Serveur d'exploration sur la glutarédoxine

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Glutaredoxin regulates autocrine and paracrine proinflammatory responses in retinal glial (muller) cells.

Identifieur interne : 000B24 ( Main/Exploration ); précédent : 000B23; suivant : 000B25

Glutaredoxin regulates autocrine and paracrine proinflammatory responses in retinal glial (muller) cells.

Auteurs : Melissa D. Shelton [États-Unis] ; Anne M. Distler ; Timothy S. Kern ; John J. Mieyal

Source :

RBID : pubmed:19074435

Descripteurs français

English descriptors

Abstract

Protein S-glutathionylation is a reversible redox-dependent post-translational modification. Many cellular functions and signal transduction pathways involve proteins whose cysteine-dependent activities are modulated by glutathionylation. Glutaredoxin (Grx1) plays a key role in such regulation because it is a specific and efficient catalyst of deglutathionylation. We recently reported an increase in Grx1 in retinae of diabetic rats and in rat retinal Müller glial cells (rMC-1) cultured in high glucose. This up-regulation of Grx1 was concomitant with NFkappaB activation and induction of intercellular adhesion molecule-1 (ICAM-1). This proinflammatory response was replicated by adenoviral-directed up-regulation of Grx1 in cells in normal glucose. The site of regulation of NFkappaB was localized to the cytoplasm, where IkappaB kinase (IKK) is a master regulator of NFkappaB activation. In the current study, inhibition of IKK activity abrogated the increase in ICAM-1 induced by high glucose or by adenoviral-directed up-regulation of Grx1. Conditioned medium from the Müller cells overexpressing Grx1 was added to fresh cultures of Müller or endothelial cells and elicited increases in the Grx1 and ICAM-1 proteins in these cells. These effects correlate with a novel finding that secretion of interleukin-6 was elevated in the cultures of Grx overexpressing cells. Also, pure interleukin-6 increased Grx1 and ICAM-1 in the rMC-1 cells. Thus, Grx1 appears to play an important role in both autocrine and paracrine proinflammatory responses. Furthermore, IKKbeta isolated from Müller cells in normal glucose medium was found to be glutathionylated on Cys-179. Hence Grx-mediated activation of IKK via deglutathionylation may play a central role in diabetic complications in vivo where Grx1 is increased.

DOI: 10.1074/jbc.M805464200
PubMed: 19074435
PubMed Central: PMC2643491


Affiliations:


