IL-33与特应性和自身免疫性疾病相关，并且如本文所报道的，它与Ag协同相互作用以显著增强啮齿动物肥大细胞中炎性细胞因子的产生，即使在没有脱粒的情况下。对潜在机制的研究表明，信号转导的协同作用发生在TGFβ激活的激酶1水平，然后通过JNK、p38 MAP激酶和AP 1向下游传递。Ag对Ca 2 +/钙调磷酸酶/NFAT通路的刺激（IL-33没有）对于Ag和IL-33之间的协同作用至关重要。例如，毒胡萝卜素对NFAT通路的选择性刺激也以钙调神经磷酸酶依赖性方式显著增强对IL-33的应答。如通过双链酶报告基因测定所示，IL-33未能刺激NFAT和AP 1的转录活性，但增强了Ag或毒胡萝卜素对这些转录因子的激活。IL-33对NFκB转录活性的强烈刺激也是协同作用的关键。这些和药理学数据表明，细胞因子的产生增强部分是由于AP 1和NFAT的激活放大以及转录因子之间的协同相互作用。IL-33可以使肥大细胞对Ag的反应向增强的细胞因子产生方向调整，从而确定Ag依赖性过敏性和自身免疫性疾病的症状和严重程度。
IL-33 is associated with atopic and autoimmune diseases and, as reported here, it interacts synergistically with Ag to markedly enhance production of inflammatory cytokines in rodent mast cells even in the absence of degranulation. Investigation of the underlying mechanisms revealed that synergy in signaling occurred at the level of TGFβ-activated kinase1 which was then transmitted downstream through JNK, p38 MAP kinase, and AP1. Stimulation of the Ca2+/calcineurin/NFAT pathway by Ag, which IL-33 did not, was critical for the synergy between Ag and IL-33. For example, selective stimulation of the NFAT pathway by thapsigargin also markedly enhanced responses to IL-33 in a calcineurin-dependent manner. As indicated by luciferase-reporter assays, IL-33 failed to stimulate the transcriptional activities of NFAT and AP1 but augmented the activation of these transcription factors by Ag or thapsigargin. Robust stimulation of NFκB transcriptional activity by IL-33 was also essential for synergy. These and pharmacologic data suggested that the enhanced production of cytokines resulted in part from amplification of the activation of AP1 and NFAT as well as co-operative interactions among transcription factors. IL-33 may retune mast cell responses to Ag towards enhanced cytokine production and thus determine the symptoms and severity of Ag-dependent allergic and autoimmune diseases.
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