Generation of nitric oxide and clearance of interferon-gamma after BCG infection are impaired in mice that lack the interferon-gamma receptor.
Mice with a targeted deletion of either the interferon (IFN)-gamma gene or the IFN-gamma receptor gene (IFN-gamma R(0/0) mice) fail to survive infection with the Bacillus Calmette-Guerin (BCG) strain of Mycobacterium bovis. Here we show that resident peritoneal macrophages isolated 2 weeks after BCG infection from IFN-gamma R(0/0) mice produced significantly less nitric oxide (NO) than wild-type macrophages. However, the response to lipopolysaccharide (LPS) was not completely abrogated in the IFN-gamma R(0/0) macrophages. BCG infection of wild-type mice led to a marked increase in their urinary nitrite/nitrate levels, as previously described. This increase in urinary nitrite/nitrate was not detected in BCG- infected IFN-gamma R(0/0) mice, indicating that no other cytokine can replace IFN-gamma as a mediator of increased NO synthesis after BCG infection in the intact organism. A comparison of circulating levels of IFN-gamma in BCG-infected animals revealed that sera from IFN-gamma R(0/0) mice contained up to 66-fold more IFN-gamma than sera from identically treated wild-type mice. To determine if the higher levels of circulating IFN-gamma were due to increased IFN-gamma synthesis, we compared the amounts of IFN-gamma mRNA present in the spleens of BCG-infected wild-type and IFN-gamma R(0/0) mice. No increase in IFN-gamma mRNA levels was detected in the spleens from IFN-gamma R(0/0) mice. Since the generation of IFN-gamma protein in cultured spleen cells was also not increased in IFN-gamma R(0/0) mice, we conclude that clearance of IFN-gamma from the circulation is impaired in IFN-gamma R(0/0) mice, thus revealing a heretofore unrecognized important role for the IFN-gamma receptor in the regulation of IFN-gamma levels in the intact organism.
Kamijo
R
R
Department of Microbiology and Kaplan Cancer Center, New York University Medical Center, USA.
Gerecitano
J
J
Shapiro
D
D
Green
S J
SJ
Aguet
M
M
Le
J
J
Vilcek
J
J
D000818:Animals; D007371:Interferon-gamma / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009163:Mycobacterium bovis; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000652:urine; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics; D013154:Spleen / Q000378:metabolism; D014376:Tuberculosis / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D008070:Lipopolysaccharides; D009566:Nitrates; D009569:Nitric Oxide; D009573:Nitrites; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor