The Role of Hepatic Stellate Cells in the Regulation of T-cell Function and the Promotion of Hepatocellular Carcinoma

Overview

Journal Int J Oncol

Specialty Oncology

Date 2012 May 30

PMID 22641338

Citations 22

Authors

Wenxiu Zhao

Weixue Su

Penghao Kuang

Lei Zhang

Jianming Liu

Zhenyu Yin

Xiaomin Wang

Affiliations

Soon will be listed here.

Abstract

Hepatic stellate cells (HSCs) have immunosuppressive abilities and may be responsible for the occurrence and development of hepatocellular carcinoma (HCC). However, the mechanisms through which HSCs affect T-cell-mediated immune responses remain unclear. The aim of this study was to elucidate these mechanisms. We examined the effect of HSCs on T-cell proliferation and apoptosis, regulatory T cells (Treg cells) and T-cell-mediated cytotoxicity using mixed leukocyte reactions (MLRs). Furthermore, we examined the cytokines present in the supernatant and the effect of this supernatant on the proliferation and migration of cancer cells. Finally, we examined the effect of HSCs on HCC cells in vivo. We found that activated HSCs induced T-cell hyporesponsiveness, accelerated activated T-cell apoptosis, increased the number of Treg cells and inhibited T-cell-mediated cytotoxicity. HSCs also enhanced the expression of some cytokines and promoted the proliferation and migration of cancer cells. Furthermore, activated HSCs were able to induce HCC proliferation and Treg cells expansion in vivo. Activated HSCs may induce T cell anergy, thereby facilitating the immunologic escape of HCC cells.

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References

Chen C, Shu K, Su Y, Tang K, Cheng C, Wu M . Cotransplantation of hepatic stellate cells attenuates the severity of graft-versus-host disease. Transplant Proc. 2010; 42(3):971-5. DOI: 10.1016/j.transproceed.2010.02.039. View

Zhao W, Zhang L, Yin Z, Su W, Ren G, Zhou C . Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice. Int J Cancer. 2011; 129(11):2651-61. DOI: 10.1002/ijc.25920. View

Bazzoni F, Beutler B . The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996; 334(26):1717-25. DOI: 10.1056/NEJM199606273342607. View

Yang H, Chou H, Gu X, Wang L, Brown K, Fung J . Mechanistic insights into immunomodulation by hepatic stellate cells in mice: a critical role of interferon-gamma signaling. Hepatology. 2009; 50(6):1981-91. PMC: 2896244. DOI: 10.1002/hep.23202. View

Friedman S . Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008; 88(1):125-72. PMC: 2888531. DOI: 10.1152/physrev.00013.2007. View

Wang H, Babic A, Mitchell H, Liu K, Wagner D . Elevated soluble ICAM-1 levels induce immune deficiency and increase adiposity in mice. FASEB J. 2005; 19(8):1018-20. DOI: 10.1096/fj.04-3094fje. View

Chau G, Wu C, Lui W, Chang T, Kao H, Wu L . Serum interleukin-10 but not interleukin-6 is related to clinical outcome in patients with resectable hepatocellular carcinoma. Ann Surg. 2000; 231(4):552-8. PMC: 1421032. DOI: 10.1097/00000658-200004000-00015. View

Amann T, Bataille F, Spruss T, Muhlbauer M, Gabele E, Scholmerich J . Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma. Cancer Sci. 2009; 100(4):646-53. PMC: 11158780. DOI: 10.1111/j.1349-7006.2009.01087.x. View

Yin Z, Jiang G, Fung J, Lu L, Qian S . ICAM-1 expressed on hepatic stellate cells plays an important role in immune regulation. Microsurgery. 2007; 27(4):328-32. DOI: 10.1002/micr.20366. View

10.

Chen C, Kuo L, Chang Y, Wu W, Goldbach C, Ross M . In vivo immune modulatory activity of hepatic stellate cells in mice. Hepatology. 2006; 44(5):1171-81. DOI: 10.1002/hep.21379. View

11.

Mikula M, Proell V, Fischer A, Mikulits W . Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent fashion. J Cell Physiol. 2006; 209(2):560-7. PMC: 2900580. DOI: 10.1002/jcp.20772. View

12.

Karin N . The multiple faces of CXCL12 (SDF-1alpha) in the regulation of immunity during health and disease. J Leukoc Biol. 2010; 88(3):463-73. DOI: 10.1189/jlb.0909602. View

13.

Xiang J, Gu X, Qian S, Chen Z . Graded function of CD80 and CD86 in initiation of T-cell immune response and cardiac allograft survival. Transpl Int. 2007; 21(2):163-8. DOI: 10.1111/j.1432-2277.2007.00590.x. View

14.

Knupfer H, Preiss R . Serum interleukin-6 levels in colorectal cancer patients--a summary of published results. Int J Colorectal Dis. 2009; 25(2):135-40. DOI: 10.1007/s00384-009-0818-8. View

15.

Knittel T, Dinter C, Kobold D, Neubauer K, Mehde M, Eichhorst S . Expression and regulation of cell adhesion molecules by hepatic stellate cells (HSC) of rat liver: involvement of HSC in recruitment of inflammatory cells during hepatic tissue repair. Am J Pathol. 1999; 154(1):153-67. PMC: 1853435. DOI: 10.1016/s0002-9440(10)65262-5. View

16.

Friedman S . Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med. 1993; 328(25):1828-35. DOI: 10.1056/NEJM199306243282508. View

17.

Friedman S . Liver fibrosis -- from bench to bedside. J Hepatol. 2003; 38 Suppl 1:S38-53. DOI: 10.1016/s0168-8278(02)00429-4. View

18.

Friedman S . Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008; 134(6):1655-69. PMC: 2888539. DOI: 10.1053/j.gastro.2008.03.003. View

19.

Gutschalk C, Herold-Mende C, Fusenig N, Mueller M . Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor promote malignant growth of cells from head and neck squamous cell carcinomas in vivo. Cancer Res. 2006; 66(16):8026-36. DOI: 10.1158/0008-5472.CAN-06-0158. View

20.

Strober W . Vitamin A rewrites the ABCs of oral tolerance. Mucosal Immunol. 2008; 1(2):92-5. DOI: 10.1038/mi.2007.22. View