Intrahepatic endothelial and Kupffer cells involved in immunosuppressive cytokines and natural killer (NK)/NK T cell disorders in viral acute hepatitis.
During acute viral hepatitis, the intrahepatic tolerance sustained by immunosuppressive cytokines such as interleukin (IL)-4, IL-10, transforming growth factor (TGF)-beta and prostaglandin E2 (PGE2), produced by Kupffer cells (KC), liver sinusoidal endothelial cells (LSEC), natural killer (NK) T cells and natural regulatory T cells may be disturbed. NK cells are recruited normally in the liver and produce interferon (IFN)-gamma to control viral replication. The use of mouse hepatitis virus type 3 (MHV3) attenuated variants showing selected tropisms for KC or LSEC have allowed determining their roles in the disturbances of immune tolerance during viral hepatitis. Groups of C57BL/6 mice were infected with the pathogenic L2-MHV3 (KC+, LSEC+), low attenuated 51.6-MHV3 (KC+, LSEC-) or high attenuated CL12-MHV3 (KC-, LSEC-) variants for the first 3 days. Results showed that IL-10, TGF-beta and PGE2 production in the liver decreased in L2-MHV3-infected mice and increased in 51.6-MHV3- and CL12-MHV3-infected mice. The ratio of IFN-gamma/IL-4 in liver decreased in L2-MHV3-infected mice, while it was not (or low) altered in mice infected with the attenuated MHV3 variant mice. Phenotypic analysis of intrahepatic mononuclear cells revealed that apoptotic NK and NK T cells increased in mice infected with the L2-MHV3, but were minor in 51.6-MHV3- and CL12-MHV3-infected mice. The numbers of CD4+ forkhead box P3+ cells increased in the livers from low pathogenic CL12-MHV3 and YAC-MHV3-infected mice. These results indicate that viral permissivity of KC and LSEC is involved in the decrease of IL-10 and PGE2, while KC may play an additional role in the apoptosis of NK and NK T cells during acute viral hepatitis.
Jacques
A
A
Université du Québec à Montréal, Montréal, Canada.
Bleau
C
C
Martin
J-P
JP
Lamontagne
L
L
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D006524:Hepatitis, Viral, Animal / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D007728:Kupffer Cells / Q000276:immunology*; D008099:Liver / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000145:classification / Q000472:pathogenicity*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014774:Virulence
D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015847:Interleukin-4; D007371:Interferon-gamma