Avaliação da ação do peptídeo sintético pm26TGF-β1, mimético de TGF-β1 humano, na apoptose induzida por TNF-α em Drosophila melanogaster

Abstract

Comprehending TNFα (Tumor Necrosis Fator alpha) and TGF-β1 (Transforming Growth Factor beta) combined action is important for understanding cell death and inflammatory processes mechanisms. The fact that there are orthologs in Drosophila melanogaster for the cytokines TNF-α (Eiger) and TGF-β1 (Dpp) and their respective receptors make fly a relevant biological model for elucidating those processes. The eiger gene has been identified as an ortholog of the gene responsible for encoding the Tumor Necrosis Factor (TNF-alpha) in mammals. Characterized as an inflammatory cytokine independent of caspase, Eiger acts on D. melanogaster inducing apoptosis through the activation of JNK (Jun N-terminal kinases), pathway, resulting in the reduced eye phenotype. Studies demonstrate that TGF-β1 can also act on JNK pathway by inducing or inhibiting cellular apoptosis, depending of the cellular context. In 2015, by the Phage Display technique, Vaz et al. selected a peptide that mimics a portion of the human TGF-β1 molecule, called pm26TGF-β1 peptide, which demonstrated high affinity for the TGF-β 1 receptor and anti-inflammatory action. The objective of this study was to evaluate the synthetic peptide pm26TGF-β1 action (similar to the human TFG-β1) in the apoptosis pathway induced by TNFα using the Drosophila melanogaster as a model organism. Our results showed that GMR-GAL4 > UAS-eiger (reduced eye phenotype) of D. melanogaster flies treated with the pm26TGF-β1 peptide have had an improvement in their survival rate and an increase in the area of the eye, even if it was not accompanied by function gain. The peptide also acted to reduce the hemocyte overall count in the third-stage larvae, suggesting an anti-inflammatory effect. These data were corroborated by the reduction of eiger (TNF-α ortholog) and wengen (TGF-β ortholog) transcript expression. Therefore, we have verified that the synthetic peptide pm26TGF-β1 acts on JNK pathway inhibiting apoptosis and validated the use of D. melanogaster as an alternative model for the cell death and inflammation processes study as well as for the screening of biologically active molecules with pharmacological potential.