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 (TFN)-gamma gen e or the IFN-gamma receptor gene (IFN-gamma R(0/0) mice) fail to survi ve infection with the Bacillus Calmette-Guerin (BCG) strain of Mycobac terium bovis. Here we show that resident peritoneal macrophages isolat ed 2 weeks after BCG infection from IFN-gamma R(0/0) mice produced sig nificantly 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 p reviously described. This increase in urinary nitrite/nitrate was not detected in BCG-infected IFN-gamma R(0/0) mice, indicating that no oth er cytokine can replace IFN-gamma as a mediator of increased NO synthe sis after BCG infection in the intact organism. A comparison of circul ating levels of IFN-gamma in BCG-infected animals revealed that sera f rom 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 high er levels of circulating IFN-gamma were due to increased IFN-gamma syn thesis, we compared the amounts of IFN-gamma mRNA present in the splee ns of BCG-infected wildtype 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 c ells 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 f or the IFN-gamma receptor in the regulation of IFN-gamma levels in the intact organism. (C) 1996 Wiley-Liss, Inc.