| Texto completo | |
| Autor(es): |
Godoy, Luiz C.
[1, 2]
;
Moretti, Ana I.
[1]
;
Jurado, Marcia C.
[1]
;
Oxer, Daniella
[1]
;
Janiszewski, Mariano
[3]
;
Ckless, Karina
[4]
;
Velasco, Irineu T.
[1]
;
Laurindo, Francisco R. M.
[5]
;
Souza, Heraldo P.
[1]
Número total de Autores: 9
|
| Afiliação do(s) autor(es): | [1] Univ Sao Paulo, Sch Med, Dept Emergency Med, Sao Paulo - Brazil
[2] MIT, Dept Biol Engn, Cambridge, MA 02139 - USA
[3] Univ Sao Paulo, Sch Med, Dept Rheumatol, Sao Paulo - Brazil
[4] SUNY Coll Plattsburgh, Dept Chem, Plattsburgh, NY 12901 - USA
[5] Univ Sao Paulo, Sch Med, Inst Heart, Lab Vasc Biol, Sao Paulo - Brazil
Número total de Afiliações: 5
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Shock; v. 33, n. 6, p. 626-633, JUN 2010. |
| Citações Web of Science: | 15 |
| Resumo | |
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-1 beta, 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. (AU) | |
| Processo FAPESP: | 03/11140-6 - Papel da dissulfeto isomerase (PDI) na modificação pós-traducional de proteínas: implicações funcionais da nitrosilação da molécula CD40 |
| Beneficiário: | Luiz Claudio Godoy |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 02/02930-0 - A via de sinalizacao cd40/cd40l na aterosclerose: controle da sua atividade por especies reativas de oxigenio e modificacao de mecanismos aterogenicos atraves do seu bloqueio. |
| Beneficiário: | Heraldo Possolo de Souza |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |