IL-6-regulated transcription factors.

Through the cloning of two transcription factors named NF-IL6 and STAT3/APRF, two types of IL-6 signal transduction pathways from the cell surface to the nucleus have been revealed. NF-IL6 is phosphorylated and activated by a Ras-dependent MAP kinase cascade, while STAT3/APRF is directly tyrosine-phosphorylated by JAK kinases that associate with the cytoplasmic portion of the receptor, and translocates to the nucleus and activates transcription (JAK-STAT pathway). STAT3 is also tyrosine phosphorylated in response to epidermal growth factor (EGF), granulocyte colony-stimulating factor (G-CSF), leptin and other IL-6-type cytokines including ciliary neurotrophic factor (CNTF), oncostatin M and leukemia inhibitory factor (LIF). Mice deficient in the genes for NF-IL6 and STAT3 were generated. NF-IL6 mice were highly susceptible to facultative intracellular bacteria owing to ineffective killing of the pathogens by the macrophages. Futhermore, the tumor cytotoxicity of macrophages from NF-IL6 KO mice was severely impaired. These results demonstrate a crucial role of NF-IL6 in macrophage bactericidal and tumoricidal activities. The target disruption of STAT3 resulted in embryonic lethality prior to gastrulation, demonstrating that STAT3 is essential for the early development of mouse embryos.