Biological functions of IFN-gamma and IFN-alpha/beta: lessons from studies in gene knockout mice.
Mice with a targeted disruption in the IFN-gamma receptor gene (IFN-gamma R0/0) provided a useful model to ask to what extent other cytokines could replace IFN-gamma in macrophage activation. In thioglycollate-elicited peritoneal macrophages from wild-typy (WT) mice, TNF enhanced nitric oxide (NO) release in the presence of IFN-gamma, though TNF alone was not effective. In macrophages from IFN-gamma R0/0 mice, which are not responsive to IFN-gamma, TNF completely failed to stimulate NO release. The NO inducing effects of IFN-alpha/beta were indistinguishable in IFN-gamma R0/0 and WT macrophages. The important role of IFN-gamma in the regulation of the induced expression of MHC class II antigen (Ia) was confirmed by showing that after systemic infection with the BCG strain of Mycobacterium bovis, peritoneal macrophages from IFN-gamma R0/0 mice had a lower level of Ia expression than macrophages from WT mice. BCG infection was not lethal for WT mice whereas all IFN-gamma R0/0 mice died 7-9 weeks after infection. It is well known that BCG infection greatly sensitizes mice to lethal action of LPS. Injection of LPS 2 weeks after BCG inoculation was significantly less lethal for IFN-gamma R0/0 mice than for WT mice. Reduced lethality of LPS correlated with a drastically reduced TNF-alpha production in the IFN-gamma R0/0 mice after BCG infection and LPS challenge. The greatly reduced ability of BCG-infected IFN-gamma R0/0 mice to produce TNF-alpha may be an important factor in their inability to resist BCG infection.(ABSTRACT TRUNCATED AT 250 WORDS)
Kamijo
R
R
Department of Microbiology, Kaplan Cancer Center, New York University Medical Center, NY 10016.
Shapiro
D
D
Gerecitano
J
J
Le
J
J
Bosland
M
M
Vilcek
J
J
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D017353:Gene Deletion; D018390:Gene Targeting; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D008262:Macrophage Activation; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics*; D009163:Mycobacterium bovis; D009569:Nitric Oxide / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D017471:Receptors, Interferon / Q000235:genetics; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D009569:Nitric Oxide; D010750:Phosphoproteins; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C494258:Irf1 protein, mouse