Clonorchis sinensis ferritin heavy chain triggers free radicals and mediates inflammation signaling in human hepatic stellate cells

Abstract

Clonorchiasis, caused by direct and continuous contact with Clonorchis sinensis, is associated with hepatobiliary damage, inflammation, periductal fibrosis, and the development of cholangiocarcinoma. Hepatic stellate cells respond to liver injury through production of proinflammatory mediators which drive fibrogenesis; however, their endogenous sources and pathophysiological roles in host cells were not determined. C. sinensis ferritin heavy chain (CsFHC) was previously confirmed as a component of excretory/secretory products and exhibited a number of extrahepatic immunomodulatory properties in various diseases. In this study, we investigated the expression pattern and biological role of CsFHC in C. sinensis. CsFHC was expressed throughout life stages of C. sinensis. More importantly, we found that treatment of human hepatic stellate cell line LX-2 with CsFHC triggered the production of free radicals via time-dependent activation of NADPH oxidase, xanthine oxidase, and inducible nitric oxide synthase. The increase in free radicals substantially promoted the degradation of cytosolic IκBα and nuclear translocation of NF-κB subunits (p65 and p50). CsFHC-induced NF-κB activation was markedly attenuated by preincubation with specific inhibitors of corresponding free radical-producing enzyme or the antioxidant. In addition, CsFHC induced an increased expression level of proinflammatory cytokines, IL-1β and IL-6, in NF-κB-dependent manner. Our results indicate that CsFHC-triggered free radical-mediated NF-κB signaling is an important factor in the chronic inflammation caused by C. sinensis infection.

Inducible nitric oxide synthase response and associated cytokine gene expression in the spleen of mice infected with Clonorchis sinensis

“…ESPs induce the expression of proinflammatory cytokines, IL-1β and IL-6, and the iNOS/NO responses in an NF-κB-dependent manner (Nam et al 2012 ). A recent study has found that C. sinensis ferritin heavy chain ( Cs FHC), which has been previously confirmed as a component of ESPs, exhibits stimulatory properties in activation of NADPH oxidase, xanthine oxidase, and iNOS (Mao et al 2014 ).…”

Liver Fluke-Associated Biliary Tract Cancer

“…Correspondingly, the expressions of pro-inflammatory cytokines such as ILβ-1 and IL-6 were upregulated through NF-κB activation. 64 , 65 In a human CCA cell line (HuCCT1) study, CsESP induced the production of intracellular free radicals through upregulation of TLR signaling transduction. 66 In summary, these immunopathologic mechanisms contribute to CCA development by generating an intense inflammation, advanced periductal fibrosis, and DNA damage.…”

Current status and perspectives of Clonorchis sinensis and clonorchiasis: epidemiology, pathogenesis, omics, prevention and control

“…ESPs from C. sinensis have been shown to play roles in the progress of this disease. As components of ESPs, secretory phospholipase A (2) ( Cs PLA2), lysophospholipase ( Cs lysoPLA), fructose-1, 6-bisphosphatase ( Cs FBPase) and Fe heavy chain protein ( Cs FHC) have been reported to directly activate human hepatic stellate cells (HSCs) and key cells in liver fibrosis and to prompt the production of collagen [ 70 – 74 ]. The TGF-β/Smad signalling pathway might be activated after infection, which might contribute to the synthesis of collagen type I and fibroplasia [ 75 ].…”