Elastin Receptor (Spliced Galactosidase) Occupancy by Elastin Peptides Counteracts Proinflammatory Cytokine Expression in Lipopolysaccharide-Stimulated Human Monocytes through NF-κB Down-Regulation

Baranek, Thomas; Debret, Romain; Antonicelli, Frank; Lamkhioued, Bouchaïb; Belaaouaj, Abderrazzaq; Hornebeck, William; Bernard, Philippe; Guenounou, Moncef; Naour, Richard Le

doi:10.4049/jimmunol.179.9.6184

Cited by 39 publications

(32 citation statements)

References 55 publications

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“…This receptor recognizes an Xaa-Gly-Xaa-Xaa-Pro-Gly (XGXXPG) motif found repeatedly in elastin. Binding to the EBP triggers chemotaxic migration and the production of proteases and cytokines (54,55). Although our studies focus on the C-terminal domain of TE, which lacks this motif, and its interactions with elastogenic cells, we speculate that TE or elastin-derived peptides that are generated during pathologic conditions might become oxidatively modified, alter the interactions with inflammatory cells, and in turn may contribute in the development of diseases, such as atherosclerosis and emphysema.…”

Section: Discussionmentioning

confidence: 96%

Oxidative Modifications of the C-terminal Domain of Tropoelastin Prevent Cell Binding

Akhtar¹,

Broekelmann

Song³

et al. 2011

Journal of Biological Chemistry

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Tropoelastin (TE), the soluble monomer of elastin, is synthesized by elastogenic cells, such as chondrocytes, fibroblasts, and smooth muscle cells (SMCs). The C-terminal domain of TE interacts with cell receptors, and these interactions play critical roles in elastic fiber assembly. We recently found that oxidation of TE prevents elastic fiber assembly. Here, we examined the effects of oxidation of TE on cell interactions. We found that SMCs bind to TE through heparan sulfate (HS), whereas fetal lung fibroblasts (WI-38 cells) bind through integrin ␣ v ␤ 3 and HS. In addition, we found that oxidation of TE by peroxynitrite (ONOO ؊ ) prevented binding of SMCs and WI-38 cells and other elastogenic cells, human dermal fibroblasts and fetal bovine chondrocytes. Because the C-terminal domain of TE has binding sites for both HS and integrin, we examined the effects of oxidation of a synthetic peptide derived from the C-terminal 25 amino acids of TE (CT-25) on cell binding. The CT-25 peptide contains the only two Cys residues in TE juxtaposed to a cluster of positively charged residues (RKRK) that are important for cell binding. ONOO ؊ treatment of the CT-25 peptide prevented cell binding, whereas reduction of the CT-25 peptide had no effect. Mass spectrometric and circular dichroism spectroscopic analyses showed that ONOO ؊ treatment modified both Cys residues in the CT-25 peptide to sulfonic acid derivatives, without altering the secondary structure. These data suggest that the mechanism by which ONOO ؊ prevents cell binding to TE is by introducing negatively charged sulfonic acid residues near the positively charged cluster.Elastic fibers are key extracellular matrix structures that provide the stretch and recoil properties of tissues such as arteries, lungs, and skin. Elastic fibers consist of two major components, elastin and microfibrils. Elastin is the predominant component of elastic fibers, comprising Ͼ90% of the total mass. Tropoelastin (TE), 2 the soluble precursor of elastin, is synthesized by elastogenic cells, such as chondrocytes, fibroblasts, endothelial cells, and smooth muscle cells (SMCs). Assembly of monomeric TE into elastic fibers is a multistep process. Upon secretion from cells, TE monomers organize into aggregates on the cell surface. These aggregates are then deposited onto pre-existing microfibrils. Microfibrillar components align the TE aggregates, which undergo cross-linking to form mature elastic fibers. Cell surface molecules, such as the 67-kDa elastin-binding protein (EBP), ␣ v ␤ 3 integrin, and glycosaminoglycans (GAGs), have been proposed to be involved in elastic fiber assembly either by promoting aggregation of TE monomers or by keeping the microfibrils close to the cell membrane through interactions with microfibrillar components (1-5).TE is mainly synthesized during late fetal and early postnatal stages of development. Synthesis of TE in normal adult tissues is negligible; however, in several cardiovascular and pulmonary diseases, such as atherosclerosis and emphysema/chronic obstr...

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Section: Discussionmentioning

confidence: 96%

Oxidative Modifications of the C-terminal Domain of Tropoelastin Prevent Cell Binding

Akhtar¹,

Broekelmann

Song³

et al. 2011

Journal of Biological Chemistry

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“…20 Inhibition of TACE suppresses the invasion of inflammatory cells and the degradation of elastin fibers. 21 In the TIMP-3 group, the elastin fibers were maintained in the epicardial area for 8 weeks after gel administration. These fibers provide elasticity to the infarcted wall 22,23 and may therefore enhance motility of the infarcted wall in the TIMP-3 group.…”

Section: Discussionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase-1 and -3 Improves Cardiac Function in an Ischemic Cardiomyopathy Model Rat

