TLR mediated GSK3ß activation suppresses CREB mediated IL-10 production to induce a protective immune response against murine visceral leishmaniasis.
Biochimie
; 107 Pt B: 235-46, 2014 Dec.
Article
em En
| MEDLINE
| ID: mdl-25223889
ABSTRACT
During Leishmania donovani (LD) infection Interleukin (IL)-10 favors parasite replication and plays a central role as a target for immune-based therapy. Glycogen synthase kinase 3 (GSK3)ß differentially regulates TLR-mediated cytokine production. CREB, an important transcription factor that induces IL-10 production is negatively regulated by GSK3ß. However, down regulation of IL-10 via CREB suppression has not been well explored in controlling LD infection. Here we demonstrate that, the TLR4 agonist 29 KDa ß 1,4-galactose terminal glycoprotein (GP29) of LD activated GSK3ß through TLR4 to induce IL-12-mediated Nitric oxide (NO) production that resulted in effective parasite clearance from macrophages. GSK3ß activation abrogated both CREB phosphorylation and IL-10 production. Two subcutaneous injections of GP29 at fortnightly intervals in a 4-week infected mouse model of LD resulted in a dominant IL-12-mediated NO production and 100% animals were protected against a subsequent challenge with virulent LD parasites. Complete absence of GP29 mediated protection with down regulated NO and IL-12 production and dominant IL-10 production in presence of the GSK3ß inhibitor, Lithium chloride reiterated the role of GSK3ß in disease resolution in the murine model of visceral leishmaniasis.
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Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas
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Proteínas de Protozoários
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Interleucina-10
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Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico
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Quinase 3 da Glicogênio Sintase
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Receptor 4 Toll-Like
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Leishmaniose Visceral
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article