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International Immunology Advance Access originally published online on February 7, 2007
International Immunology 2007 19(3):311-320; doi:10.1093/intimm/dxl148
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

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

Junko Sawaki1,2, Hiroko Tsutsui3,4, Nobuki Hayashi2,4, Koubun Yasuda2,4, Shizuo Akira5, Takakuni Tanizawa1 and Kenji Nakanishi2,4

1 Department of Pediatrics
2 Department of Immunology and Medical Zoology
3 Department of Microbiology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya 663-8501, Japan
4 Core Research of Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
5 Department of Host defenses, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

Correspondence to: K. Nakanishi; E-mail: nakaken{at}hyo-med.ac.jp

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.

Keywords: CCL3, CCL4, IFN-{gamma}, IL-12, NK lytic activity

Transmitting editor: T. Hamaoka

Received 23 October 2006, accepted 22 December 2006.


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