title: Type 1 cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways.
abstract: 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-gamma production by NK cells. Here, we investigated whether TLR agonists can replace IL-18 for production of IFN-gamma 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-gamma in response to TLR2 or TLR7 agonists only when co-stimulated with IL-12, indicating that TLR agonists synergize with IL-12 for IFN-gamma. The tlr2(-/-) or tlr7(-/-) NK cells could not produce IFN-gamma 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-gamma, 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-gamma 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.
authors.affiliation: Department of Pediatrics, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya 663-8501, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sawaki
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Nobuki
authors.initials: N
authors.lastname: Hayashi
authors.forename: Koubun
authors.initials: K
authors.lastname: Yasuda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Takakuni
authors.initials: T
authors.lastname: Tanizawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D011425:Propionibacterium acnes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000172:deficiency; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000172:deficiency; D051193:Toll-Like Receptors / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
chemical_list: D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D020382:Interleukin-18; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D010457:Peptidoglycan; C499308:Rag2 protein, mouse; C493486:Tlr2 protein, mouse; C477038:Tlr7 protein, mouse; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D006151:Guanosine; D018664:Interleukin-12; D007371:Interferon-gamma; C068562:loxoribine; D011070:Poly I-C