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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Cornelia Richter
  • Martina Herrero San Juan
  • Jutta Will
  • Ralf P. Brandes
  • Ulrich Kalinke
  • Shizuo Akira
  • Josef M. Pfeilsehifter
  • Malin Hultqvist
  • Rikard Holmdahl
  • Heinfried H. Radeke
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
Original languageEnglish
Pages (from-to)4183-4191
JournalJournal of Immunology
Volume182
Issue number7
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)