Type 1 cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways

• Published in: International immunology 2007-03, Vol.19 (3), p.311-320
• Main Authors: Sawaki, Junko, Tsutsui, Hiroko, Hayashi, Nobuki, Yasuda, Koubun, Akira, Shizuo, Tanizawa, Takakuni, Nakanishi, Kenji
• Format: Article
• Language: English
• Subjects: Animals; CCL3; CCL4; Cells, Cultured; Chemokines - biosynthesis; Cytokines - biosynthesis; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Guanosine - analogs & derivatives; Guanosine - pharmacology; IFN-γ; IL-12; Interferon-gamma - biosynthesis; Interleukin-12 - deficiency; Interleukin-12 - genetics; Interleukin-18 - deficiency; Interleukin-18 - genetics; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lipopolysaccharides - pharmacology; Liver - cytology; Liver - metabolism; Membrane Glycoproteins - deficiency; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88 - deficiency; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; NF-kappa B - metabolism; NK lytic activity; Peptidoglycan - pharmacology; Poly I-C - pharmacology; Propionibacterium; Propionibacterium acnes - immunology; Th1 Cells - immunology; Th1 Cells - metabolism; Toll-Like Receptor 2 - deficiency; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 7 - deficiency; Toll-Like Receptors - deficiency; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxl148

It is well established that IL-18R- and toll-like receptor (TLR)-mediated signalings share a common signal pathway mediated by signal adaptor, MyD88, and that IL-18 synergizes with IL-12 for IFN-γ production by NK cells. Here, we investigated whether TLR agonists can replace IL-18 for production of IFN-γ by NK cells. Freshly isolated NK cells possessed functional LPS receptor composed of TLR4/MD2 complex and of CD14, and also expressed other various tlrs. Hepatic CD3−DX5+ NK cells produced IFN-γ in response to TLR2 or TLR7 agonists only when co-stimulated with IL-12, indicating that TLR agonists synergize with IL-12 for IFN-γ. The tlr2−/− or tlr7−/− NK cells could not produce IFN-γ in response to IL-12 plus TLR2 or TLR7 ligands, respectively, indicating requirement of the corresponding TLRs. Furthermore, upon stimulation with these combinations, wild-type NK cells produced type 1 chemokines, such as CCL3, CCL4 and CCL5 as well. NK cells from bacterium (e.g. Propionibacterium acnes)-inoculated rag2−/− mice, when compared with those from naive mice, exhibited significantly enhanced capacity to produce these CC chemokines and IFN-γ, suggesting that microbial infection enhances responsiveness of NK cells to TLR agonists. These results indicate that upon microbial infection, macrophages produce IL-12 that renders NK cells highly responsive to TLR agonists to produce IFN-γ and chemokines, which might in turn recruit and fully activate macrophages, leading to the development of inflammatory foci presumably necessary for efficient microbial eradication. Thus, NK cells, like T cells, induce orchestrated immune responses in collaboration with macrophages to show potent host defense effects during early infectious phase.