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1.
J Dermatol Sci ; 103(3): 156-166, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34334258

RESUMO

BACKGROUND: Acne vulgaris is a prevalent skin disease lacking effective and well-tolerated treatment. An earlier study indicated that resveratrol (RVT) has therapeutic effects in acne patients through unknown mechanisms. OBJECTIVES: To evaluate the effects of RVT on linoleic acid (LA)-induced lipogenesis and peptidoglycan (PGN)-induced inflammation in cultured SZ95 sebocytes in vitro, and to investigate the underlying mechanisms. METHODS: RNA-sequencing was used to analyze the whole transcriptome. Nile red staining was used to detect intracellular neutral lipids, whereas lipidomics was used to investigate changes in the lipid profile in sebocytes. Interleukin (IL)-1ß and IL-6 mRNA and protein levels were assessed through quantitative real-time PCR and Enzyme-linked immunosorbent assay, respectively. Western blot was used to evaluate the expression of lipogenesis-related proteins, the inflammatory signaling pathway, and the AMP-activated protein kinase (AMPK) pathway. Further, specific small interfering RNA (siRNA) was used to knockdown sirtuin-1 (SIRT1) expression. RESULTS: RVT inhibited the lipogenesis-related pathway and nuclear factor-kappa B (NF-κB) signaling pathway in SZ95 sebocytes. It also downregulated LA-induced lipogenesis, the expression of lipid-related proteins, and the contents of unsaturated fatty acids. Besides, RVT promoted SIRT1 expression and deacetylation of the NF-κB p65 subunit, thereby lowering IL-1ß and IL-6 secretion under PGN induction. Furthermore, pretreatment with AMPK inhibitor Compound C abolished RVT-mediated sebosuppressive and anti-inflammation effects. Meanwhile, SIRT1 silencing abrogated the anti-inflammatory potential of RVT. CONCLUSION: In human SZ95 sebocytes, RVT exhibits sebosuppressive and anti-inflammatory effects partially through the AMPK pathway, which may justify the role of RVT treatment in acne vulgaris.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Acne Vulgar/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Resveratrol/farmacologia , Glândulas Sebáceas/efeitos dos fármacos , Acne Vulgar/imunologia , Acne Vulgar/patologia , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Ácido Linoleico/farmacologia , Lipogênese/efeitos dos fármacos , Lipogênese/imunologia , Peptidoglicano/imunologia , Resveratrol/uso terapêutico , Glândulas Sebáceas/citologia , Glândulas Sebáceas/imunologia , Glândulas Sebáceas/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Sirtuína 1/genética , Sirtuína 1/metabolismo
2.
Int Immunopharmacol ; 98: 107897, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34182243

RESUMO

Alcoholism represents a predisposing factor for liver-related morbidity and mortality worldwide. Pogostemon cablin has been widely used in China for the treatment of digestive system diseases. Patchouli oil, the major active fraction of Pogostemon cablin, can ameliorate alcohol-induced acute liver injury (ALI). However, patchouli alcohol (PA),a principal bioactive ingredient of PO, exerts a protection against ALI remains elusive. Thepresentwork focused on the hepatoprotection of PA against acute ethanol-induced hepatotoxicity in rats. In this study, male Wistar rats orally received PA (10, 20, or 40 mg/kg), PO (400 mg/kg) and silymarin (200 mg/kg) for ten days. On the 8th day, the rats orally received 65% ethanol (10 mL/kg, 6.5 g/kg) every 12 h for 3 days. Results showed that PA wasfound to reduce alcohol-induced ALI, as evidenced bysignificantly alleviated histopathologicalalterations, decreased the elevation ofALT and AST levels, and enhancedthe alcoholdehydrogenase(ADH) andaldehyde dehydrogenase (ALDH) activities. Additionally, PA markedly suppressed ROS levels and increased antioxidant enzyme activities via the CYP2E1/ROS/Nrf2/HO-1 pathway. PA regulated lipid accumulation by markedly inhibiting the expression of lipogenesis-related genes and stimulating that of lipolysis-relatedgenes, which were associated with the activation of theAMPKpathway. What's more, PA pretreatment also restored acute alcohol-inducedalterationsin gut barrier function, colonic histopathology, and gut microbiota richness and evenness. PA pretreatment alleviated gut-origin LPS-inducedinflammation by inhibiting the MyD88/TLR4/NF-κB signal pathway. In general, PA ameliorates ethanol-induced ALI via restoration of CYP2E1/ROS/Nrf2/HO-1-mediatedoxidativestressand AMPK-mediated fat accumulation, as well as alleviation of gut-LPS-leakage-induced inflammation regulated by the MyD88/TLR4/NF-κB signaling pathway.


Assuntos
Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/efeitos dos fármacos , Falência Hepática Aguda/tratamento farmacológico , Fígado/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Lipogênese/efeitos dos fármacos , Lipogênese/imunologia , Lipólise/efeitos dos fármacos , Lipólise/imunologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Fígado/imunologia , Fígado/patologia , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
3.
Nat Commun ; 11(1): 6296, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293558

RESUMO

Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.


Assuntos
ATP Citrato (pro-S)-Liase/deficiência , Macrófagos/metabolismo , Placa Aterosclerótica/imunologia , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/genética , Idoso , Animais , Apoptose/imunologia , Colesterol/biossíntese , Colágeno/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos/biossíntese , Feminino , Fibrose , Perfilação da Expressão Gênica , Humanos , Lipidômica , Lipogênese/imunologia , Receptores X do Fígado/metabolismo , Ativação de Macrófagos , Macrófagos/imunologia , Masculino , Camundongos Knockout , Necrose/imunologia , Necrose/patologia , Fagocitose , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/patologia
4.
World J Gastroenterol ; 26(2): 109-133, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31969775

RESUMO

At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a "wound healing" process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.


