The Receptor for Advanced Glycation End Products Is Highly Expressed in the Skin and Upregulated by AGE and Tumor Necrosis Factor-alpha

Lohwasser, Christina; Neureiter, Daniel; Weigle, Bernd; Kirchner, Thomas; Schuppan, Detlef

doi:10.1111/j.0022-202x.2005.23936.x

Cited by 5 publications

(5 citation statements)

References 41 publications

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“…Here, we demonstrated that keratinocytes expressed RAGE protein and that the incubation of keratinocytes with the specific RAGE ligand AGE–BSA resulted in significant upregulation of RAGE expression. These results are consistent with in vivo studies using immunohistochemical staining in human skin tissues showing that RAGE was predominantly found in keratinocytes, fibroblasts and dendrocytes (35). It has been demonstrated that AGEs induce NF‐κB activation through a variety of signal transduction pathways, suggesting that this is a potential mechanism for the effect of AGEs on RAGE.…”

Section: Discussionsupporting

confidence: 91%

Involvement of RAGE, MAPK and NF‐κB pathways in AGEs‐induced MMP‐9 activation in HaCaT keratinocytes

Zhu

Ren

Yang

et al. 2012

Experimental Dermatology

101

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Advanced glycation end products (AGEs) exert divergent effects on the pathogenesis of diabetes complications. Excessive expression of matrix metalloproteinases-9 (MMP-9) is deleterious to the cutaneous wound-healing process in the context of diabetes. However, the effect of AGEs on MMP-9 induction in skin cells and the exact molecular mechanisms involved are still poorly understood. In this study, we investigated the effect of AGEs on the production of MMP-9 in HaCaT keratinocytes and characterized the signal transduction pathways activated by AGEs that are involved in MMP-9 regulation. We showed that AGE-BSA increased MMP-9 expression in HaCaT cells at both the protein and mRNA levels. The stimulatory effect of AGE-BSA on MMP-9 was attenuated by inhibitors of extracellular-signal-regulated kinase (ERK1/2, U0126), p38 mitogen-activated protein kinase (MAPK, SB203580) and NF-κB, but not c-Jun N-terminal kinase. Furthermore, receptor for advanced glycation end products (RAGE) was expressed in keratinocytes, and incubation with AGE-BSA resulted in a significant upregulation of RAGE expression in a dose-dependent manner. Silencing of the RAGE gene prevented AGE-BSA-induced MMP-9 activation and the phosphorylation of ERK1/2 and p38 MAPK. We also observed the involvement of NF-κB in AGE-BSA-induced MMP-9 activation, which was not blocked by U0126 and SB203580. These results suggest that AGEs may play an important role in the impairment of diabetic wound healing by upregulating MMP-9 expression in keratinocytes via the RAGE, ERK1/2 and p38 MAPK pathways; activation of NF-κB is also involved in this process. These pathways may represent potential targets for drug interventions to improve diabetic wound healing, a process in which MMP-9 plays a critical role.

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Section: Discussionsupporting

confidence: 91%

Involvement of RAGE, MAPK and NF‐κB pathways in AGEs‐induced MMP‐9 activation in HaCaT keratinocytes

Zhu

Ren

Yang

et al. 2012

Experimental Dermatology

101

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“…Extracellular S100B regulates cell functions via activation of surface receptors . RAGE or CD166/ALCAM has been identified as a S100B surface receptor in a variety of cell types , including fibroblasts, dendrocytes and keratinocytes in the skin . However, no report about the receptor in melanocytes has been published.…”

Section: Discussionmentioning

confidence: 99%

S100B as a potential biomarker for the detection of cytotoxicity of melanocytes

Cheong

Noh

Kim

et al. 2014

Experimental Dermatology

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Skin irritation is one of the most common adverse reactions in hydroquinone (HQ) and retinoic acid (RA). Although melanocytes have rarely been considered to be involved in skin irritation, RA and particularly HQ could induce melanocyte toxicity, resulting in depigmentation. We chose S100B as a candidate gene for melanocytotoxicity from a genome-wide transcriptional profiling analysis after applying irritant doses of HQ, RA and sodium lauryl sulphate (SLS) to cultures of keratinocytes and/or melanocytes. In this study, the role of S100B on melanocyte viability and cytotoxicity was examined. S100B was detected in melanocytes, but not in keratinocytes or fibroblasts. Melanocytes after treatment with increasing concentrations of HQ, RA, SLS and urushiol showed significant increases in intracellular and extracellular S100B expression with reduced viable cell number and increased release of lactate dehydrogenase. No RAGE expression and no significant function of CD166/ALCAM in melanocyte survival and cytotoxicity favoured the role of intracellular S100B in chemically irritated melanocytes. S100B knock-down increased apoptosis through inhibition of PI3K/AKT, NF-κB and ERK activation, suggesting the increased intracellular S100B expression by chemical irritation as a compensatory reaction to reduce cytotoxicity. The numerical decrease in S100B/c-kit-double-positive melanocytes was also examined in human skin epidermis irritated by HQ or RA with stronger staining intensities of S100B. Collectively, the decrease in viable cell number by reduced intracellular S100B levels in vitro and by chemical irritation in vivo suggests that S100B could be a potential biomarker for melanocytes cytotoxicity.

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“…In particular, the fibroblasts found in tumors are called "activated fibroblasts", also sometimes referred to as myofibroblasts. The possibility that RAGE regulates fibroblasts is supported by studies showing that skin fibroblasts respond to AGEs by increasing their expression of RAGE and the cytokine TNF [134]. Activation of RAGE on synovial fibroblasts has been found to increase MCP-1 synthesis, which was sufficient to induce the chemotaxis of monocytes [135].…”

Section: Rage Effects Within the Cancer Microenvironmentmentioning

confidence: 99%

RAGE and RAGE Ligands in Cancer

Logsdon

Fuentes

Huang

et al. 2007

CMM

186

170

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The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor with multiple ligands that is known to play a key role in several diseases, including diabetes, arthritis, and Alzheimer's disease. Recent evidence indicates that this receptor also has an important role in cancer. RAGE ligands, which include the S100/calgranulins and high-mobility group box 1 (HMGB1) ligands, are expressed and secreted by cancer cells and are associated with increased metastasis and poorer outcomes in a wide variety of tumors. These ligands can interact in an autocrine manner to directly activate cancer cells and stimulate proliferation, invasion, chemoresistance, and metastasis. RAGE ligands derived from cancer cells can also influence a variety of important cell types within the tumor microenvironment, including fibroblasts, leukocytes, and vascular cells, leading to increased fibrosis, inflammation, and angiogenesis. Several of the cells in the tumor microenvironment also produce RAGE ligands. Most of the cancer-promoting effects of RAGE ligands are the result of their interaction with RAGE. However, these ligands also often have separate intracellular roles, and some may interact with other extracellular targets, so it is not currently possible to assign all of their effects to RAGE activation. Despite these complications, the bulk of the evidence supports the premise that the ligand-RAGE axis is an important target for therapeutic intervention in cancer.

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The Receptor for Advanced Glycation End Products Is Highly Expressed in the Skin and Upregulated by AGE and Tumor Necrosis Factor-alpha

Cited by 5 publications

References 41 publications

Involvement of RAGE, MAPK and NF‐κB pathways in AGEs‐induced MMP‐9 activation in HaCaT keratinocytes

Involvement of RAGE, MAPK and NF‐κB pathways in AGEs‐induced MMP‐9 activation in HaCaT keratinocytes

S100B as a potential biomarker for the detection of cytotoxicity of melanocytes

RAGE and RAGE Ligands in Cancer

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