RESUMO
Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti-inflammatory immune response. However, the exact mechanism by which vitamin B6 plays the anti-inflammatory role is still unclear. Here, we report a novel mechanism of preventing excessive inflammation by vitamin B6 via reduction in the accumulation of sphingosine-1-phosphate (S1P) in a S1P lyase (SPL)-dependent manner in macrophages. Vitamin B6 supplementation decreased the expression of pro-inflammatory cytokines by suppressing nuclear factor-κB and mitogen-activated protein kinases signalling pathways. Furthermore, vitamin B6-reduced accumulation of S1P by promoting SPL activity. The anti-inflammatory effects of vitamin B6 were inhibited by S1P supplementation or SPL deficiency. Importantly, vitamin B6 supplementation protected mice from lethal endotoxic shock and attenuated experimental autoimmune encephalomyelitis progression. Collectively, these findings revealed a novel anti-inflammatory mechanism of vitamin B6 and provided guidance on its clinical use.
Assuntos
Aldeído Liases/metabolismo , Inflamação/metabolismo , Lisofosfolipídeos/metabolismo , Macrófagos/metabolismo , Esfingosina/análogos & derivados , Vitamina B 6/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Progressão da Doença , Encefalomielite Autoimune Experimental/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Choque/metabolismo , Transdução de Sinais , Esfingosina/metabolismoRESUMO
It is known that vitamin B1 (VB1) has a protective effect against oxidative retinal damage induced by anti-tuberculosis drugs. However, it remains unclear whether VB1 regulates immune responses during Mycobacterium tuberculosis (MTB) infection. We report here that VB1 promotes the protective immune response to limit the survival of MTB within macrophages and in vivo through regulation of peroxisome proliferator-activated receptor γ (PPAR-γ). VB1 promotes macrophage polarization into classically activated phenotypes with strong microbicidal activity and enhanced tumor necrosis factor-α and interleukin-6 expression at least in part by promoting nuclear factor-κB signaling. In addition, VB1 increases mitochondrial respiration and lipid metabolism and PPAR-γ integrates the metabolic and inflammatory signals regulated by VB1. Using both PPAR-γ agonists and deficient mice, we demonstrate that VB1 enhances anti-MTB activities in macrophages and in vivo by down-regulating PPAR-γ activity. Our data demonstrate important functions of VB1 in regulating innate immune responses against MTB and reveal novel mechanisms by which VB1 exerts its function in macrophages.
Assuntos
Imunidade Inata , Mycobacterium tuberculosis/imunologia , PPAR gama/metabolismo , Tiamina/metabolismo , Tuberculose/imunologia , Tuberculose/metabolismo , Animais , Biomarcadores , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/efeitos dos fármacos , Imunofenotipagem , Metabolismo dos Lipídeos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Tiamina/farmacologia , Tuberculose/microbiologiaRESUMO
The mechanisms by which vitamins regulate immunity and their effect as an adjuvant treatment for tuberculosis have gradually become very important research topics. Studies have found that vitamin B5 (VB5) can promote epithelial cells to express inflammatory cytokines. We aimed to examine the proinflammatory and antibacterial effect of VB5 in macrophages infected with Mycobacterium tuberculosis (MTB) strain H37Rv and the therapeutic potential of VB5 in vivo with tuberculosis. We investigated the activation of inflammatory signal molecules (NF-κB, AKT, JNK, ERK, and p38), the expression of two primary inflammatory cytokines (tumor necrosis factor and interleukin-6) and the bacterial burdens in H37Rv-infected macrophages stimulated with VB5 to explore the effect of VB5 on the inflammatory and antibacterial responses of macrophages. We further treated the H37Rv-infected mice with VB5 to explore VB5's promotion of the clearance of H37Rv in the lungs and the effect of VB5 on regulating the percentage of inflammatory cells. Our data showed that VB5 enhanced the phagocytosis and inflammatory response in macrophages infected with H37Rv. Oral administration of VB5 decreased the number of colony-forming units of H37Rv in lungs of mice at 1, 2, and 4 weeks after infection. In addition, VB5 regulated the percentage of macrophages and promoted CD4+ T cells to express interferon-γ and interleukin-17; however, it had no effect on the percentage of polymorphonuclear neutrophils, CD4+ and CD8+ T cells. In conclusion, VB5 significantly inhibits the growth of MTB by regulating innate immunity and adaptive immunity.
Assuntos
Proliferação de Células/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Mycobacterium tuberculosis/fisiologia , Ácido Pantotênico/uso terapêutico , Tuberculose/tratamento farmacológico , Complexo Vitamínico B/uso terapêutico , Imunidade Adaptativa , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Imunidade Inata , Inflamação , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Tuberculose/imunologia , Tuberculose/microbiologiaRESUMO
Absence of effective therapeutic methods for avascular necrosis of femoral head (ANFH) is still perplexing the world's medical community. Bone marrow mesenchymal stem cells (BMSCs) adoptive cell therapy combined with core decompression is a promising modality, which is highly dependent on the cellular activities of BMSCs. Hepatocyte growth factor (HGF) is a survival factor for BMSCs, yet the underlying mechanism is not fully elucidated. In this study, the effects of multiplicity of infections (MOIs) of recombinant adenovirus carrying HGF gene (rAd-HGF) on human BMSC proliferation and osteogenic differentiation were systemically examined. Infection of rAd-HGF produced secretory HGF and promoted hBMSC proliferation in a MOI-dependent manner, while the osteogenesis was also strengthened as indicated by enhanced calcium nodule formation with the strongest effects achieved at MOI = 250. Blocking the activities of c-MET or its downstream signaling pathways, WNT, ERK1/2, and PI3K/AKT led to differential consequents. Specifically, blockage of the WNT pathway significantly promoted osteogenic differentiation, which also showed additive effects when combined application with rAd-HGF. Our data demonstrated the pro-osteogenic effects of optimized MOIs of rAd-HGF, while inhibition of WNT pathway or activation of PI3K/AKT pathway may act as candidate adjuvant modalities for promoting osteogenic differentiation in rAd-HGF-modified hBMSC treatment on ANFH.