Department of Medicine, Division of Infectious Diseases and Immunology
Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease
Natural killer (NK) cells are important for innate immunity in particular through the production of IFN-gamma and GM-CSF. Both cytokines are important in restoration of immune function of tolerized leukocytes under inflammatory events. The expression of TLRs in NK cells has been widely studied by analyzing the mRNA of these receptors, rarely seeking their protein expression. We previously showed that murine spleen NK cells express TLR9 intracellularly and respond to CpG oligodeoxynucleotide (CpG-ODN) by producing IFN-gamma and GM-CSF. However, to get such production the presence of accessory cytokines (such as IL-15 and IL-18) was required, whereas CpG-ODN or accessory cytokines alone did not induce IFN-gamma or GM-CSF. We show here that TLR9 overlaps with the Golgi apparatus in NK cells. Furthermore, CpG-ODN stimulation in the presence of accessory cytokines induces the phosphorylation of c-Jun, STAT3, and IkappaBalpha. IFN-gamma and GM-CSF production requires NF-kappaB and STAT3 activation as well as Erk-dependent mechanisms for IFN-gamma and p38 signaling for GM-CSF. Using knock-out-mice, we show that UNC93b1 and IL-12 (produced by NK cells themselves) are also necessary for IFN-gamma and GM-CSF production. IFN-gamma production was found to be MyD88- and TLR9-dependent, whereas GM-CSF was TLR9-independent but dependent on STING (stimulator of interferon genes), a cytosolic adaptor recently described for DNA sensing. Our study thereby allows us to gain insight into the mechanisms of synergy between accessory cytokines and CpG-ODN in NK cells. It also identifies a new and alternative signaling pathway for CpG-ODN in murine NK cells.
Cytokine, Interferon, Natural Killer (NK) cell, Signal Transduction, Toll-like Receptors (TLR), GM-CSF, IFN-gamma, STING, TLR9
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Copyright © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher PDF posted after 12 months as allowed by the publisher's author rights policy at https://www.asbmb.org/journals-news/editorial-policies.
DOI of Published Version
This research was originally published in: J Biol Chem. 2013 Apr 12;288(15):10715-21. doi: 10.1074/jbc.M112.435602. Epub 2013 Feb 26. Link to article on publisher's site
The Journal of biological chemistry
Souza-Fonseca-Guimaraes F, Parlato M, DeOliveira RB, Golenbock DT, Fitzgerald KA, Shalova IN, Biswas SK, Cavaillon J, Adib-Conquy M. (2013). Interferon-gamma and granulocyte/monocyte colony-stimulating factor production by natural killer cells involves different signaling pathways and the adaptor stimulator of interferon genes (STING). Infectious Diseases and Immunology Publications. https://doi.org/10.1074/jbc.M112.435602. Retrieved from https://escholarship.umassmed.edu/infdis_pp/364