TARGETED DISRUPTION OF THE NF-IL6 GENE DISCLOSES ITS ESSENTIAL ROLE IN BACTERIA KILLING AND TUMOR-CYTOTOXICITY BY MACROPHAGES

To investigate the role of NF-IL6 in vivo, we have generated NF-IL6 (- /-) mice by gene targeting. NF-IL6 (-/-) mice were highly susceptible to infection by Listeria monocytogenes. Electron microscopic observati on revealed the escape of a large number of pathogens from the phagoso me to the cytoplasm in activated macrophages from NF-IL6 (-/-) mice. F urthermore, the tumor cytotoxicity of macrophages from NF-IL6 (-/-) mi ce was severely impaired. However, cytokines involved in macrophage ac tivation, such as TNF and IFN gamma, were induced normally in NF-IL6 ( -/-) mice. Nitric oxide (NO) formation was induced to a similar extent in macrophages from both wild-type and NF-IL6 (-/-) mice. These resul ts demonstrate the crucial role of NF-IL6 in macrophage bactericidal a nd tumoricidal activities as well as the existence of a NO-independent mechanism of these activities. We also demonstrate that NF-IL6 is ess ential for the induction of G-CSF in macrophages and fibroblasts.