RGD Reference Report - Loss of CD40 endogenous S-nitrosylation during inflammatory response in endotoxemic mice and patients with sepsis. - Rat Genome Database

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Loss of CD40 endogenous S-nitrosylation during inflammatory response in endotoxemic mice and patients with sepsis.

Authors: Godoy, LC  Moretti, AI  Jurado, MC  Oxer, D  Janiszewski, M  Ckless, K  Velasco, IT  Laurindo, FR  Souza, HP 
Citation: Godoy LC, etal., Shock. 2010 Jun;33(6):626-33.
RGD ID: 5490974
Pubmed: PMID:20473113   (View Abstract at PubMed)
DOI: DOI:10.1097/SHK.0b013e3181cb88e6   (Journal Full-text)

Signal transduction through the surface molecule CD40 is critical for cellular activation in immunoinflammatory states such as sepsis. The mechanisms regulating this pathway are not completely understood. Because CD40 displays potentially regulatory cysteine residues and CD40 is probably exposed to NO in the inflammatory milieu, we hypothesized that S-nitrosylation, the interaction of NO with cysteines residues, acts as a post-translational modification on CD40, coregulating the signaling activity and, therefore, the level of cellular activation. As assessed by the biotin switch and the reduction/chemiluminescence S-nitrosylation detection techniques, CD40 was found to be S-nitrosylated endogenously and upon exposure to NO donors in both human and murine macrophages. S-nitrosylation of CD40 was associated with milder activation by its ligand (CD40L), leading to reduced in vitro cytokine (IL-1beta, IL-12, and TNF-alpha) production, which was reversed in the presence of inhibitors of NO synthesis. S-nitrosylated CD40 was found in resting RAW 246.7 macrophages and BALB/c mice peritoneal macrophages, turning into the denitrosylated state upon in vitro or systemic exposure, respectively, to LPS. Moreover, monocytes from patients with sepsis displayed denitrosylated CD40 in contrast to the CD40 S-nitrosylation measured in healthy individuals. Finally, in an attempt to explain how S-nitrosylation regulates CD40 activation, we demonstrate that NO affects the redistribution of CD40 on the cell surface, which is a requirement for optimal signal transduction. Our results support a novel post-translational regulatory mechanism in which the CD40 signal may be, at least in part, dependent on cellular activation-induced receptor denitrosylation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Endotoxemia  ISOCd40 (Mus musculus)5490974; 5490974protein:decreased nitrosylation:macrophageRGD 
Endotoxemia  IDA 5490974protein:decreased nitrosylation:macrophageRGD 
Sepsis  IDA 5490974protein:decreased nitrosylation:monocyteRGD 
Sepsis  ISOCD40 (Homo sapiens)5490974; 5490974protein:decreased nitrosylation:monocyteRGD 

Objects Annotated

Genes (Rattus norvegicus)
Cd40  (CD40 molecule)

Genes (Mus musculus)
Cd40  (CD40 antigen)

Genes (Homo sapiens)
CD40  (CD40 molecule)


Additional Information