RESUMO
PURPOSE: Obesity is usually associated with low-grade inflammation, which impairs insulin action. The amino acid, taurine (TAU), regulates glucose homeostasis and lipid metabolism and presents anti-inflammatory actions. Here, we evaluated whether inflammatory markers are altered in the serum and retroperitoneal adipose tissue of monosodium glutamate (MSG) obese rats, supplemented or not with TAU. METHODS: Male Wistar rats received subcutaneous injections of MSG (4 mg/kg body weight/day, MSG group) or hypertonic saline (CTL) during the first 5 days of life. From 21 to 120 days of age, half of each of the MSG and CTL groups received 2.5 % TAU in their drinking water (CTAU and MTAU). RESULTS: At 120 days of age, MSG rats were obese and hyperinsulinemic. TAU supplementation reduced fat deposition without affecting insulinemia in MTAU rats. MSG rats presented increased pIκ-Bα/Iκ-Bα protein expression in the retroperitoneal adipose tissue. TAU supplementation decreased the ratio of pIκ-Bα/Iκ-Bα protein, possibly contributing to the increased Iκ-Bα content in MTAU adipose tissue. Furthermore, MSG obesity or supplementation did not alter TNF-α, IL-1ß or IL-6 content in adipose tissue. In contrast, MSG rats presented lower serum TNF-α, IL-4 and IL-10 concentrations, and these alterations were prevented by TAU treatment. CONCLUSION: MSG obesity in rats was not associated with alterations in pro-inflammatory markers in retroperitoneal fat stores; however, reductions in the serum concentrations of anti-inflammatory cytokines and of TNF-α were observed. TAU treatment decreased adiposity, and this effect was associated with the normalization of circulating TNF-α and IL-4 concentrations in MTAU rats.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Suplementos Nutricionais , Regulação da Expressão Gênica , Gordura Intra-Abdominal/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Obesidade/dietoterapia , Taurina/uso terapêutico , Adiposidade , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Hiperinsulinismo/dietoterapia , Hiperinsulinismo/etiologia , Hiperinsulinismo/imunologia , Hiperinsulinismo/metabolismo , Proteínas I-kappa B/agonistas , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Injeções Subcutâneas , Interleucina-4/antagonistas & inibidores , Interleucina-4/sangue , Interleucina-4/metabolismo , Gordura Intra-Abdominal/imunologia , Masculino , Inibidor de NF-kappaB alfa/agonistas , Inibidor de NF-kappaB alfa/genética , Obesidade/etiologia , Obesidade/imunologia , Obesidade/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Ratos Wistar , Glutamato de Sódio/administração & dosagem , Glutamato de Sódio/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We have previously demonstrated that 1α,25 dihydroxy-vitamin D(3) (1α,25(OH)(2)D(3)) has antiproliferative effects on the growth of endothelial cells transformed by the viral G protein-coupled receptor associated to Kaposi sarcoma (vGPCR). In this work, we have investigated whether 1α,25(OH)(2)D(3) exerts its growth inhibitory effects by inhibiting the Nuclear Factor κ B (NFκB) pathway which is highly activated by vGPCR. Cell proliferation studies demonstrated that 1α,25(OH)(2)D(3), similarly to bortezomib, a proteosome inhibitor that suppresses the activation of NFκB, reduced the proliferation of endothelial cells transformed by vGPCR (SVEC-vGPCR). The activity of NFκB in these cells decreased by 70% upon 1α,25(OH)(2)D(3) treatment. Furthermore, time and dose response studies showed that the hormone significantly decreased NFκB and increased IκBα mRNA and protein levels in SVEC-vGPCR cells, whereas in SVEC only IκBα increased significantly. Moreover, NFκB translocation to the nucleus was inhibited and occurred by a mechanism independent of NFκB association with vitamin D(3) receptor (VDR). 1α,25(OH)(2)D(3)-induced increase in IκBα required de novo protein synthesis, and was independent of MAPK and PI3K/Akt pathways. Altogether, these results suggest that down-regulation of the NFκB pathway is part of the mechanism involved in the antiproliferative effects of 1α,25(OH)(2)D(3) on endothelial cells transformed by vGPCR.
Assuntos
Antineoplásicos/farmacologia , Calcitriol/farmacologia , Células Endoteliais/efeitos dos fármacos , Herpesvirus Humano 8/genética , Proteínas I-kappa B/agonistas , NF-kappa B/antagonistas & inibidores , Receptores de Quimiocinas/genética , Receptores Virais/genética , Ácidos Borônicos/farmacologia , Bortezomib , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/genética , NF-kappa B/metabolismo , Transporte Proteico , Pirazinas/farmacologia , Receptores de Calcitriol/metabolismo , Transdução de SinaisRESUMO
Autoimmune diseases, such as systemic lupus erythematosus (SLE), result from deficiencies in self-antigen tolerance processes, which require regulated dendritic cell (DC) function. In this study we evaluated the phenotype of DCs during the onset of SLE in a mouse model, in which deletion of the inhibitory receptor FcgammaRIIb leads to the production of anti-nuclear antibodies and glomerulonephritis. Splenic DCs from FcgammaRIIb-deficient mice suffering from SLE showed increased expression of co-stimulatory molecules. Furthermore, diseased mice showed an altered function of the nuclear factor-kappaB (NF-kappaB) transcription factor, which is involved in DC maturation. Compared with healthy animals, expression of the inhibitory molecule IkappaB-alpha was significantly decreased in mice suffering from SLE. Consistently, pharmacological inhibition of NF-kappaB activity in FcgammaRIIb-deficient mice led to reduced susceptibility to SLE and prevented symptoms, such as anti-nuclear antibodies and kidney damage. Our data suggest that the occurrence of SLE is significantly influenced by alterations of NF-kappaB function, which can be considered as a new therapeutic target for this disease.