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J Hepatol. 2015 Feb;62(2):354-62. doi: 10.1016/j.jhep.2014.08.050. Epub 2014 Sep 6.

C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis.

Author information

1
Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Histology & Embryology, Third Military Medical University, Chongqing, China.
2
Department of Immunology, Third Military Medical University, Chongqing, China.
3
Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.
4
Department of Medical Genetics, Third Military Medical University, Chongqing, China.
5
Department of Laboratory Medicine, Daping Hospital, Third Military Medical University, Chongqing, China.
6
Institute of Hepatobiliary Surgery & Southwest Hospital, Third Military Medical University, District Shapingba, Chongqing, China.
7
Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
8
Department of Histology & Embryology, Third Military Medical University, Chongqing, China.
9
Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China. Electronic address: b.davis.zhu@gmail.com.
10
Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Immunology, Third Military Medical University, Chongqing, China. Electronic address: guobomail@gmail.com.

Abstract

BACKGROUND & AIMS:

Viral fulminant hepatitis (FH) is a disease with a high mortality rate. Activation of the complement system correlates with the development of FH. However, the key factors mediating complement activation in FH remain elusive.

METHODS:

Liver tissues were isolated from FH patients infected by hepatitis B virus (HBV) and from mice infected with murine hepatitis virus strain 3 (MHV-3). Wild type mice were treated with or without antagonists of C5aR or TNF-α, and mice deficient for C5aR (C5aR(-/-)), Fgl2 (Fgl2(-/-)), and Tnfα (Tnfα(-/-)) mice were not treated with the antagonists. C5b-9, C5aR, FGL2, CD31, CD11b, fibrin, TNF-α, and complement C3 cleavage products were detected by immunohistochemistry, immunofluorescence, or ELISA. Sorted liver sinusoidal endothelial cells (LSECs) or myeloid-derived (CD11b(+)) cells were stimulated with C5a, TNF-α or MHV-3 in vitro. The mRNA expressions levels of Fgl2 and Tnfα were determined by qRT-PCR analyses.

RESULTS:

We observed that complement activation, coagulation and pro-inflammatory cytokine production were upregulated in the HBV(+) patients with FH. Similar observations were made in the murine FH models. Complement activation and coagulation were significantly reduced in MHV-3 infected mice in the absence of C5aR, Tnfα or Fgl2. The MHV-3 infected C5aR(-/-) mice exhibited reduced numbers of infiltrated inflammatory CD11b(+) cells and a reduced expression of TNF-α and FGL2. Moreover, C5a administration stimulated TNF-α production by CD11b(+) cells, which in turn promoted the expression of FGL2 in CD31(+) LSEC-like cells in vitro. Administration of antagonists against C5aR or TNF-α ameliorated MHV-3-induced FH.

CONCLUSIONS:

Our results demonstrate that C5aR, TNF-α, and FGL2 form an integral network that contributes to coagulation and complement activation, and suggest that those are potential therapeutic targets in viral FH intervention.

KEYWORDS:

C5a/C5aR; Complement; Fibrinogen-like protein 2 (FGL2)/fibroleukin; Fulminant hepatitis

PMID:
25200905
DOI:
10.1016/j.jhep.2014.08.050
[Indexed for MEDLINE]

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