A synergistic interferon-gamma production is induced by mouse hepatitis virus in interleukin-12 (IL-12)/IL-18-activated natural killer cells and modulated by carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a receptor.
The production of interferon-gamma (IFN-gamma) by infiltrating natural killer (NK) cells in liver is involved in the control of mouse hepatitis virus (MHV) infection. The objectives of this study were to identify the mechanisms used by MHV type 3 to modulate the production of IFN-gamma by NK cells during the acute hepatitis in susceptible C57BL/6 mice. Ex vivo and in vitro experiments revealed that NK cells, expressing carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a (the MHV receptor), can produce a higher level of IFN-gamma in the presence of both L2-MHV3 and interleukin-12 (IL-12)/IL-18. The synergistic production of IFN-gamma by NK cells depends on viral replication rather than viral fixation only, because it is inhibited or not induced in cells infected with ultraviolet-inactivated viruses and in cells from Ceacam1a(-/-) mice infected with virulent viruses. The synergistic IFN-gamma production involves the p38 mitogen-activated protein kinase (MAPK) rather than the extracellular signal-regulated kinase-1/2 MAPK signalling pathway. However, the signal triggered through the engagement of CEACAM1a decreases the production of IFN-gamma, when these molecules are cross-linked using specific monoclonal antibodies. These results suggest that control of acute hepatitis by IFN-gamma-producing NK cells may depend on both production of IL-12 and IL-18 in the liver environment and viral infection of NK cells.
Jacques
Alexandre
A
Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC, Canada.
Bleau
Christian
C
Turbide
Claire
C
Beauchemin
Nicole
N
Lamontagne
Lucie
L
D000208:Acute Disease; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000821:virology; D006524:Hepatitis, Viral, Animal / Q000276:immunology* / Q000821:virology; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000819:agonists / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D006517:Murine hepatitis virus / Q000276:immunology*; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
D002070:Butadienes; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020382:Interleukin-18; D009570:Nitriles; D011725:Pyridines; D011994:Recombinant Proteins; C113580:U 0126; D018664:Interleukin-12; D007371:Interferon-gamma; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580