Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4

Voelcker, Verena; Gebhardt, Carl; Averbeck, Marco; Saalbach, Anja; Wolf, Verena; Weih, Falk; Sleeman, Jonathan; Anderegg, Ulf; Simon, Jan C.

doi:10.1111/j.1600-0625.2007.00638.x

Cited by 122 publications

(108 citation statements)

References 34 publications

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“…5), suggesting a role of TLR4 in motility. Similar results were previously obtained in melanoma cells where the abrogation of TLR4 by short interference RNA inhibited the motility induced by short HA oligosaccharides (49). Another HA receptor (i.e.…”

Section: Resultssupporting

confidence: 78%

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Glycosaminoglycans and Glucose Prevent Apoptosis in 4-Methylumbelliferone-treated Human Aortic Smooth Muscle Cells

Vigetti

Rizzi

Moretto

et al. 2011

Journal of Biological Chemistry

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Smooth muscle cells (SMCs) have a pivotal role in cardiovascular diseases and are responsible for hyaluronan (HA) deposition in thickening vessel walls. HA regulates SMC proliferation, migration, and inflammation, which accelerates neointima formation. We used the HA synthesis inhibitor 4-methylumbelliferone (4-MU) to reduce HA production in human aortic SMCs and found a significant increase of apoptotic cells. Interestingly, the exogenous addition of HA together with 4-MU reduced apoptosis. A similar anti-apoptotic effect was observed also by adding other glycosaminoglycans and glucose to 4-MU-treated cells. Furthermore, the anti-apoptotic effect of HA was mediated by Toll-like receptor 4, CD44, and PI3K but not by ERK1/2. Hyaluronan (HA)3 is one of the most abundant glycosaminoglycans (GAGs) in extracellular matrices (ECMs) and is composed of linear, unsulfated repetitions of D-glucuronic acid and N-acetylglucosamine. In mammals, two specific HA synthases (HAS1 and -2) produce high molecular weight HA (HMW-HA), in the range of millions of Da, whereas the other isoenzyme (HAS3) synthesizes HA of lower molecular mass, in the range of several thousands of Da (1). The size of HA depends also on specific degrading enzymes (i.e. hyaluronidases) that can produce bioactive HA oligosaccharides. Therefore, in vivo, HA chains can greatly vary in lengths and can differently regulate cell behavior through interactions with several receptors, including CD44, RHAMM (receptor for HA-mediated motility), lymphatic vessel endothelial receptor 1 (Lyve-1), HA receptor for endocytosis (HARE), and Toll-like Receptor 4 (TLR4) (2).In cardiovascular pathologies, HA accumulates during neointima formation and alters smooth muscle cell (SMC) behavior (3). In some pathological conditions, contractile SMCs dedifferentiate to form a synthetic phenotype characterized by a high production of ECM components, including HA and versican, by synthesis of ECM-modifying metalloproteinases (4) and by increased rates of proliferation and migration. Therefore, SMCs acquire the capability to invade the vascular tunica intima, thereby contributing to vessel wall thickening. HMW-HA is involved in the modulation of SMC migration and proliferation through interaction with CD44 (5-7), which can mediate a signaling cascade inside the cell that activates different pathways, including PI3K, AKT, and ERK1/2 (8).We demonstrated previously that human aortic SMC (AoSMC) migration is strictly dependent on HA-CD44 signaling and recently reported that the HA synthesis inhibitor 4-methylumbelliferone (4-MU) reduced proatherosclerotic properties of AoSMCs by decreasing cell migration and proliferation and by inhibiting monocyte binding to the HA-rich ECM that contributes to inflammation (9, 10). Moreover, we found that the simultaneous addition of HMW-HA to 4-MUtreated AoSMCs restored cell proliferation to the levels of controls. Therefore, the aim of this study was to investigate at the molecular level the effects of HMW-HA after 4-MU treatment of AoSMCs and the pathway...

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Section: Resultssupporting

confidence: 78%

“…Therefore, the role of CD44 in TLRs signaling is becoming critical in light of recent literature reporting the modulation of the NF-kB pathway throughout not only HA (15) but also other proinflammatory secreted molecules as tumor necrosis factor-inducible gene 6 (49).…”

Section: Resultsmentioning

confidence: 99%

Glycosaminoglycans and Glucose Prevent Apoptosis in 4-Methylumbelliferone-treated Human Aortic Smooth Muscle Cells

Vigetti

Rizzi

Moretto

et al. 2011

Journal of Biological Chemistry

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“…7,26 These fragments can induce NF-kB activation, 27 and thereby proinflammatory gene expression through TLR2 and TLR4 signaling. [28][29][30][31] Indeed, CD44 KO mice showed impaired clearance of HA in bleomycin-induced lung inflammation accompanied by sustained accumulation of inflammatory cells. 12 In line, we found significantly increased HA concentrations in BALF from CD44 KO mice at 4 and 10 days after sublethal pneumonia, suggesting that, such as in bleomycin-induced lung inflammation, CD44 facilitates the resolution of inflammation during pneumococcal pneumonia, at least in part through clearance of HA from the lungs.…”

