Natural production and functional effects of alternatively spliced interleukin-4 protein in asthma.
Natural production and functional effects of alternatively spliced interleukin-4 protein in asthma.
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DOI：
10.1016/j.cyto.2011.12.017
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发表时间：
2012-04
期刊：
影响因子：
3.8
通讯作者：
Atamas, Sergei P.
中科院分区：
文献类型：
--
作者：
Luzina, Irina G.;Lockatell, Virginia;Lavania, Sachin;Pickering, Edward M.;Kang, Phillip H.;Bashkatova, Yulia N.;Andreev, Sergey M.;Atamas, Sergei P.
我们先前已经描述了IL-4 mRNA的选择性剪接亚型，其省略外显子2并被称为IL-4δ2。然而，IL-4δ2蛋白的天然产生及其与疾病的关联先前尚未评估，这是由于无法获得与IL-4δ2相互作用而与全长IL-4无交叉反应性的抗体。我们使用了一种独特的单克隆抗体（mAb），它与IL-4δ2反应，但不与IL-4反应，并观察到IL-4δ2是由哮喘患者的T细胞天然产生的，但不是来自健康对照。佛波酯（PMA）/离子霉素（Ionomycin）激活的细胞产生IL-4δ2和IL-4的动力学不同，IL-4δ2在48 - 72 h增加，IL-4在24 h达到峰值。IL-4δ2 mRNA的稳态水平在供体之间差异显著，并且与相应的蛋白质水平不一致，表明蛋白质产生的转录后调节。极化的Th 1或Th 2淋巴细胞不是IL-4δ2的主要来源。用IL- 4δ2刺激培养的T淋巴细胞导致IFN-γ、IL-10、IL-6、MCP-1和TNF-α的产生升高，患者和对照组之间IFN-γ、IL-10和IL-6的产生存在显著差异。因此，IL- 4δ2不仅作为mRNA而且作为蛋白质由除Th 1或Th 2以外的细胞天然产生。它是转录后调节的，与过敏性哮喘有关，并调节初级T淋巴细胞产生其他细胞因子。选择性剪接的白细胞介素-4可能是一种新的生物标志物，一种病理生理学参与者，也可能是未来哮喘治疗的分子靶点。
We have previously described an alternatively spliced isoform of IL-4 mRNA that omits exon 2 and is termed IL-4δ2. However, the natural production of IL-4δ2 protein and its association with disease have not been previously assessed due to unavailability of an antibody that interacts with IL-4δ2 without cross-reactivity with full length IL-4. We used a unique monoclonal antibody (mAb) that reacts with IL-4δ2, but not with IL-4, and observed that IL-4δ2 is naturally produced by T cells from patients with asthma, but not from healthy controls. The kinetics of IL-4δ2 and IL-4 production by phorbol myristate acetate (PMA)/ionomycin-activated cells differed, with IL-4δ2 increasing at 48 – 72 h and IL-4 peaking at 24 h. The steady-state levels of IL-4δ2 mRNA varied significantly among the donors and were discordant with the corresponding protein levels, suggesting post-transcriptional regulation of protein production. Polarized Th1 or Th2 lymphocytes were not a major source of IL-4δ2. Stimulation of cultured T lymphocytes with IL- 4δ2 caused elevated production of IFN-γ, IL-10, IL-6, MCP-1, and TNF-α, with notable differences between patients and controls in the production of IFN-γ, IL-10, and IL-6. Thus, IL- 4δ2 is natively produced not only as mRNA but also as a protein by cells other than Th1 or Th2. It is regulated post-transcriptionally, is associated with allergic asthma, and regulates production of other cytokines by primary T lymphocytes. Alternatively spliced interleukin-4 may be a new biomarker, a pathophysiological player, and possibly a molecular target for future therapies in asthma.
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DOI：
10.1177/039463200702000417
发表时间：
2007-10-01
影响因子：
3.5
作者：
Orsini, B.;Vivas, J. R.;D'Elios, M. M.
通讯作者：
D'Elios, M. M.
影响因子：
6.4
作者：
Fletcher, HA;Owiafe, P;Brookes, RH
通讯作者：
Brookes, RH
影响因子：
14.2
作者：
Glare, EM;Divjak, W;Walters, EH
通讯作者：
Walters, EH
影响因子：
6.4
作者：
Luzina, Irina G.;Lockatell, Virginia;Atamas, Sergei P.
通讯作者：
Atamas, Sergei P.
影响因子：
1.8
作者：
Waldvogel, AS;Lepage, MF;Heussler, VT
通讯作者：
Heussler, VT