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

Abstract

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 larger 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 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 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.

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

“…Paclitaxel, notably at 5-30 mM, was thus proposed as a TLR4 ligand (Takeda et al, 2003). One of the nuclear targets in the TLR-mediated signaling pathway is NF-IL6, a member of the C/EBP family of transcription factors (Tanaka et al, 1995). NF-IL6 was originally identified as a transcription factor that specifically binds to an IL-1 responsive element in the IL-6 gene promoter (Akira et al, 1990), and was subsequently shown to play an important role in LPS-induced gene expression in macrophages (Gorgoni et al, 2001;Uematsu et al, 2002).…”

Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

“…As C/EBPb is implicated in the regulation of many different molecular and physiological processes, it is possible that systemic factors are involved in the increased keratinocyte apoptosis as well as the subsequent lack of skin tumorigenesis in carcinogen treated C/EBPb À/À mice. C/EBPb null mice (C/EBPb À/À ) have major defects in their immune system (Screpanti et al, 1995;Tanaka et al, 1995) and C/EBPb is known to be involved in the regulation of numerous cytokines (Poli, 1998) some of which are important in Ras-tumorigenesis (Sparmann and Bar-Sagi, 2005). It is a distinct possibility that the increase in epidermal keratinocyte apoptosis in DMBA-treated C/EBPb À/À mice and subsequent lack of tumor development could be of a systemic nature, perhaps involving alterations in the expression of nonkeratinocyte-derived cytokines.…”

Tyrosine 759 of the cytokine receptor gp130 is involved in Listeria monocytogenes susceptibility

“…with 2 × 10 5 colony forming units (CFU) of L. monocytogenes (a laboratory strain, 27 kindly provided by Dr Y Dohi) on day 0. This strain was verified by PCR analysis to possess the inlA gene, which is specific for the L. monocytogenes strain.…”