RESUMO
Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of CNS diseases such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia. In the present study, we investigated the effect of pranoprofen, a non-steroidal anti-inflammatory drug (NSAID), on endoplasmic reticulum stress responses in the primary cultured glial cells. Pranoprofen inhibited ER stress-induced glucose regulated protein 78 (GRP78) expression, an ER-localized molecular chaperon. Moreover, pranoprofen inhibited ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) expression, an apoptotic transcription factor. ER stress-induced phosphorylation of alpha-subunit of eukaryotic initiation factor-2 (eIF2alpha) has been reported to be involved in CHOP induction. Interestingly, pranoprofen alone induced eIF2alpha phosphorylation, which was further increased by ER stress. On the other hand, ER stress-induced X-box-binding protein 1 (XBP-1) splicing was inhibited in pranoprofen-treated cells. Thus, the inhibitory effect of pranoprofen on ER stress-related genes (GRP78 and CHOP) would be mediated through the inhibition of XBP-1 splicing. In the present study, pranoprofen has been suggested to affect ER stress. The present results may have important implications for understanding ER stress-related diseases.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzopiranos/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Neuroglia/fisiologia , Propionatos/farmacologia , Animais , Células Cultivadas , DNA Complementar/genética , Retículo Endoplasmático/fisiologia , Chaperona BiP do Retículo Endoplasmático , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Camundongos , Chaperonas Moleculares/genética , Neuroglia/efeitos dos fármacos , Reação em Cadeia da Polimerase , RNA/efeitos dos fármacos , RNA/genética , RNA/isolamento & purificação , Fator de Transcrição CHOP/genéticaRESUMO
Leptin is an important circulating signal for inhibiting food intake and body weight gain. In recent years, "leptin resistance" has been considered to be one of the main causes of obesity. However, the detailed mechanisms of leptin resistance are poorly understood. Increasing evidence has suggested that stress signals, which impair endoplasmic reticulum (ER) function, lead to an accumulation of unfolded proteins, which results in ER stress. In the present study, we hypothesized that ER stress is involved in leptin resistance. Tunicamycin, thapsigargin, or brefeldin A was used to induce ER stress. The activation status of leptin signals was measured by Western blotting analysis using a phospho-(Tyr705) signal transducer and activator of transcription 3 (STAT3) antibody. We observed that ER stress markedly inhibited leptin-induced STAT3 phosphorylation. In contrast, ER stress did not affect leptin-induced c-Jun NH(2)-terminal kinase activation. These results suggest that ER stress induces leptin resistance. ER stress-induced leptin resistance was mediated through protein tyrosine phosphatase 1B but not through suppressors of cytokine signaling 3. It is noteworthy that a chemical chaperone, which could improve the protein-folding capacity, reversed ER stress-induced leptin resistance. Moreover, homocysteine, which induces ER stress, caused leptin resistance both in vitro and in vivo. Together, these findings suggest that the pathological mechanism of leptin resistance is derived from ER stress.
