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)
Authors
Souza-Fonseca-Guimaraes, FernandoParlato, Marianna
DeOliveira, Rosane B.
Golenbock, Douglas T.
Fitzgerald, Katherine A.
Shalova, Irina N.
Biswas, Subhra K.
Cavaillon, Jean-Marc
Adib-Conquy, Minou
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2013-04-12Keywords
CytokineInterferon
Natural Killer (NK) cell
Signal Transduction
Toll-like Receptors (TLR)
GM-CSF
IFN-gamma
STING
TLR9
Immunity
Immunology and Infectious Disease
Immunology of Infectious Disease
Infectious Disease
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1074/jbc.M112.435602Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35152PubMed ID
23443666Related Resources
Rights
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.ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M112.435602