RAGE signaling sustains inflammation and promotes tumor development

Gebhardt, Christoffer; Riehl, Astrid; Durchdewald, Moritz; Németh, Júlia; Fürstenberger, Gerhard; Müller‐Decker, Karin; Enk, Alexander H.; Arnold, Bernd; Bierhaus, Angelika; Nawroth, Peter P.; Heß, Jochen; Angel, Peter

doi:10.1084/jem.20070679

Cited by 340 publications

(313 citation statements)

References 37 publications

(80 reference statements)

Supporting

Mentioning

296

Contrasting

Unclassified

Order By: Relevance

“…It is known that S100A8/A9 binds to RAGE and TLR4 (18,19). Our flow cytometry data indicated that murine NK cells expressed RAGE, but not TLR4, on their surface (Fig.…”

Section: S100a8/a9 Activated Nk Cells Through Ragementioning

confidence: 59%

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Narumi¹,

Miyakawa²,

Ueda³

et al. 2015

The Journal of Immunology

101

View full text Add to dashboard Cite

S100A8/A9, a proinflammatory protein, is upregulated in inflammatory diseases, and also has a tumor-promoting activity by the recruitment of myeloid cells and tumor cell invasion. However, whether the expression of S100A8/A9 in tumors predicts a good or poor prognosis is controversial in the clinical setting. In this study, to clarify the in vivo role of S100A8/A9 in the tumor microenvironment, we s.c. inoculated Pan02 cells stably expressing S100A8 and S100A9 proteins (Pan02-S100A8/A9) in syngeneic C57BL/6 mice. Unexpectedly, after small tumor nodules were once established, they rapidly disappeared. Flow cytometry showed that the number of NK cells in the tumors was increased, and an administration of anti-asialoGM1 Ab for NK cell depletion promoted the growth of Pan02-S100A8/A9 s.c. tumors. Although the S100A8/A9 proteins alone did not change the IFN-γ expression of NK cells in vitro, a coculture with Pan02 cells, which express Rae-1, induced IFN-γ production, and Pan02-S100A8/A9 cells further increased the number of IFN-γ+ NK cells, suggesting that S100A8/A9 enhanced the NK group 2D ligand-mediated intracellular activation pathway in NK cells. We then examined whether NK cell activation by S100A8/A9 was via their binding to receptor of advanced glycation end product (RAGE) by using the inhibitors. RAGE antagonistic peptide and anti-RAGE Ab inhibited the IFN-γ production of NK cells induced by S100A8/A9 proteins, and an administration of FPS-ZM1, a RAGE inhibitor, significantly enhanced the in vivo growth of Pan02-S100A8/A9 tumors. We thus found a novel activation mechanism of NK cells via S100A8/A9–RAGE signaling, which may open a novel perspective on the in vivo interaction between inflammation and innate immunity.

show abstract

“…It is known that S100A8/A9 binds to RAGE and TLR4 (18,19). Our flow cytometry data indicated that murine NK cells expressed RAGE, but not TLR4, on their surface (Fig.…”

Section: S100a8/a9 Activated Nk Cells Through Ragementioning

confidence: 59%

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Narumi¹,

Miyakawa²,

Ueda³

et al. 2015

The Journal of Immunology

101

View full text Add to dashboard Cite

show abstract

“…The S100A12 protein has a number of different target proteins, such as the pattern recognition receptor RAGE (receptor for advanced glycation end products)125, 126 and plays a central role in the innate and acquired immune response 113, 127…”

Section: Biomarkers In Chronic Inflammatory Enteropathies Of Dogsmentioning

confidence: 99%

Clinical utility of currently available biomarkers in inflammatory enteropathies of dogs

Heilmann

Steiner

2018

Veterinary Internal Medicne

108

View full text Add to dashboard Cite

Chronic inflammatory enteropathies (CIE) in dogs are a group of disorders that are characterized by chronic persistent or recurrent signs of gastrointestinal disease and histologic evidence of mucosal inflammation. These CIEs are classified as either food‐responsive, antibiotic‐responsive, or immunosuppressant‐responsive enteropathy. Patients not clinically responding to immunomodulatory treatment are grouped as nonresponsive enteropathy and dogs with intestinal protein loss as protein‐losing enteropathy. Disease‐independent clinical scoring systems were established in dogs for assessment of clinical disease severity and patient monitoring during treatment. Histopathologic and routine clinicopathologic findings are usually not able to distinguish the subgroups of CIE. Treatment trials are often lengthy and further diagnostic tests are usually at least minimally invasive. Biomarkers that can aid in defining the presence of disease, site of origin, severity of the disease process, response to treatment, or a combination of these would be clinically useful in dogs with CIE. This article summarizes the following biomarkers that have been evaluated in dogs with CIE during the last decade, and critically evaluates their potential clinical utility in dogs with CIE: functional biomarkers (cobalamin, methylmalonic acid, folate, α1‐proteinase inhibitor, immunoglobulin A), biochemical biomarkers (C‐reactive protein, perinuclear anti‐neutrophilic cytoplasmic antibodies, 3‐bromotyrosine, N‐methylhistamine, calprotectin, S100A12, soluble receptor of advanced glycation end products, cytokines and chemokines, alkaline phosphatase), microbiomic biomarkers (microbiome changes, dysbiosis index), metabolomic biomarkers (serum metabolome), genetic biomarkers (genomic markers, gene expression changes), and cellular biomarkers (regulatory T cells). In addition, important performance criteria of diagnostic tests are briefly reviewed.

show abstract

“…Quantitative real-time polymerase chain reaction (RQ-PCR) analysis was performed as described previously. 16 Primers used for RQ-PCR analysis are listed in Supporting Table 2. Target gene cycle of threshold values were normalized to the corresponding cycle of threshold values of Hprt (for mouse samples) or LAMINB1 (for human samples) using the change in cycle of threshold method.…”

Section: Animalsmentioning

confidence: 99%

S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis

et al. 2009

Self Cite

View full text Add to dashboard Cite

The nuclear factor-kappaB (NF-B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-B-deficient and NF-B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)H epatocellular carcinoma (HCC) is the most frequent type of liver cancer and one of the most prevalent causes of cancer mortality worldwide. These tumors arise at sites of chronic liver injury, inflammation, and hepatocyte proliferation provoked by several causes such as chronic hepatitis B and C viral infection, chronic alcohol consumption, and aflatoxin B1-contaminated food. 1,2 Despite remarkable improvements in diagnosis, only limited therapeutic options exist, most of them with minimal clinical benefit. 2 Moreover, there is

show abstract

RAGE signaling sustains inflammation and promotes tumor development

Cited by 340 publications

References 37 publications

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Clinical utility of currently available biomarkers in inflammatory enteropathies of dogs

S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis

Contact Info

Product

Resources

About