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

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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.

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Acknowledgments

This work was supported by the National Key Basic Research and Development Project of China (973 project; no. 2010CB530000), National S & T Major Program (no. 2012ZX10004-220), National Natural Science Foundation of China (no. 81101270 and no. 81171602), Fundamental Research Funds for the Central Universities (no. 3164015).

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Authors and Affiliations

  1. Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China

    Qiang Mao, Zhizhi Xie, Xiaoyun Wang, Wenjun Chen, Mengyu Ren, Mei Shang, Huali Lei, Yanli Tian, Shan Li, Pei Liang, Tingjin Chen, Chi Liang, Jin Xu, Xuerong Li, Yan Huang & Xinbing Yu

  2. Key Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China

    Qiang Mao, Zhizhi Xie, Xiaoyun Wang, Wenjun Chen, Mengyu Ren, Mei Shang, Huali Lei, Yanli Tian, Shan Li, Pei Liang, Tingjin Chen, Chi Liang, Jin Xu, Xuerong Li, Yan Huang & Xinbing Yu

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  1. Qiang Mao
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  2. Zhizhi Xie
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  9. Shan Li
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  13. Jin Xu
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  14. Xuerong Li
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  15. Yan Huang
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  16. Xinbing Yu
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Correspondence to Yan Huang or Xinbing Yu.

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Qiang Mao and Zhizhi Xie contributed equally to this work.

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Mao, Q., Xie, Z., Wang, X. et al. Clonorchis sinensis ferritin heavy chain triggers free radicals and mediates inflammation signaling in human hepatic stellate cells. Parasitol Res 114, 659–670 (2015). https://doi.org/10.1007/s00436-014-4230-0

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  • DOI: https://doi.org/10.1007/s00436-014-4230-0

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