Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma

Abstract

Opisthorchis viverrini 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 O. viverrini 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 O. viverrini 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 O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA.

Inflammatory Response in Caco-2 Cells Stimulated with Anisakis Messengers of Pathogenicity

“…In addition, the association between Anisakis and tumorigenic potential is also not completely understood. Helminths such as flukes (among several, including Schistosoma haematobium, Opisthorchis viverrini, and Clonorchis sinensis ) are capable of significant tumor-promoting activity [ 17 , 18 , 19 ]. Reports of tumor co-localization with Anisakis L3 and L3 mimicking metastatic lesions are increasing [ 20 , 21 , 22 ] and, interestingly, cases have been reported mainly in countries with a higher prevalence of anisakiasis [ 23 , 24 ].…”

Genotypic and allelic distribution of IFN‐γ +874T/A and TGF‐β1 −509C/T single‐nucleotide polymorphisms in human immunodeficiency virus‐infected Thais

“…Although frequencies of IFN-γ +874T/A SNP were examined in Thai subjects with different diseases and healthy control, 15,16 our study has reported the genotypes and alleles in PLWH. Previous studies indicated the +874 TT genotype as a high IFN-γ producer 3,4 and the AA genotype appeared to be associated with the susceptibility to HIV infection in Indian and Brazilian ethnic groups.…”

Carcinoma of the Liver in Children and Adolescents

“…PFIC2 represents a specific, previously unrecognized risk for HCC in infants. In BSEP deficiency, there is poor excretion of bile salts through the canalicular membrane, resulting in constant exposure of hepatocytes to bile salts, leading to chronic inflammation and carcinogenesis (90,91,108,(134)(135)(136)(137)(138)(139)(140)(141)(142). HCC occurs in 5-15% of pediatric patients with BSEP deficiency, mostly in the second year of life (143)(144)(145)(146).…”