Interferon-α Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?
Interferon-α Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?
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DOI：
10.1002/art.25042
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发表时间：
2009-12-01
影响因子：
--
通讯作者：
Wettero, Jonas
中科院分区：
文献类型：
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作者：
Enocsson, Helena;Sjowall, Christopher;Wettero, Jonas
客观的。 C 反应蛋白 (CRP) 由肝细胞在炎症过程中响应白细胞介素 6 (IL-6) 合成。尽管 IL-6 水平升高和广泛的全身炎症，但在大多数病毒感染和系统性红斑狼疮 (SLE) 疾病发作期间，血清 CRP 水平仍然较低。由于病毒感染和SLE的特点都是高水平的干扰素-α（IFN α），因此本研究的目的是确定这种细胞因子是否可以抑制CRP的诱导。方法。在 CRP 启动子和荧光素酶报告基因转染的人肝癌细胞系 Hep-G2 中研究了所有 12 种 IFN α 亚型对 IL-6 和 IL-1 β 诱导的 CRP 启动子活性的干扰。通过酶联免疫吸附测定分析原代人肝细胞的 CRIP 分泌。结果。 CRP 启动子活性受到所有单一 IFN α 亚型以及生物学相关 IFN α 亚型的 2 种不同混合物的抑制。最显着的效果是使用白细胞产生的 IFN α 混合物（1,000 IU/ml 时抑制 56%）。 IFN α 的抑制作用在原代人肝细胞中得到证实。 CRP 启动子抑制呈剂量依赖性，并通过 I 型 IFN 受体介导。转铁蛋白的产生和 Hep-G2 增殖/活力不受 IFN α 的影响。结论。目前的研究表明，IFN α 是 CRP 启动子活性和 CRP 分泌的抑制剂。这一发现与之前观察到的 SLE 疾病发作期间 IFN α 上调和 CRP 反应减弱的观察结果一致。鉴于 IFN α 和 CRP 在免疫反应中的基本作用，我们的结果对于了解 SLE 的发病机制非常重要，也可能有助于了解病毒和细菌感染之间 CRP 反应的差异。
Objective. C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFN alpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP.Methods. The interference of all 12 IFN alpha subtypes with CRP promoter activity induced by IL-6 and IL-1 beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRIP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay.Results. CRP promoter activity was inhibited by all single IFN alpha subtypes, as well as by 2 different mixtures of biologically relevant IFN alpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFN alpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFN alpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFN alpha.Conclusion. The current study demonstrates that IFN alpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFN alpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFN alpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.