Section: Discussionmentioning

confidence: 99%

“…7,26 These fragments can induce NF-kB activation, 27 and thereby proinflammatory gene expression. [28][29][30][31] CD44 has been shown to have an important role in the clearance of HA from the airways during bleomycin-or LPS-induced lung inflammation, 8,12 and the accumulation of HA fragments contributes to the perpetuation of inflammation in these models. 12,32 Therefore, we considered it of interest to investigate whether CD44 has a part in the clearance of HA during the resolution phase of S. pneumoniae-induced pneumonia.…”

Section: Cd44 Deficiency Is Associated With Accumulation Of Ha Fragmementioning

confidence: 99%

The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia

Windt

Hoogendijk

Vos

et al. 2011

Laboratory Investigation

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Streptococcus pneumoniae is the most prevalent pathogen causing community-acquired pneumonia. CD44 is a transmembrane adhesion molecule, expressed by a wide variety of cell types, that has several functions in innate and adaptive immune responses. In this study, we tested the hypothesis that CD44 is involved in the host response during pneumococcal pneumonia. On intranasal infection with a lethal dose of S. pneumoniae CD44-knockout (KO) mice showed a prolonged survival when compared with wild-type mice, which was accompanied by a diminished pulmonary bacterial growth and reduced dissemination to distant body sites. Whereas, proinflammatory cytokine responses and lung pathology were not affected, CD44 deficiency resulted in increased early neutrophil influx into the lung. In separate experiments, we confirmed a detrimental role of CD44 in host defense against pneumococci during sublethal pneumonia, as demonstrated by an improved capacity of CD44 KO mice to clear a low infectious dose. In addition, CD44 appeared important for the resolution of lung inflammation during sublethal pneumonia, as shown by histopathology of lung tissue slides. In conclusion, we show here that CD44 facilitates bacterial outgrowth and dissemination during pneumococcal pneumonia, which in lethal infection results in a prolonged survival of CD44 KO mice. Moreover, during sublethal pneumonia CD44 contributes to the resolution of the inflammatory response.

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“…A variety of endogenous substances, including fibrinogen, hyaluronic acid, and heatshock proteins, can trigger TLR4 signaling. Interestingly, low molecular weight fragments of hyaluronic acid, a degradation product of the extracellular matrix, activate TLR4 signaling in melanoma cells and increase their motility (Voelcker et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Takazawa

Kiniwa

Ogawa

et al. 2014

Tohoku J. Exp. Med.

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Immune cell Toll-like receptors (TLRs) recognize conserved microbial components, leading to immune and inflammatory responses. However, TLRs are also expressed in cancer cells, including melanoma cells, which express TLR2-4. TLR4 ligands have received attention as immunotherapies; therefore, we assessed the expression of TLR4 in human melanoma specimens (29 primary lesions and 28 metastatic lesions) representing different types of melanoma. A high percentage (≥ 90%) of melanoma lesions expressed TLR4, as judged by immunohistochemistry. Next, the role of TLR4 in cell proliferation and migration was assessed using the TLR4-positive (TLR4 + ) melanoma cell lines 501mel and 888mel, and TLR4-negative (TLR4 -) 928mel melanoma cells. Lipopolysaccharide (LPS), a TLR4 agonist, increased the proliferation of TLR4 + melanoma cells but not of TLR4 -928mel cells. The proliferation-inducing effect of LPS in 888mel cells was abolished by blockade of TLR4 signaling via treatment with short interfering RNA (siRNA) targeting TLR4 or myeloid differentiation primary response gene 88 (MyD88), a molecule downstream of TLR4. However, knockdown of TLR4 or MyD88 expression did not affect the LPS-induced proliferation of 501mel cells, suggesting that residual TLR4 signaling is sufficient to maintain cell proliferation. By contrast, LPS increased the migration of TLR4 + melanoma cells, and this effect was substantially inhibited by TLR4 or MyD88 knockdown. Furthermore, TLR4 knockdown decreased cell migration even in the absence of LPS, suggesting the presence of an endogenous TLR4 ligand(s) in melanoma cells. TLR4 signaling may contribute to melanoma progression, and caution should be exercised when using TLR4 ligands as adjuvant therapy for cancer.

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Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4

Cited by 122 publications

References 34 publications

Glycosaminoglycans and Glucose Prevent Apoptosis in 4-Methylumbelliferone-treated Human Aortic Smooth Muscle Cells

Glycosaminoglycans and Glucose Prevent Apoptosis in 4-Methylumbelliferone-treated Human Aortic Smooth Muscle Cells

The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

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