Splice isoforms of human interleukin-4 are functionally active in mice in vivo
Splice isoforms of human interleukin-4 are functionally active in mice in vivo
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DOI：
10.1111/j.1365-2567.2010.03393.x
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发表时间：
2011-03-01
期刊：
影响因子：
6.4
通讯作者：
Atamas, Sergei P.
中科院分区：
文献类型：
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作者：
Luzina, Irina G.;Lockatell, Virginia;Atamas, Sergei P.
白细胞介素-4（IL-4）以物种特异性方式作用于培养的细胞，尽管一些报道表明人IL-4可能在啮齿动物体内具有功能活性。后一个发现，如果是真的，将不仅提供了新的hIL-4靶向治疗在动物中的临床前测试的可能性，但也提出了新的机会，IL-4及其受体的机制研究。常规IL-4由四个外显子编码，而其研究较少的可变剪接同种型由外显子1、3和4编码（IL-4 δ 2）。复制缺陷型腺病毒介导的hIL-4亚型（hIL-4或hIL-4 delta 2）基因传递到小鼠肺部引起类似的T和B淋巴细胞肺浸润，但不是嗜酸性粒细胞。与hIL-4 delta 2相比，hIL-4 delta 2诱导的肺细胞因子环境变化存在显著差异，hIL-4 delta 2诱导更高水平的促炎性（肿瘤坏死因子-α、IL-1和单核细胞趋化蛋白-1）和1型T辅助细胞（IL-12和干扰素-γ）细胞因子。内源性小鼠（m）IL-4或mIL-4 delta 2 mRNA没有升高，mIL-4的生殖系缺陷不影响肺浸润的程度。当与哮喘的卵清蛋白模型相结合时，hIL-4 delta 2比hIL-4刺激更大的淋巴细胞积累。由hIL-4或hIL-4 δ 2表达诱导的淋巴细胞肺浸润被mIL-4 R α或鼠信号转导子和转录激活子6的种系缺陷减弱，但未完全消除，表明这些信号分子介导小鼠中hIL-4同种型的体内效应。这些发现表明，剪接异构体的人IL-4在小鼠体内的功能活性，并部分共享相应的物种特异性异构体的影响。
P>Interleukin-4 (IL-4) acts on cultured cells in a species-specific fashion, although several reports have suggested that human (h) IL-4 may be functionally active in rodents in vivo. The latter finding, if true, would not only offer possibilities for pre-clinical testing of novel hIL-4-targeting therapies in animals, but also suggests new opportunities for mechanistic studies of IL-4 and its receptors. Conventional IL-4 is encoded by four exons, whereas its poorly studied alternatively spliced isoform is encoded by exons 1, 3 and 4 (IL-4 delta 2). Replication-deficient adenovirus-mediated gene delivery of hIL-4 isoforms (hIL-4 or hIL-4 delta 2) to mouse lungs caused similar pulmonary infiltration of T and B lymphocytes, but not eosinophils. There were significant differences in the changes of pulmonary cytokine milieu induced by hIL-4 compared with hIL-4 delta 2, with hIL-4 delta 2 inducing higher levels of pro-inflammatory (tumour necrosis factor-alpha, IL-1, and monocyte chemotactic protein-1) and T helper type 1 (IL-12 and interferon-gamma) cytokines. There was no elevation in endogenous mouse (m) IL-4 or mIL-4 delta 2 mRNAs, and germ-line deficiency of mIL-4 did not affect the degree of pulmonary infiltration. When combined with an ovalbumin model of asthma, hIL-4 delta 2 stimulated a greater accumulation of lymphocytes than did hIL-4. Pulmonary infiltration of lymphocytes induced by expression of hIL-4 or hIL-4 delta 2 was attenuated, but not completely abrogated, by germ-line deficiency of mIL-4R alpha or murine signal transducer and activator of transcription 6, suggesting that these signalling molecules mediate the in vivo effects of hIL-4 isoforms in mice. These findings suggest that splice isoforms of human IL-4 are functionally active in vivo in mice, and partially share the effects of the corresponding species-specific isoforms.