The human parasite Leishmania amazonensis downregulates iNOS expression via NF-?B p50/p50 homodimer: role of the PI3K/Akt pathway.

ABSTRACT: Leishmania amazonensis activates the NF-?B transcriptional repressor homodimer (p50/p50) and promotes nitric oxide synthase (iNOS) downregulation. We investigated the role of PI3K/Akt in p50/p50 NF-?B activation and the effect on iNOS expression in L. amazonensis infection. The increased occupancy of p50/p50 on the iNOS promoter of infected macrophages was observed and we demonstrated that both p50/p50 NF-?B induction and iNOS downregulation in infected macrophages depended on PI3K/Akt activation. Importantly, the intracellular growth of the parasite was also impaired during PI3K/Akt signalling inhibition and in macrophages knocked-down for Akt 1 expression. It was also observed that the increased nuclear levels of p50/p50 in L. amazonensis-infected macrophages were associated with reduced phosphorylation of 907 Ser p105, the precursor of p50. Corroborating these data, we demonstrated the increased levels of phospho-9 Ser GSK3? in infected macrophages, which is associated with GSK3? inhibition and, consequently, its inability to phosphorylate p105. Remarkably, we found that the levels of pPTEN 370 Ser, a negative regulator of PI3K, increased due to L. amazonensis infection. Our data support the notion that PI3K/Akt activity is sustained during the parasite infection, leading to NF-?B 105 phosphorylation and further processing to originate p50/p50 homodimers and the consequent downregulation of iNOS expression.

SUBMITTER: Calegari-Silva TC 

PROVIDER: S-EPMC4593669 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature