Azithromycin suppresses CD4(+) T-cell activation by direct modulation of mTOR activity.
Sci Rep
; 4: 7438, 2014 Dec 11.
Article
en En
| MEDLINE
| ID: mdl-25500904
ABSTRACT
Advanced macrolides, such as azithromycin (AZM) or clarithromycin (CLM), are antibiotics with immunomodulatory properties. Here we have sought to evaluate their in vitro influence on the activation of CD4(+) T-cells. Isolated CD4(+) T-cells were stimulated with agonistic anti-CD3/anti-CD28 monoclonal antibodies in the presence of 0.6â
mg/L, 2.5â
mg/L, 10â
mg/L or 40â
mg/L AZM or CLM. Cell proliferation, cytokine level in supernatants and cell viability was assessed. Intracellular signaling pathways were evaluated using reporter cell lines, FACS analysis, immunoblotting and in vitro kinase assays. AZM inhibited cell proliferation rate and cytokine secretion of CD4(+) T-cells in a dose-dependent manner. Similarly, high concentrations of CLM (40â
mg/L) also suppressed these T-cell functions. Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein, a downstream target of mTOR. This effect was also observed at 40â
mg/L CLM. In vitro kinase studies using recombinant mTOR showed that AZM inhibited mTOR activity. In contrast to rapamycin, this inhibition was independent of FKBP12. We show for the first time that AZM and to a lesser extent CLM act as immunosuppressive agents on CD4(+) T-cells by inhibiting mTOR activity. Our results might have implications for the clinical use of macrolides.
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1
Base de datos:
MEDLINE
Asunto principal:
Activación de Linfocitos
/
Linfocitos T CD4-Positivos
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Azitromicina
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Serina-Treonina Quinasas TOR
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Inmunosupresores
Idioma:
En
Revista:
Sci Rep
Año:
2014
Tipo del documento:
Article