Klein Matthias, Klein-Hessling Stefan, Palmetshofer Alois, Serfling Edgar, Tertilt Christine, Bopp Tobias, Heib Valeska, Becker Marc, Taube Christian, Schild Hansjörg, Schmitt Edgar, Stassen Michael
Institute for Immunology, University of Mainz, Germany.
J Immunol. 2006 Nov 15;177(10):6667-74. doi: 10.4049/jimmunol.177.10.6667.
By virtue of their ability to express a plethora of biologically highly active mediators, mast cells (MC) are involved in both adaptive and innate immune responses. MC-derived Th2-type cytokines are thought to act as local amplifiers of Th2 reactions, including chronic inflammatory disorders such as allergic asthma, whereas MC-derived TNF-alpha is a critical initiator of antimicrobial defense. In this study, we demonstrate that the transcription factors NFATc1 and NFATc2 are part of a MC-specific signaling network that regulates the expression of TNF-alpha and IL-13, whereas NFATc3 is dispensable. Primary murine bone marrow-derived MC from NFATc2(-/-) mice, activated by either ionomycin or IgE/Ag cross-link, display a strong reduction in the production of these cytokines, compared with bone marrow-derived MC from wild-type mice. Detailed analyses of TNF-alpha and IL-13 expression using small interfering RNA-mediated knockdown reveals that both NFATc2 and NFATc1 are able to drive the expression of these cytokines, whereas neither degranulation nor the expression of IL-6 depends on NFAT activity. These results support the view that high NFAT activity is necessary for TNF-alpha and IL-13 promoter induction in MC, irrespective of whether NFATc2 or NFATc1 or a combination of both is present.
肥大细胞（MC）凭借其表达大量生物活性高的介质的能力，参与适应性免疫和先天性免疫反应。MC衍生的Th2型细胞因子被认为是Th2反应的局部放大器，包括过敏性哮喘等慢性炎症性疾病，而MC衍生的肿瘤坏死因子-α（TNF-α）是抗菌防御的关键启动因子。在本研究中，我们证明转录因子活化T细胞核因子c1（NFATc1）和活化T细胞核因子c2（NFATc2）是MC特异性信号网络的一部分，该网络调节TNF-α和白细胞介素-13（IL-13）的表达，而活化T细胞核因子c3（NFATc3）则是可有可无的。与野生型小鼠的骨髓来源的MC相比，来自NFATc2基因敲除小鼠的原代鼠骨髓来源的MC，经离子霉素或免疫球蛋白E/抗原（IgE/Ag）交联激活后，这些细胞因子的产生显著减少。使用小干扰RNA介导的敲低对TNF-α和IL-13表达进行详细分析表明，NFATc2和NFATc1都能够驱动这些细胞因子的表达，而脱颗粒和IL-6的表达均不依赖于NFAT活性。这些结果支持这样一种观点，即无论存在NFATc2还是NFATc1或两者的组合，高NFAT活性对于MC中TNF-α和IL-13启动子的诱导都是必需的。
