Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages

• Published in: Cell 1995-01, Vol.80 (2), p.353-361
• Main Authors: Tanaka, Takashi, Akira, Shizuo, Yoshida, Kanji, Umemoto, Masanori, Yoneda, Yoshihiro, Shirafuji, Naoki, Fujiwara, Hiroshi, Suematsu, Sachiko, Yoshida, Nobuaki, Kishimoto, Tadamitsu
• Format: Article
• Language: English
• Subjects: Animals; Arginine - analogs & derivatives; Arginine - pharmacology; Base Sequence; Biological Assay; CCAAT-Enhancer-Binding Proteins; Cytotoxicity, Immunologic; DNA Primers; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Granulocyte Colony-Stimulating Factor - analysis; Granulocyte Colony-Stimulating Factor - biosynthesis; Hydrogen Peroxide - metabolism; Interferon-gamma - pharmacology; Interleukin-6 - physiology; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeriosis - immunology; Macrophage Activation; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - physiology; Mice; Mice, Mutant Strains; Mice, Transgenic; Molecular Sequence Data; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Nuclear Proteins - physiology; omega-N-Methylarginine; Polymerase Chain Reaction; Stem Cells; Superoxides - metabolism; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/0092-8674(95)90418-2

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 observation revealed the escape of a large number of pathogens from the phagosome to the cytoplasm in activated macrophages from NF-IL6 (-/-) mice. Furthermore, the tumor cytotoxicity of macrophages from NF-IL6 (-/-) mice was severely impaired. However, cytokines involved in macrophage activation, such as TNF and IFNγ, 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 results demonstrate the crucial role of NF-IL6 in macrophage bactericidal and tumoricidal activities as well as the existence of a NO-independent mechanism of these activities. We also demonstrate that NF-IL6 is essential for the induction of G-CSF in macrophages and fibroblasts.