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J Cell Biochem ; 119(9): 7844-7854, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29943842

RESUMO

Leishmania is a protozoan parasite that resides and replicates in macrophages and causes leishmaniasis. The parasite alters the signaling cascade in host macrophages and evades the host machinery. Small G-proteins are GTPases, grouped in 5 different families that play a crucial role in the regulation of cell proliferation, cell survival, apoptosis, intracellular trafficking, and transport. In particular, the Ras family of small G-proteins has been identified to play a significant role in the cellular functions mentioned before. Here, we studied the differential expression of the most important small G-proteins during Leishmania infection. We found major changes in the expression of different isoforms of Ras, mainly in N-Ras. We observed that Leishmania donovani infection led to enhanced N-Ras expression, whereas it inhibited K-Ras and H-Ras expression. Furthermore, an active N-Ras pull-down assay showed enhanced N-Ras activity. L donovani infection also increased extracellular signal-regulated kinase 1/2 phosphorylation and simultaneously decreased p38 phosphorylation. In contrast, pharmacological inhibition of Ras led to reduction in the phosphorylation of extracellular signal-regulated kinase 1/2 and enhanced the phosphorylation of p38 in Leishmania-infected cells, which could lead to increased interleukin-12 expression and decreased interleukin-10 expression. Indeed, farnesylthiosalicyclic acid (a Ras inhibitor), when used at the effective level in L donovani-infected macrophages, reduced amastigotes in the host macrophages. Thus, upregulated N-Ras expression during L donovani infection could be a novel immune evasion strategy of Leishmania and would be a potential target for antileishmanial immunotherapy.


Assuntos
Leishmania donovani/patogenicidade , Leishmaniose Visceral/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica , Humanos , Leishmaniose Visceral/genética , Leishmaniose Visceral/parasitologia , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fosforilação , Células THP-1 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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