LOSS OF CD40 ENDOGENOUS S-NITROSYLATION DURING INFLAMMATORY RESPONSE IN ENDOTOXEMIC MICE AND PATIENTS WITH SEPSIS
| Autor: | Karina Ckless, Mariano Janiszewski, Marcia C. Jurado, Daniella Oxer, Luiz C. Godoy, Ana Iochabel Soares Moretti, Irineu Tadeu Velasco, Francisco R.M. Laurindo, Heraldo Possolo de Souza |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
medicine.medical_treatment CD40 Ligand Down-Regulation Inflammation Biology Nitric Oxide Critical Care and Intensive Care Medicine Cell Line Nitric oxide Mice chemistry.chemical_compound Downregulation and upregulation Sepsis medicine Animals Humans Nitric Oxide Donors CD40 Antigens Receptor Aged CD40 Macrophages hemic and immune systems S-Nitrosylation Middle Aged Endotoxemia Cell biology Cytokine chemistry Immunology Emergency Medicine biology.protein Cytokines medicine.symptom Signal transduction Protein Processing Post-Translational Signal Transduction |
| Zdroj: | Shock. 33:626-633 |
| ISSN: | 1073-2322 |
| DOI: | 10.1097/shk.0b013e3181cb88e6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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