Enocsson Helena, Sjöwall Christopher, Skogh Thomas, Eloranta Maija-Leena, Rönnblom Lars, Wetterö Jonas
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Arthritis Rheum. 2009 Dec;60(12):3755-60. doi: 10.1002/art.25042.
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 (IFNalpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP.
The interference of all 12 IFNalpha subtypes with CRP promoter activity induced by IL-6 and IL-1beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay.
CRP promoter activity was inhibited by all single IFNalpha subtypes, as well as by 2 different mixtures of biologically relevant IFNalpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFNalpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFNalpha 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 IFNalpha.
The current study demonstrates that IFNalpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFNalpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFNalpha 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.
C反应蛋白（CRP）是肝细胞在炎症期间响应白细胞介素-6（IL-6）而合成的。尽管IL-6水平升高且存在广泛的全身炎症，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水平仍保持较低。由于病毒感染和SLE均以高水平的α干扰素（IFNα）为特征，本研究的目的是确定这种细胞因子是否能抑制CRP的诱导。
在转染了CRP启动子和荧光素酶报告基因的人肝癌细胞系Hep-G2中，研究了所有12种IFNα亚型对IL-6和IL-1β诱导的CRP启动子活性的干扰。采用酶联免疫吸附测定法分析原代人肝细胞的CRP分泌情况。
所有单一IFNα亚型以及两种生物学相关的IFNα亚型不同混合物均抑制CRP启动子活性。使用白细胞产生的IFNα混合物时观察到最显著的效果（在1000 IU/ml时抑制率为56%）。IFNα在原代人肝细胞中的抑制作用得到证实。CRP启动子抑制呈剂量依赖性，且通过I型干扰素受体介导。转铁蛋白产生以及Hep-G2增殖/活力不受IFNα影响。
本研究表明IFNα是CRP启动子活性和CRP分泌的抑制剂。这一发现与先前在SLE疾病发作期间IFNα上调和CRP反应减弱的观察结果一致。鉴于IFNα和CRP在免疫反应中的重要作用，我们的结果对于理解SLE的发病机制具有重要意义，也可能有助于理解病毒感染和细菌感染之间CRP反应的差异。
