RESUMO
Suppressors of cytokine signaling (SOCS) exhibit diverse antiinflammatory effects. Since ROS acts as a critical mediator of inflammation, we have investigated the anti-inflammatory mechanisms of SOCS via ROS regulation in monocytic/macrophagic cells. Using PMA-differentiated monocytic cell lines and primary BMDMs transduced with SOCS1 or shSOCS1, the LPS/TLR4-induced inflammatory signaling was investigated by analyzing the levels of intracellular ROS, antioxidant factors, inflammasome activation, and pro-inflammatory cytokines. The levels of LPS-induced ROS and the production of pro-inflammatory cytokines were notably down-regulated by SOCS1 and up-regulated by shSOCS1 in an NAC-sensitive manner. SOCS1 up-regulated an ROS-scavenging protein, thioredoxin, via enhanced expression and binding of NRF-2 to the thioredoxin promoter. SOCS3 exhibited similar effects on NRF-2/thioredoxin induction, and ROS downregulation, resulting in the suppression of inflammatory cytokines. Notably thioredoxin ablation promoted NLRP3 inflammasome activation and restored the SOCS1-mediated inhibition of ROS and cytokine synthesis induced by LPS. The results demonstrate that the anti-inflammatory mechanisms of SOCS1 and SOCS3 in macrophages are mediated via NRF-2-mediated thioredoxin upregulation resulting in the downregulation of ROS signal. Thus, our study supports the anti-oxidant role of SOCS1 and SOCS3 in the exquisite regulation of macrophage activation under oxidative stress. [BMB Reports 2020; 53(12): 640-645].
Assuntos
Inflamassomos/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Animais , Anti-Inflamatórios/imunologia , Citocinas/análise , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Regiões Promotoras Genéticas/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 Supressora da Sinalização de Citocina/fisiologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Células THP-1 , Tiorredoxinas/metabolismo , Tiorredoxinas/farmacologia , Receptor 4 Toll-LikeRESUMO
Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by ß-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of ß-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; C max, 52.1 mg/L vs 53.0 mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUClast and C max (95.7 [85.9-106.5] and 98.3 [91.6-105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary.