Uchinaka

Kawaguchi²,

Mori³

et al. 2014

Tissue Engineering Part A

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Matrix metalloproteinases (MMPs) and a family of tissue inhibitors of metalloproteinases (TIMPs) may contribute to myocardial remodeling in heart failure. TIMPs are the main inhibitors of MMPs and have other MMP-independent functions. Because little is known of the role of TIMPs in the heart, we examined the effects of TIMPs on cardiac fibroblasts (CFs) and cardiomyocytes. In vitro, TIMP-1-4 enhanced smooth muscle actin (SMA) expression in CFs, and TIMP-1 and TIMP-3 enhanced the expression of phosphorylated Smad-3 and phosphorylated transforming growth factor (TGF)-β type 1 receptor in CFs; this effect was inhibited by TGF-β receptor blocker SB-505124. TIMPs-1, -3, and -4 also inhibited the FAK, AKT, and ERK pathways that induce cardiac hypertrophy. TIMP-1 and TIMP-2 suppressed apoptosis in cardiomyocytes; in contrast, TIMP-4 induced apoptosis in CFs. TIMP-2 stimulated collagen synthesis. Collagen gels containing TIMP-1 or TIMP-3, which exhibit cardioprotective effects in vitro, were transplanted to the left ventricular anterior wall of a rat heart model of myocardial infarction. Gel-released TIMP-1 and TIMP-3 significantly improved cardiac function and myocardial remodeling and enhanced SMA expression in the infarcted area in ischemic cardiomyopathy model rats. Further, the transplantation of TIMP-1 or TIMP-3 gels inhibited apoptosis in the ischemic myocardium and reduced MMP-2 activity. TIMPs may be an ideal target of cardiac regeneration therapy.

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“…For example, the human galactosidase gene GLB1 is alternatively transcribed into a low-abundance splice isoform missing three exons (Morreau et al 1989). It turned out that this short isoform codes for an elastin receptor (Privitera et al 1998) and is involved in inflammatory processes (Baranek et al 2007). Modrek and Lee (2003) have also reasoned that splice-isoform levels should be controlled on the basis of comparisons of splice isoforms as ''internal paralogs'' of duplicated genes.…”

Section: Discussionmentioning

confidence: 99%

Constant Splice-Isoform Ratios in Human Lymphoblastoid Cells Support the Concept of a Splico-Stat

et al. 2011

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Splicing generates mature transcripts from genes in pieces in eukaryotic cells. Overwhelming evidence has accumulated that alternative routes in splicing are possible for most human and mammalian genes, thereby allowing formation of different transcripts from one gene. No function has been assigned to the majority of identified alternative splice forms, and it has been assumed that they compose inert or tolerated waste from aberrant or noisy splicing. Here we demonstrate that five human transcription units (WT1, NOD2, GNAS, RABL2A, RABL2B) have constant splice-isoform ratios in genetically diverse lymphoblastoid cell lines independent of the type of alternative splicing (exon skipping, alternative donor/acceptor, tandem splice sites) and gene expression level. Even splice events that create premature stop codons and potentially trigger nonsense-mediated mRNA decay are found at constant fractions. The analyzed alternative splicing events were qualitatively but not quantitatively conserved in corresponding chimpanzee cell lines. Additionally, subtle splicing at tandem acceptor splice sites (GNAS, RABL2A/B) was highly constrained and strongly depends on the upstream donor sequence content. These results also demonstrate that unusual and unproductive splice variants are produced in a regulated manner. . DNA-encoded genetic information is kept separately in the chromosomes of a eukaryotic nucleus and is decoded via RNA intermediates, which are processed and transmitted to their destinations, for example, to the sites of cytoplasmic protein synthesis. Genes in pieces (composed of exons spaced apart by introns) additionally depend on a splice apparatus (spliceosome) that uses splice signals in a primary transcript to recognize exon-intron boundaries (splice sites) and to accurately cut out introns and join exons. Often, splicing generates different mature transcripts from the same gene, a process called alternative splicing (AS). This is achieved by alternative usage of splice sites in precursor RNA transcripts. In this way, the complexity of transcriptomes and proteomes is increased in eukaryotic organisms. Obviously, AS events need control to ensure formation of proper splice forms and ratios.Sequence motifs matching the splice-site consensus are very common in primary transcripts, but only a minute fraction of them are used by the spliceosome. This specificity is achieved by further sequence and structural information within the premature transcript recognized by different proteins. A complex network of highly combinatorial molecular interactions ensures the tissue-, developmental-, and elicitor-specific formation of spliced transcripts and is regulated at multiple points (Hertel 2008;Smith et al. 2008).Millions of short, single-pass cDNA sequence reads have accumulated in databases as expressed sequence tags supplemented from next-generation transcriptome sequencing data, both of which indicate that AS affects almost any multi-exon gene of any mammalian genome (Mortazavi et al. 2008;Wang et al. 2008).Howev...

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Elastin Receptor (Spliced Galactosidase) Occupancy by Elastin Peptides Counteracts Proinflammatory Cytokine Expression in Lipopolysaccharide-Stimulated Human Monocytes through NF-κB Down-Regulation

Cited by 39 publications

References 55 publications

Oxidative Modifications of the C-terminal Domain of Tropoelastin Prevent Cell Binding

Oxidative Modifications of the C-terminal Domain of Tropoelastin Prevent Cell Binding

Tissue Inhibitor of Metalloproteinase-1 and -3 Improves Cardiac Function in an Ischemic Cardiomyopathy Model Rat

Constant Splice-Isoform Ratios in Human Lymphoblastoid Cells Support the Concept of a Splico-Stat

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