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Abstract

During chronic hepatitis C virus (HCV) infections, HCV antigens establish cross-tolerance of endotoxins, but additional lipopolysaccharide (LPS) stimulation effects in this condition are poorly understood.

This study aims to investigate the effects of the upregulated LPS on MMP and TIMP expression during chronic hepatitis C infection.

In the present study, we analysed the effect of HCV antigens and LPS stimulation on peripheral blood mononuclear cells (PBMCs) both and . Macrophages from HCV patients were isolated and their association with endotoxin tolerance was examined. MMP/TIMP1 expression and the related signalling pathways in macrophages were analysed. The macrophage and Huh7.5 cell co-culture model was used to analyse the effects of the cross-tolerance on collagen I deposition.

LPS levels were found to be significantly higher in HCV patients, particularly in those with HCV-induced liver fibrosis. In addition, although LPS serum level was occasionally upregulated in the patients, it did not induce intense immune response in PBMCs due to endotoxin cross-tolerance, and this was measured according to the changes in IL-6 and TNF-α levels. However, TIMP1 expression increased significantly during stimulation, exhibiting a tolerance/resistance phenotype, which was associated with TGF-β/Erk activation in macrophages. However, MMP levels did not increase due to endotoxin tolerance, which ultimately led to MMP/TIMP imbalance and influenced the deposition of collagen I.

Increased LPS stimulation of macrophage during HCV antigen-induced endotoxin cross-tolerance contributes to MMP/TIMP1 imbalance and collagen I deposition.

Funding
This study was supported by the:
  • National Natural Science Foundation of China (NSFC) (Award 81670529)
    • Principle Award Recipient: FAN CHAO
  • This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License.
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/content/journal/jmm/10.1099/jmm.0.001185
2020-04-03
2024-11-13
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References

