Hashiguchi Masaaki, Kobayashi Ayano, Kashiwakura Yuji, Kojima Hidefumi, Kanno Yumiko, Kurosu Akira, Tokudome Shogo, Kobata Tetsuji
Department of Immunology, School of Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan,
Cytotechnology. 2014 May;66(3):373-82. doi: 10.1007/s10616-013-9585-z. Epub 2013 Aug 11.
IL-5 plays important roles in eosinophil differentiation, expansion, and recruitment. The regulation of IL-5 seems critical for the treatment of eosinophil-mediated allergic reactions. However, the precise mechanisms for IL-5 regulation remain unknown. In this study, we investigated how IL-5 production is regulated. The transduction of GATA-3 into a murine T cell hybridoma resulted in acquiring the ability to produce IL-5 in response to an antigenic stimulus like Th2 cells. This production was dependent on the cAMP-PKA pathway, but not on p38 activation. Transduction of NIK largely impaired IL-5 production. RelA and RelB similarly impaired IL-5 production. RelA decreased not only IL-5 protein amount but mRNA. RelA also inhibited Il5-luciferase reporter activity. The transduction of GATA-3 decreased the expression of Tbx21 and Eomes, but the additional transduction of RelA abrogated the decreased expression of GATA-3-induced Tbx21 and Eomes. Furthermore, the transduction of T-bet or Eomes into the GATA-3-transduced T cell hybridoma impaired IL-5 production. These results suggested that strong enhancement of the NFκB pathway downregulates IL-5 production and upregulates T-box protein expression to shift an immune response from Th2 to inflammatory Th1.
白细胞介素-5（IL-5）在嗜酸性粒细胞的分化、扩增和募集过程中发挥着重要作用。IL-5的调控对于治疗嗜酸性粒细胞介导的过敏反应似乎至关重要。然而，IL-5调控的确切机制仍不清楚。在本研究中，我们探究了IL-5的产生是如何被调控的。将GATA-3转导至小鼠T细胞杂交瘤中，使其获得了像辅助性T细胞2（Th2）一样在抗原刺激下产生IL-5的能力。这种产生依赖于环磷酸腺苷-蛋白激酶A（cAMP-PKA）途径，而不依赖于p38的激活。NF-κB诱导激酶（NIK）的转导极大地损害了IL-5的产生。RelA和RelB同样损害了IL-5的产生。RelA不仅降低了IL-5蛋白的量，还降低了其信使核糖核酸（mRNA）水平。RelA还抑制了Il5-荧光素酶报告基因的活性。GATA-3的转导降低了T盒转录因子21（Tbx21）和Eomesodermin（Eomes）的表达，但RelA的额外转导则消除了GATA-3诱导的Tbx21和Eomes表达的降低。此外，将T-bet或Eomes转导至GATA-3转导的T细胞杂交瘤中会损害IL-5的产生。这些结果表明，NFκB途径的强烈增强会下调IL-5的产生，并上调T盒蛋白的表达，从而使免疫反应从Th2型转变为炎症性辅助性T细胞1（Th）型。
