Surapaitoon Arpa, Suttiprapa Sutas, Mairiang Eimorn, Khuntikeo Narong, Pairojkul Chawalit, Bethony Jeffrey, Brindley Paul J, Sripa Banchob
Biomedical Sciences, Graduate School, Khon Kaen University, Khon Kaen, Thailand.
WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Center, Khon Kaen, Thailand.
Korean J Parasitol. 2017 Jun;55(3):295-304. doi: 10.3347/kjp.2017.55.3.295. Epub 2017 Jun 30.
infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with who presented with APF+ or APF-, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1β, IL-6, IFN-γ, LT-α, and TNF-α were significantly increased in CCA patients compared with non-CCA (APF- and APF+) cases. Polymorphisms in genes encoding IL-1β-511C/T, IL-6-174G/C, IFN-γ +874T/A, LT-α +252A/G, and TNF-α -308G/A were then investigated by using PCR-RFLP or allele specific-PCR (AS-PCR) analyses. In the CCA cases, LT-α +252A/G and TNF-α -308G/A heterozygous and homozygous variants showed significantly higher levels of these cytokines than the wild type. By contrast, levels of cytokines in wild type of IFN-γ +874T/A were significantly higher than the variants in CCA cases. IFN-γ +874T/A polymorphisms were associated with advanced periductal fibrosis, whereas IL-6 -174G/C polymorphisms were associated with CCA. To our knowledge, these findings provide the first demonstration that infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA.
感染会引发慢性炎症，少数受感染个体还会发展为晚期导管周围纤维化（APF）和胆管癌（CCA）。炎性细胞因子和/或其基因多态性可能与这些胆道疾病相关。因此，我们对510例经腹部超声检查确诊为APF阳性或阴性的泰国感染患者以及CCA患者的细胞因子基因多态性与细胞因子产生之间的关联进行了研究。用排泄-分泌（ES）产物刺激外周血单个核细胞（PBMCs）后，测定培养上清液中促炎和抗炎细胞因子的水平。与非CCA（APF阴性和APF阳性）病例相比，CCA患者的促炎细胞因子IL-1β、IL-6、IFN-γ、LT-α和TNF-α显著升高。然后通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）或等位基因特异性PCR（AS-PCR）分析，研究编码IL-1β-511C/T、IL-6-174G/C、IFN-γ +874T/A、LT-α +252A/G和TNF-α -308G/A基因的多态性。在CCA病例中，LT-α +252A/G和TNF-α -308G/A的杂合和纯合变体显示这些细胞因子的水平显著高于野生型。相比之下，IFN-γ +874T/A野生型的细胞因子水平在CCA病例中显著高于变体。IFN-γ +874T/A多态性与晚期导管周围纤维化相关，而IL-6 -174G/C多态性与CCA相关。据我们所知，这些发现首次证明携带几种特定细胞因子基因多态性的感染个体易发生纤维化和CCA。
