Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC, Canada.
Immunology. 2009 Sep;128(1 Suppl):e551-61. doi: 10.1111/j.1365-2567.2008.03030.x. Epub 2008 Dec 18.
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.
γ-干扰素（IFN-γ）由浸润的自然杀伤（NK）细胞产生，参与控制小鼠肝炎病毒（MHV）感染。本研究的目的是鉴定 MHV 型 3 用于在易感 C57BL/6 小鼠急性肝炎期间调节 NK 细胞产生 IFN-γ的机制。离体和体外实验表明，表达癌胚抗原相关细胞粘附分子（CEACAM）1a（MHV 受体）的 NK 细胞在存在 L2-MHV3 和白细胞介素 12（IL-12）/白细胞介素 18（IL-18）的情况下可以产生更高水平的 IFN-γ。NK 细胞协同产生 IFN-γ取决于病毒复制而不仅仅是病毒固定，因为在用紫外线失活病毒感染的细胞中和在用毒力病毒感染的 Ceacam1a(-/-) 小鼠的细胞中，它被抑制或未被诱导。协同 IFN-γ产生涉及 p38 丝裂原活化蛋白激酶（MAPK），而不是细胞外信号调节激酶-1/2 MAPK 信号通路。然而，通过 CEACAM1a 的交联触发的信号会降低 IFN-γ的产生，当使用特异性单克隆抗体交联这些分子时。这些结果表明，IFN-γ产生的 NK 细胞对急性肝炎的控制可能取决于肝脏环境中 IL-12 和 IL-18 的产生以及 NK 细胞的病毒感染。
