Fujiwara H, Hanissian S H, Tsytsykova A, Geha R S
Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Enders 8th Floor, 300 Longwood Avenue, Boston, MA 02115-5747, USA.
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5866-71. doi: 10.1073/pnas.94.11.5866.
The cytokines interleukin (IL)-4 and IL-13 play a critical role in inducing Cepsilon germline transcripts and IgE isotype switching in human B cells. The IL-4 receptor (IL-4R) in B cells is composed of two chains, the IL-4-binding IL-4Ralpha chain, which is shared with the IL-13R, and the IL-2Rgamma (gammac) chain, which is shared with IL-7R, IL-9R, and IL-15R. IL-4 induces Cepsilon germline transcripts and IgE isotype switching in B cells from patients with gammac chain deficiency. Induction of Cepsilon germline transcripts by IL-4 in B cells that lack the gammac chain may involve signaling via the IL-13R. Alternatively, the IL-4Ralpha chain may transduce intracellular signals that lead to Cepsilon gene transcription independently of its association with other chains. We show that ligand-induced homodimerization of chimeric surface receptors consisting of the extracellular and transmembrane domains of the erythropoietin receptor and of the intracellular domain of IL-4Ralpha induces Janus kinase 1 (Jak1) activation, STAT6 activation, and Cepsilon germline transcripts in human B cell line BJAB. Disruption of the Jak1-binding proline-rich Box1 region of IL-4Ralpha abolished signaling by this chimeric receptor. Furthermore, B cells transfected with a chimeric CD8alpha/IL-4Ralpha receptor, which is expressed on the cell surface as a homodimer, constitutively expressed Cepsilon germline transcripts. These results suggest that homodimerization of the IL-4Ralpha chain is sufficient to transduce Jak1-dependent intracellular signals that lead to IgE isotype switching.
细胞因子白细胞介素（IL）-4和IL-13在诱导人类B细胞中Cε种系转录本和IgE同种型转换方面发挥着关键作用。B细胞中的IL-4受体（IL-4R）由两条链组成，即与IL-13R共享的结合IL-4的IL-4Rα链，以及与IL-7R、IL-9R和IL-15R共享的IL-2Rγ（γc）链。IL-4可诱导γc链缺陷患者B细胞中的Cε种系转录本和IgE同种型转换。IL-4在缺乏γc链的B细胞中诱导Cε种系转录本可能涉及通过IL-13R进行信号传导。或者，IL-4Rα链可能独立于其与其他链的结合转导导致Cε基因转录的细胞内信号。我们发现，由促红细胞生成素受体的细胞外和跨膜结构域以及IL-4Rα的细胞内结构域组成的嵌合表面受体的配体诱导的同源二聚化可诱导人B细胞系BJAB中的Janus激酶1（Jak1）激活、STAT6激活和Cε种系转录本。破坏IL-4Rα的Jak1结合富含脯氨酸的Box1区域可消除该嵌合受体的信号传导。此外，用嵌合CD8α/IL-4Rα受体转染的B细胞在细胞表面以同源二聚体形式表达，其组成性地表达Cε种系转录本。这些结果表明，IL-4Rα链的同源二聚化足以转导导致IgE同种型转换的Jak1依赖性细胞内信号。