  1. Marchesi JR, Adams DH, Fava F, Hermes GDA, Hirschfield GM et al. The gut microbiota and host health: a new clinical frontier. Gut 2016; 65:330–339 [View Article][PubMed]
    [Google Scholar]
  2. Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 2012; 590:447–458 [View Article]
    [Google Scholar]
  3. Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014; 146:1513–1524 [View Article]
    [Google Scholar]
  4. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140:805–820 [View Article]
    [Google Scholar]
  5. Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology 2014; 59:328–339 [View Article][PubMed]
    [Google Scholar]
  6. Sandler NG, Koh C, Roque A, Eccleston JL, Siegel RB et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 2011; 141:1220–1230 [View Article]
    [Google Scholar]
  7. Dolganiuc A, Oak S, Kodys K, Golenbock DT, Finberg RW et al. Hepatitis C core and nonstructural 3 proteins trigger Toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology 2004; 127:1513–1524 [View Article]
    [Google Scholar]
  8. Sakata K, Hara M, Terada T, Watanabe N, Takaya D et al. Hcv NS3 protease enhances liver fibrosis via binding to and activating TGF-β type I receptor. Sci Rep 2013; 3:3243 [View Article]
    [Google Scholar]
  9. Adhyatmika A, Putri KSS, Beljaars L, Melgert BN. The elusive antifibrotic macrophage. Front Med 2015; 2:81 [View Article][PubMed]
    [Google Scholar]
  10. Duarte S, Baber J, Fujii T, Coito AJ. Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix Biology 2015; 44-46:147–156 [View Article]
    [Google Scholar]
  11. Newby AC. Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol 2008; 28:2108–2114 [View Article]
    [Google Scholar]
  12. Ren JP, Ying RS, Cheng YQ, Wang L, El Gazzar M et al. Hcv-Induced miR146a controls SOCS1/STAT3 and cytokine expression in monocytes to promote regulatory T-cell development. J Viral Hepat 2016; 23:755–766 [View Article]
    [Google Scholar]
  13. Pena OM, Pistolic J, Raj D, Fjell CD, Hancock REW. Endotoxin tolerance represents a distinctive state of alternative polarization (M2) in human mononuclear cells. J.i. 2011; 186:7243–7254 [View Article]
    [Google Scholar]
  14. Chase AJ, Bond M, Crook MF, Newby AC. Role of nuclear factor-κB activation in metalloproteinase-1, -3, and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo . Arterioscler Thromb Vasc Biol 2002; 22:765–771 [View Article]
    [Google Scholar]
  15. Herman MP, Sukhova GK, Libby P et al. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation 2001; 104:1899–1904
    [Google Scholar]
  16. Sarén P, Welgus HG, Kovanen PT. Tnf-Alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol 1996; 157:4159–4165[PubMed]
    [Google Scholar]
  17. Hall M-C, Young DA, Waters JG, Rowan AD, Chantry A et al. The comparative role of activator protein 1 and Smad factors in the regulation of TIMP-1 and MMP-1 gene expression by transforming growth factor-beta 1. J Biol Chem 2003; 278:10304–10313 [View Article][PubMed]
    [Google Scholar]
  18. Kwak H-J, Park M-J, Cho H, Park C-M, Moon S-I et al. Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol Cancer Res 2006; 4:209–220 [View Article][PubMed]
    [Google Scholar]
  19. Fields J, Cisneros IE, Borgmann K, Ghorpade A. Extracellular regulated kinase 1/2 signaling is a critical regulator of Interleukin-1β-Mediated astrocyte tissue inhibitor of metalloproteinase-1 expression. PLoS One 2013; 8:e56891 [View Article]
    [Google Scholar]
  20. Tang W, Yang J, Zhang F, Guo H, Peng F et al. Activation of extracellular signal-regulated kinase 1/2 and Sp1 may contribute to the expression of tissue inhibitor of metalloproteinases-1 induced by transforming growth factor-β1 in human pulmonary arterial smooth muscle cells. Cytotherapy 2014; 16:225–233 [View Article]
    [Google Scholar]
  21. Morris MC, Gilliam EA, Li L. Innate immune programing by endotoxin and its pathological consequences. Front Immunol 2015; 5:680 [View Article]
    [Google Scholar]
  22. Pan H, Ding E, Hu M, Lagoo AS, Datto MB et al. Smad4 is required for development of maximal endotoxin tolerance. J Immunol 2010; 184:5502–5509 [View Article][PubMed]
    [Google Scholar]
  23. Sly LM, Rauh MJ, Kalesnikoff J, Song CH, Krystal G. Lps-Induced upregulation of SHIP is essential for endotoxin tolerance. Immunity 2004; 21:227–239 [View Article]
    [Google Scholar]
  24. Gao L, Coope H, Grant S, Ma A, Ley SC et al. ABIN1 protein cooperates with TAX1BP1 and A20 proteins to inhibit antiviral signaling. J Biol Chem 2011; 286:36592–36602 [View Article][PubMed]
    [Google Scholar]
  25. Moustakas A, Heldin C-H. Non-Smad TGF-beta signals. J Cell Sci 2005; 118:3573–3584 [View Article][PubMed]
    [Google Scholar]
  26. Yamashita M, Fatyol K, Jin C, Wang X, Liu Z et al. Traf6 mediates Smad-independent activation of JNK and p38 by TGF-β. Mol Cell 2008; 31:918–924 [View Article]
    [Google Scholar]
  27. Kashiwada M, Shirakata Y, Inoue J-I, Nakano H, Okazaki K et al. Tumor necrosis factor Receptor–associated factor 6 (TRAF6) stimulates extracellular Signal–regulated kinase (ERK) activity in CD40 signaling along a Ras-independent pathway. J Exp Med 1998; 187:237–244 [View Article]
    [Google Scholar]
  28. Newton K, Matsumoto ML, Wertz IE, Kirkpatrick DS, Lill JR et al. Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies. Cell 2008; 134:668–678 [View Article]
    [Google Scholar]
  29. Meng Z, Zhao T, Zhou K, Zhong Q, Wang Y et al. A20 ameliorates intracerebral hemorrhage-induced inflammatory injury by regulating TRAF6 polyubiquitination. J Immunol 2017; 198:820–831 [View Article][PubMed]
    [Google Scholar]
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