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Immunol Lett. 2014 Mar-Apr;158(1-2):25-32. doi: 10.1016/j.imlet.2013.11.008. Epub 2013 Nov 25.

Tumor necrosis factor α (TNF-α) receptor-I is required for TNF-α-mediated fulminant virus hepatitis caused by murine hepatitis virus strain-3 infection.

Author information

1
Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China; Undergraduate Administration Office, Third Military Medical University, Chongqing 400037, People's Republic of China.
2
Department of Otorhinolaryngology and Head-Neck Surgery, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037, People's Republic of China.
3
Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China.
4
Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People's Republic of China. Electronic address: yongwench@163.com.

Abstract

TNF-α plays an essential role in the pathogenesis of fulminant virus hepatitis (FH) caused by infection with murine hepatitis virus strain-3 (MHV-3). However, the specific TNF-α receptors (TNFR) involved in this disease and how they mediate this effect are uncertain. Here, we showed that the expression of TNFR1 and TNFR2 in the liver and spleen was triggered by MHV-3. However, only TNFR1(-/-) mice were resistant to MHV-3 mediated FH, as displayed by a dramatic decrease in tissue necrosis and cell apoptosis in the infected spleens and livers from TNFR1(-/-) mice, as well as prolonged survival in these mice compared to wild type littermate controls. Mechanistically, TNFR1 deficiency directly impeded the serum and tissue levels of fibrinogen-like protein 2 (FGL2), a virus-induced procoagulant molecule that promotes cell apoptosis. Additionally, the expression of apoptosis-associated molecules, Fas and Fas ligand (FasL) in the infected organs from TNFR1(-/-) mice were also decreased. Moreover, the infiltration of neutrophils rather than Foxp3(+) regulatory T cells, which produce proinflammatory factors and FGL2 directly, into the infected liver and spleen tissues was also decreased in TNFR1(-/-) mice. These combined results indicate that signaling through TNFR1 plays an essential role in the pathogenesis of FH caused by MHV-3 infection, and interruption of this signaling pathway could be useful for clinical therapy.

KEYWORDS:

FGL2; Murine hepatitis virus strain-3; Neutrophils; TNFR1

PMID:
24286726
DOI:
10.1016/j.imlet.2013.11.008
[Indexed for MEDLINE]
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