title: Free radicals enzymatically triggered by Clonorchis sinensis excretory-secretory products cause NF-κB-mediated inflammation in human cholangiocarcinoma cells.
abstract: Chronic clonorchiasis, caused by direct and continuous contact with Clonorchis sinensis worms and their excretory-secretory products, is associated with hepatobiliary damage, inflammation, periductal fibrosis and even development of cholangiocarcinoma. Our previous report revealed that intracellular reactive oxygen species were generated in C. sinensis excretory-secretory product-treated human cholangiocarcinoma cells; however, their endogenous sources and pathophysiological roles in host cells were not determined. In the present study, we found that treatment of human cholangiocarcinoma cells with excretory-secretory products triggered increases in free radicals via a time-dependent activation of NADPH oxidase, xanthine oxidase and inducible nitric oxide synthase. This increase in free radicals substantially promoted the degradation of cytosolic IκB-α, nuclear translocation of nuclear factor-κB subunits (RelA and p50), and increased κB consensus DNA-binding activity. Excretory-secretory product-induced nuclear factor-κB activation was markedly attenuated by preincubation with specific inhibitors of each free radical-producing enzyme or the antioxidant, N-acetylcysteine. Moreover, excretory-secretory products induced an increase in the mRNA and protein expression of the proinflammatory cytokines, IL-1β and IL-6, in an nuclear factor-κB-dependent manner, indicating that enzymatic production of free radicals in ESP-treated cells participates in nuclear factor-κB-mediated inflammation. These findings provide new insights into the pathophysiological role of C. sinensis excretory-secretory products in host chronic inflammatory processes, which are initial events in hepatobiliary diseases.
authors.affiliation: Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Joo-Hyun
authors.initials: JH
authors.lastname: Nam
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Moon
authors.forename: In Ki
authors.initials: IK
authors.lastname: Kim
authors.forename: Myoung-Ro
authors.initials: MR
authors.lastname: Lee
authors.forename: Sung-Jong
authors.initials: SJ
authors.lastname: Hong
authors.forename: Joong Ho
authors.initials: JH
authors.lastname: Ahn
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Chung
authors.forename: Jhang Ho
authors.initials: JH
authors.lastname: Pak
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003004:Clonorchis sinensis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism*; D020869:Gene Expression Profiling; D015801:Helminth Proteins / Q000276:immunology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D020543:Proteome / Q000032:analysis; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D005609:Free Radicals; D015801:Helminth Proteins; D016328:NF-kappa B; D020543:Proteome