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  • Title: Generation of nitric oxide and clearance of interferon-gamma after BCG infection are impaired in mice that lack the interferon-gamma receptor.
    Author: Kamijo R, Gerecitano J, Shapiro D, Green SJ, Aguet M, Le J, Vilcek J.
    Journal: J Inflamm; ; 46(1):23-31. PubMed ID: 8832969.
    Abstract:
    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.
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