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Le document en format XML

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<term>Animals (MeSH)</term>
<term>Autocrine Communication (MeSH)</term>
<term>Cell Line, Transformed (MeSH)</term>
<term>Diabetes Complications (enzymology)</term>
<term>Diabetes Complications (genetics)</term>
<term>Diabetes Complications (pathology)</term>
<term>Gene Expression Regulation, Enzymologic (drug effects)</term>
<term>Gene Expression Regulation, Enzymologic (genetics)</term>
<term>Glucose (metabolism)</term>
<term>Glutaredoxins (biosynthesis)</term>
<term>Glutaredoxins (genetics)</term>
<term>I-kappa B Kinase (genetics)</term>
<term>I-kappa B Kinase (metabolism)</term>
<term>Inflammation (enzymology)</term>
<term>Inflammation (genetics)</term>
<term>Inflammation (pathology)</term>
<term>Intercellular Adhesion Molecule-1 (biosynthesis)</term>
<term>Intercellular Adhesion Molecule-1 (genetics)</term>
<term>Interleukin-6 (biosynthesis)</term>
<term>Interleukin-6 (pharmacology)</term>
<term>NF-kappa B (genetics)</term>
<term>NF-kappa B (metabolism)</term>
<term>Neuroglia (enzymology)</term>
<term>Neuroglia (pathology)</term>
<term>Paracrine Communication (MeSH)</term>
<term>Rats (MeSH)</term>
<term>Retina (enzymology)</term>
<term>Retina (pathology)</term>
<term>Up-Regulation (drug effects)</term>
<term>Up-Regulation (genetics)</term>
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<term>Adenoviridae (MeSH)</term>
<term>Animaux (MeSH)</term>
<term>Communication autocrine (MeSH)</term>
<term>Communication paracrine (MeSH)</term>
<term>Complications du diabète (anatomopathologie)</term>
<term>Complications du diabète (enzymologie)</term>
<term>Complications du diabète (génétique)</term>
<term>Facteur de transcription NF-kappa B (génétique)</term>
<term>Facteur de transcription NF-kappa B (métabolisme)</term>
<term>Glucose (métabolisme)</term>
<term>Glutarédoxines (biosynthèse)</term>
<term>Glutarédoxines (génétique)</term>
<term>I-kappa B Kinase (génétique)</term>
<term>I-kappa B Kinase (métabolisme)</term>
<term>Inflammation (anatomopathologie)</term>
<term>Inflammation (enzymologie)</term>
<term>Inflammation (génétique)</term>
<term>Interleukine-6 (biosynthèse)</term>
<term>Interleukine-6 (pharmacologie)</term>
<term>Lignée de cellules transformées (MeSH)</term>
<term>Molécule-1 d'adhérence intercellulaire (biosynthèse)</term>
<term>Molécule-1 d'adhérence intercellulaire (génétique)</term>
<term>Névroglie (anatomopathologie)</term>
<term>Névroglie (enzymologie)</term>
<term>Rats (MeSH)</term>
<term>Régulation de l'expression des gènes codant pour des enzymes (effets des médicaments et des substances chimiques)</term>
<term>Régulation de l'expression des gènes codant pour des enzymes (génétique)</term>
<term>Régulation positive (effets des médicaments et des substances chimiques)</term>
<term>Régulation positive (génétique)</term>
<term>Rétine (anatomopathologie)</term>
<term>Rétine (enzymologie)</term>
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<term>Glutaredoxins</term>
<term>Intercellular Adhesion Molecule-1</term>
<term>Interleukin-6</term>
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<term>Glutaredoxins</term>
<term>I-kappa B Kinase</term>
<term>Intercellular Adhesion Molecule-1</term>
<term>NF-kappa B</term>
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<term>I-kappa B Kinase</term>
<term>NF-kappa B</term>
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<term>Complications du diabète</term>
<term>Inflammation</term>
<term>Névroglie</term>
<term>Rétine</term>
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<term>Glutarédoxines</term>
<term>Interleukine-6</term>
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<term>Régulation de l'expression des gènes codant pour des enzymes</term>
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<term>Complications du diabète</term>
<term>Inflammation</term>
<term>Névroglie</term>
<term>Rétine</term>
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<term>Inflammation</term>
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<term>Retina</term>
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<term>Diabetes Complications</term>
<term>Gene Expression Regulation, Enzymologic</term>
<term>Inflammation</term>
<term>Up-Regulation</term>
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<term>Complications du diabète</term>
<term>Facteur de transcription NF-kappa B</term>
<term>Glutarédoxines</term>
<term>I-kappa B Kinase</term>
<term>Inflammation</term>
<term>Molécule-1 d'adhérence intercellulaire</term>
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<term>Régulation positive</term>
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<term>Facteur de transcription NF-kappa B</term>
<term>Glucose</term>
<term>I-kappa B Kinase</term>
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<term>Diabetes Complications</term>
<term>Inflammation</term>
<term>Neuroglia</term>
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<term>Animaux</term>
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<term>Communication paracrine</term>
<term>Lignée de cellules transformées</term>
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<div type="abstract" xml:lang="en">Protein S-glutathionylation is a reversible redox-dependent post-translational modification. Many cellular functions and signal transduction pathways involve proteins whose cysteine-dependent activities are modulated by glutathionylation. Glutaredoxin (Grx1) plays a key role in such regulation because it is a specific and efficient catalyst of deglutathionylation. We recently reported an increase in Grx1 in retinae of diabetic rats and in rat retinal Müller glial cells (rMC-1) cultured in high glucose. This up-regulation of Grx1 was concomitant with NFkappaB activation and induction of intercellular adhesion molecule-1 (ICAM-1). This proinflammatory response was replicated by adenoviral-directed up-regulation of Grx1 in cells in normal glucose. The site of regulation of NFkappaB was localized to the cytoplasm, where IkappaB kinase (IKK) is a master regulator of NFkappaB activation. In the current study, inhibition of IKK activity abrogated the increase in ICAM-1 induced by high glucose or by adenoviral-directed up-regulation of Grx1. Conditioned medium from the Müller cells overexpressing Grx1 was added to fresh cultures of Müller or endothelial cells and elicited increases in the Grx1 and ICAM-1 proteins in these cells. These effects correlate with a novel finding that secretion of interleukin-6 was elevated in the cultures of Grx overexpressing cells. Also, pure interleukin-6 increased Grx1 and ICAM-1 in the rMC-1 cells. Thus, Grx1 appears to play an important role in both autocrine and paracrine proinflammatory responses. Furthermore, IKKbeta isolated from Müller cells in normal glucose medium was found to be glutathionylated on Cys-179. Hence Grx-mediated activation of IKK via deglutathionylation may play a central role in diabetic complications in vivo where Grx1 is increased.</div>
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<AbstractText>Protein S-glutathionylation is a reversible redox-dependent post-translational modification. Many cellular functions and signal transduction pathways involve proteins whose cysteine-dependent activities are modulated by glutathionylation. Glutaredoxin (Grx1) plays a key role in such regulation because it is a specific and efficient catalyst of deglutathionylation. We recently reported an increase in Grx1 in retinae of diabetic rats and in rat retinal Müller glial cells (rMC-1) cultured in high glucose. This up-regulation of Grx1 was concomitant with NFkappaB activation and induction of intercellular adhesion molecule-1 (ICAM-1). This proinflammatory response was replicated by adenoviral-directed up-regulation of Grx1 in cells in normal glucose. The site of regulation of NFkappaB was localized to the cytoplasm, where IkappaB kinase (IKK) is a master regulator of NFkappaB activation. In the current study, inhibition of IKK activity abrogated the increase in ICAM-1 induced by high glucose or by adenoviral-directed up-regulation of Grx1. Conditioned medium from the Müller cells overexpressing Grx1 was added to fresh cultures of Müller or endothelial cells and elicited increases in the Grx1 and ICAM-1 proteins in these cells. These effects correlate with a novel finding that secretion of interleukin-6 was elevated in the cultures of Grx overexpressing cells. Also, pure interleukin-6 increased Grx1 and ICAM-1 in the rMC-1 cells. Thus, Grx1 appears to play an important role in both autocrine and paracrine proinflammatory responses. Furthermore, IKKbeta isolated from Müller cells in normal glucose medium was found to be glutathionylated on Cys-179. Hence Grx-mediated activation of IKK via deglutathionylation may play a central role in diabetic complications in vivo where Grx1 is increased.</AbstractText>
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<LastName>Distler</LastName>
<ForeName>Anne M</ForeName>
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<LastName>Kern</LastName>
<ForeName>Timothy S</ForeName>
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<DescriptorName UI="D009457" MajorTopicYN="N">Neuroglia</DescriptorName>
<QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
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<DescriptorName UI="D012160" MajorTopicYN="N">Retina</DescriptorName>
<QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
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<MeshHeading>
<DescriptorName UI="D015854" MajorTopicYN="N">Up-Regulation</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
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