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Induction of NFκB responses by the S100A9 protein is TLR4-dependent.

Riva, Matteo LU ; Källberg, Eva LU ; Björk, Per; Hancz, Dora; Vogl, Thomas; Roth, Johannes; Ivars, Fredrik LU and Leanderson, Tomas LU (2012) In Immunology 137(2). p.172-182
Abstract
Interactions between danger and pathogen-associated molecular patterns (DAMP and PAMP) and pattern recognition receptors such as Toll-like receptors (TLRs) are critical for the regulation of the inflammatory process via activation of NFκB and cytokine secretion. In this report, we investigated the capacity of LPS-free S100A9 (DAMP) protein to activate human and mouse cells compared to lipoprotein-free LPS (PAMP). Firstly, we showed that LPS and S100A9 were able to increase NFκB activity followed by increased cytokine and nitric oxide (NO) secretion both in human THP-1 cells and mouse bone marrow-derived dendritic cells (BM-DC). Surprisingly, although S100A9 triggered a weaker cytokine response compared to LPS, we found that S100A9 more... (More)
Interactions between danger and pathogen-associated molecular patterns (DAMP and PAMP) and pattern recognition receptors such as Toll-like receptors (TLRs) are critical for the regulation of the inflammatory process via activation of NFκB and cytokine secretion. In this report, we investigated the capacity of LPS-free S100A9 (DAMP) protein to activate human and mouse cells compared to lipoprotein-free LPS (PAMP). Firstly, we showed that LPS and S100A9 were able to increase NFκB activity followed by increased cytokine and nitric oxide (NO) secretion both in human THP-1 cells and mouse bone marrow-derived dendritic cells (BM-DC). Surprisingly, although S100A9 triggered a weaker cytokine response compared to LPS, we found that S100A9 more potently induced IκBα degradation and hence NFkB activation. Both the S100A9- and LPS-induced response was completely absent in TLR4 knock-out mice, while it was only slightly affected in RAGE knock-out mice. Also, we showed that LPS and S100A9 NFkB induction were strongly reduced in the presence of specific inhibitors of TLR-signaling. Chloroquine reduced S100A9 but not LPS signaling, indicating that S100A9 may need to be internalized in order to be fully active as a TLR4 inducer. This was confirmed using A488-labeled S100A9 that was internalized in THP-1 cells, showing a raise in fluorescence after 30 minutes at 37°C. Chloroquine treatment significantly reduced the fluorescence. In summary, our data indicate that both human and mouse S100A9 are TLR4 agonists. Importantly, S100A9 induced stronger NFκB activation albeit weaker cytokine secretion than LPS, suggesting that S100A9 and LPS activated NFκB in a qualitative distinct manner. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd, Immunology. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
inflammation, DAMP, nuclear factor-?B, pathogen-associated molecular, patterns, THP-1, Toll-like receptor 4
in
Immunology
volume
137
issue
2
pages
172 - 182
publisher
Wiley-Blackwell
external identifiers
  • wos:000308405700007
  • pmid:22804476
  • scopus:84865786588
ISSN
0019-2805
DOI
10.1111/j.1365-2567.2012.03619.x
language
English
LU publication?
yes
id
40691753-fdf2-47ad-9898-eed5fb62cd97 (old id 2967054)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22804476?dopt=Abstract
date added to LUP
2012-08-09 19:37:29
date last changed
2017-11-12 03:10:35
@article{40691753-fdf2-47ad-9898-eed5fb62cd97,
  abstract     = {Interactions between danger and pathogen-associated molecular patterns (DAMP and PAMP) and pattern recognition receptors such as Toll-like receptors (TLRs) are critical for the regulation of the inflammatory process via activation of NFκB and cytokine secretion. In this report, we investigated the capacity of LPS-free S100A9 (DAMP) protein to activate human and mouse cells compared to lipoprotein-free LPS (PAMP). Firstly, we showed that LPS and S100A9 were able to increase NFκB activity followed by increased cytokine and nitric oxide (NO) secretion both in human THP-1 cells and mouse bone marrow-derived dendritic cells (BM-DC). Surprisingly, although S100A9 triggered a weaker cytokine response compared to LPS, we found that S100A9 more potently induced IκBα degradation and hence NFkB activation. Both the S100A9- and LPS-induced response was completely absent in TLR4 knock-out mice, while it was only slightly affected in RAGE knock-out mice. Also, we showed that LPS and S100A9 NFkB induction were strongly reduced in the presence of specific inhibitors of TLR-signaling. Chloroquine reduced S100A9 but not LPS signaling, indicating that S100A9 may need to be internalized in order to be fully active as a TLR4 inducer. This was confirmed using A488-labeled S100A9 that was internalized in THP-1 cells, showing a raise in fluorescence after 30 minutes at 37°C. Chloroquine treatment significantly reduced the fluorescence. In summary, our data indicate that both human and mouse S100A9 are TLR4 agonists. Importantly, S100A9 induced stronger NFκB activation albeit weaker cytokine secretion than LPS, suggesting that S100A9 and LPS activated NFκB in a qualitative distinct manner. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd, Immunology.},
  author       = {Riva, Matteo and Källberg, Eva and Björk, Per and Hancz, Dora and Vogl, Thomas and Roth, Johannes and Ivars, Fredrik and Leanderson, Tomas},
  issn         = {0019-2805},
  keyword      = {inflammation,DAMP,nuclear factor-?B,pathogen-associated molecular,patterns,THP-1,Toll-like receptor 4},
  language     = {eng},
  number       = {2},
  pages        = {172--182},
  publisher    = {Wiley-Blackwell},
  series       = {Immunology},
  title        = {Induction of NFκB responses by the S100A9 protein is TLR4-dependent.},
  url          = {http://dx.doi.org/10.1111/j.1365-2567.2012.03619.x},
  volume       = {137},
  year         = {2012},
}