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Ncf1 Provides a Reactive Oxygen Species-Independent Negative Feedback Regulation of TLR9-Induced IL-12p70 in Murine Dendritic Cells

Richter, Cornelia; Juan, Martina Herrero San; Will, Jutta; Brandes, Ralf P.; Kalinke, Ulrich; Akira, Shizuo; Pfeilsehifter, Josef M.; Hultqvist, Malin LU ; Holmdahl, Rikard LU and Radeke, Heinfried H. (2009) In Journal of Immunology 182(7). p.4183-4191
Abstract
Permanent exposure to pathogens requires decisions toward tolerance or immunity as a prime task of dendritic cells. The molecular mechanisms preventing uncontrolled immune responses are not completely clear. We investigated the regulatory function of Ncf1, an organizing protein of NADPH oxidase, in the signaling cascade of Toll-like receptors. TLR9-stimulated spleen cells from both Ncf1-deficient and B10.Q mice with a point mutation in exon 8 of Ncf1 exhibited increased IL-12p70 secretion compared with controls. This finding was restricted to stimulatory CpG2216 and not induced by CpG2088. Because only CpG/TLR9-induced IL-12p70 was regulated by Ncf1, we used TRIF-/- and MyD88(-/-) cells to show that TLR9/MyD88 was primarily affected.... (More)
Permanent exposure to pathogens requires decisions toward tolerance or immunity as a prime task of dendritic cells. The molecular mechanisms preventing uncontrolled immune responses are not completely clear. We investigated the regulatory function of Ncf1, an organizing protein of NADPH oxidase, in the signaling cascade of Toll-like receptors. TLR9-stimulated spleen cells from both Ncf1-deficient and B10.Q mice with a point mutation in exon 8 of Ncf1 exhibited increased IL-12p70 secretion compared with controls. This finding was restricted to stimulatory CpG2216 and not induced by CpG2088. Because only CpG/TLR9-induced IL-12p70 was regulated by Ncf1, we used TRIF-/- and MyD88(-/-) cells to show that TLR9/MyD88 was primarily affected. Interestingly, additional experiments revealed that spleen cells from NOX2/gp91(phox)-deficient mice and the blocking of electron transfer by diphenylene iodonium had no influence on CpG-induced IL-12p70, confirming an NADPH oxidase-independent function of Ncf1. Finally, proving the in vivo relevance CpG adjuvant-guided OVA immunization resulted in a strong augmentation of IL-12p70-dependent Th1 IFN-gamma response only in Ncf1-deficient mice. These data suggest for the first time an important role for Ncf1 in, the fine tuning of the TLR9/MyD88 pathway in vitro and in vivo that is independent of its role as an activator of NOX2. The Journal of Immunology, 2009,182: 4183-4191. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
182
issue
7
pages
4183 - 4191
publisher
American Association of Immunologists
external identifiers
  • wos:000264574600031
  • scopus:64249162497
ISSN
1550-6606
DOI
10.4049/jimmunol.0800795
language
English
LU publication?
yes
id
587a6816-eb6a-4f3f-8c35-ddf54cb7a528 (old id 1401464)
date added to LUP
2009-06-15 11:01:55
date last changed
2017-07-02 03:56:31
@article{587a6816-eb6a-4f3f-8c35-ddf54cb7a528,
  abstract     = {Permanent exposure to pathogens requires decisions toward tolerance or immunity as a prime task of dendritic cells. The molecular mechanisms preventing uncontrolled immune responses are not completely clear. We investigated the regulatory function of Ncf1, an organizing protein of NADPH oxidase, in the signaling cascade of Toll-like receptors. TLR9-stimulated spleen cells from both Ncf1-deficient and B10.Q mice with a point mutation in exon 8 of Ncf1 exhibited increased IL-12p70 secretion compared with controls. This finding was restricted to stimulatory CpG2216 and not induced by CpG2088. Because only CpG/TLR9-induced IL-12p70 was regulated by Ncf1, we used TRIF-/- and MyD88(-/-) cells to show that TLR9/MyD88 was primarily affected. Interestingly, additional experiments revealed that spleen cells from NOX2/gp91(phox)-deficient mice and the blocking of electron transfer by diphenylene iodonium had no influence on CpG-induced IL-12p70, confirming an NADPH oxidase-independent function of Ncf1. Finally, proving the in vivo relevance CpG adjuvant-guided OVA immunization resulted in a strong augmentation of IL-12p70-dependent Th1 IFN-gamma response only in Ncf1-deficient mice. These data suggest for the first time an important role for Ncf1 in, the fine tuning of the TLR9/MyD88 pathway in vitro and in vivo that is independent of its role as an activator of NOX2. The Journal of Immunology, 2009,182: 4183-4191.},
  author       = {Richter, Cornelia and Juan, Martina Herrero San and Will, Jutta and Brandes, Ralf P. and Kalinke, Ulrich and Akira, Shizuo and Pfeilsehifter, Josef M. and Hultqvist, Malin and Holmdahl, Rikard and Radeke, Heinfried H.},
  issn         = {1550-6606},
  language     = {eng},
  number       = {7},
  pages        = {4183--4191},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Ncf1 Provides a Reactive Oxygen Species-Independent Negative Feedback Regulation of TLR9-Induced IL-12p70 in Murine Dendritic Cells},
  url          = {http://dx.doi.org/10.4049/jimmunol.0800795},
  volume       = {182},
  year         = {2009},
}