The role of apoptosis in regulating the course of intracellular microbial infection is not well understood. We studied the relationship between apoptotic regulation and bacillus Calmette-Guérin (BCG) treatment in murine peritoneal exudate macrophages (PEM) and the J774 macrophage cell line. In both PEM and J774 cells, mRNA expression of the anti-apoptotic gene, A1, was selectively induced by BCG treatment as compared with other bcl2 family members (bcl-w, bcl-2, bcl-xl, bcl-xs, bax, bak, bad). In PEM, A1 expression was maximal by 8 h postinfection and was abrogated by the proteasomal inhibitor MG-132. The induction was independent of protein synthesis as well as the p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways and did not require live organism. Three genes encoding closely related isoforms of A1 were all expressed; however, the A1-a isoform displayed the greatest fold induction in PEM. BCG-induced A1 expression was associated with protection of host macrophages from NO-mediated apoptosis in both PEM and J774 cells. BCG-mediated protection was abrogated in PEM derived from A1-a−/− mice, indicating a requirement of A1-a for survival of inflammatory macrophages.
Cytokines trigger activation of different lymphocyte populations, resulting in augmentation of humoral and cell-mediated immunity. We have examined the role of IFN-gamma in mediating AK-5 tumor regression. High levels of circulating IFN-gamma and IL-2 marked the process of regression. Moreover, interaction of immune NK cells with antibody-tagged AK-5 resulted in IFN-gamma secretion, providing in vitro evidence for the involvement of this cytokine. IFN-gamma and IL-2 potentiated the cytolytic activity of naive NK cells, suggesting their role in antitumor activity. Furthermore, pretreatment of immune NK cells with protein tyrosine kinase inhibitor downregulated the IFN-gamma release, suggesting that the secretion of IFN-gamma is phosphorylation dependent. Nonimmune cells could be induced to secrete IFN-gamma when exposed to rIL-12, demonstrating IL-12 dependence in inducing IFN-gamma release. In vivo administration of anti-IFN-gamma inhibited the cytotoxic activity and the process of tumor regression, further substantiating the role of IFN-gamma in regulating the rejection of AK-5 tumor. These observations suggest a definitive role for IFN-gamma in AK-5 regression. This cytokine in concert with IL-2 and IL-12 might aid in designing effective anticancer therapy.
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