Induction of nuclear factor-kappaB responses by the S100A9 protein is Toll-like receptor-4-dependent.
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Riva M, Kallberg E, Bjork P, Hancz D, Vogl T, Roth J, Ivars F, Leanderson T
Induction of nuclear factor-kappaB responses by the S100A9 protein is Toll-like receptor-4-dependent.
Immunology. 2012 Oct;137(2):172-82. doi: 10.1111/j.1365-2567.2012.03619.x.
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- 22804476 [ View in PubMed]
- Abstract
Interactions between danger-associated molecular patterns (DAMP) and pathogen-associated molecular patterns (PAMP) and pattern recognition receptors such as Toll-like receptors (TLRs) are critical for the regulation of the inflammatory process via activation of nuclear factor-kappaB (NF-kappaB) and cytokine secretion. In this report, we investigated the capacity of lipopolysaccharide (LPS) -free S100A9 (DAMP) protein to activate human and mouse cells compared with lipoprotein-free LPS (PAMP). First, we showed that LPS and S100A9 were able to increase NF-kappaB activity followed by increased cytokine and nitric oxide (NO) secretion both in human THP-1 cells and in mouse bone marrow-derived dendritic cells. Surprisingly, although S100A9 triggered a weaker cytokine response than LPS, we found that S100A9 more potently induced IkappaBalpha degradation and hence NF-kappaB activation. Both the S100A9-induced response and the LPS-induced response were completely absent in TLR4 knockout mice, whereas it was only slightly affected in RAGE knockout mice. Also, we showed that LPS and S100A9 NF-kappaB induction were strongly reduced in the presence of specific inhibitors of TLR-signalling. Chloroquine reduced S100A9 but not LPS signalling, indicating that S100A9 may need to be internalized to be fully active as a TLR4 inducer. This was confirmed using A488-labelled S100A9 that was internalized in THP-1 cells, showing a raise in fluorescence after 30 min at 37 degrees . Chloroquine treatment significantly reduced the fluorescence. In summary, our data indicate that both human and mouse S100A9 are TLR4 agonists. Importantly, S100A9 induced stronger NF-kappaB activation albeit weaker cytokine secretion than LPS, suggesting that S100A9 and LPS activated NF-kappaB in a qualitatively distinct manner.