Assuntos
Hepatite C Crônica/patologia , Cirrose Hepática/imunologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Imunidade Adaptativa , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Biópsia , Modelos Animais de Doenças , Progressão da Doença , Reposicionamento de Medicamentos , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Imunidade Inata , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Inflamassomos/imunologia , Inflamassomos/metabolismo , Lipogênese/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Cirrose Hepática/terapia , Miofibroblastos/transplante , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Resultado do Tratamento
5.
Arch Dermatol Res ; 311(7): 563-571, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31127384

RESUMO

When anti-acne alternatives from dietary and plant sources are ingested, systemic alterations of interleukin (IL)-4, IL-10, IL-12 and interferon (IFN)-γ, individually or simultaneously, are induced at a 0.1-10.0-fold (×) range of normal physiological concentrations (1×). However, little is known about the effects of these cytokines on excess sebum, a pathophysiological factor of acne development. In this study, human sebocytes were treated with 0.1-10.0× of IL-4, IL-10, IL-12 and IFN-γ for 3 or 5 days to elucidate the effects on lipid content. Treatment with individual cytokines decreased the lipid content at specific concentrations rather than in a concentration-dependent manner. Specifically, 5.0× of IL-4, 5.0× of IFN-γ (5.0IFN), and 0.5×, 5.0× and 10.0× of IL-10 for 3 days, and 0.5× of IL-4 (0.5IL4) for 5 days decreased lipid content to 87.6-93.0% of the control. Treatment with other concentrations of IL-4, IL-10 and IFN-γ, and 0.1-10.0× of IL-12 did not alter lipid content. Combined treatment with 0.5IL4, 5.0IFN and 0.5× of IL-10 for 3 or 5 days decreased the lipid content more than each individual treatment. However, this effect was more evident after 3 days, in parallel with decreased levels of triglycerides, cholesterol esters and free fatty acids, the major lipid compositions of sebocytes, and decreased protein expression of fatty acid synthase (FAS) and mature sterol response element-binding protein-1 (SREBP-1), the lipogenesis-related factors, without altered cell proliferation. We demonstrated that suppressed IL-4 and IL-10 with enhanced IFN-γ synergistically decreased lipid content and protein expression of FAS and mature SREBP-1 in human sebocytes.


Assuntos
Ácido Graxo Sintases/metabolismo , Glândulas Sebáceas/metabolismo , Sebo/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Acne Vulgar/dietoterapia , Acne Vulgar/imunologia , Acne Vulgar/patologia , Linhagem Celular , Proliferação de Células , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Lipídeos/análise , Lipogênese/imunologia , Cultura Primária de Células , Glândulas Sebáceas/citologia , Glândulas Sebáceas/imunologia , Sebo/química , Sebo/imunologia
6.
Monoclon Antib Immunodiagn Immunother ; 38(2): 60-69, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31009338

RESUMO

CD28 superagonist (CD28SA), a therapeutic immunomodulatory monoclonal antibody triggered rapid and exaggerated activation of CD4+ effector memory T cells (TEMs) in humans with unwanted serious adverse effects. It is well known that distinct metabolic programs determine the fate and responses of immune cells. In this study, we show that human CD4+ TEMs stimulated with CD28SA adopt a metabolic program similar to those of tumor cells with enhanced glucose utilization, lipid biosynthesis, and proliferation in hypoxic conditions. Identification of metabolic profiles underlying hyperactive T cell activation would provide a platform to test safety of immunostimulatory antibodies.


Assuntos
Antígenos CD28/imunologia , Linfócitos T CD4-Positivos/imunologia , Glicólise/imunologia , Lipogênese/imunologia , Ativação Linfocitária/imunologia , Neoplasias/metabolismo , Acetilcoenzima A/metabolismo , Anticorpos Monoclonais/imunologia , Antígenos CD28/metabolismo , Proliferação de Células , Glucose/metabolismo , Humanos , Memória Imunológica , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Quinases/metabolismo , Linfócitos T Reguladores/imunologia , Células Tumorais Cultivadas
7.
Sci Rep ; 9(1): 4007, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850619

RESUMO

Reproducible animal models to recapitulate the pathophysiology of non-alcoholic fatty liver disease (NAFLD) are urgently required to improve the understanding of the mechanisms of liver injury and to explore novel therapeutic options. Current guidelines recommend life-style interventions as first-line therapy for NAFLD and these types of intervention are considered standard-of-care. The current study establishes a reproducible mouse model of a life-style intervention in NAFLD using voluntary wheel running (VWR). Male C57BL/6J mice were fed a high-fat, high-carbohydrate diet (HFD) to induce NAFLD or a corresponding control diet for 12 weeks. Starting at week 9 of the obesogenic NAFLD diet, mice were randomized to either free access to a running wheel or being single caged resembling a sedentary (SED) life-style. VWR induced a transient weight reduction in HFD-fed mice up until week 10. In contrast to the SED mice, VWR mice exhibited normal ALT at the end of the intervention, while the metabolic alterations including elevated fasting glucose, insulin, triglyceride, and total cholesterol levels remained almost unchanged. Additionally, VWR prevented HFD-induced hepatic steatosis by alterations in key liver metabolic processes including the induction of fatty acid ß-oxidation and lipogenesis inhibition following increased AMP-activated protein kinase (AMPK)-α activity. Phosphorylation of the serine kinase Akt in hepatic tissue was enhanced following VWR. Furthermore, VWR mice were protected from HFD-induced expression of pro-inflammatory cytokines, chemokines and liver macrophage infiltration. The SED/HFD group exhibited increasing activity of hepatic nuclear factor (NF)-κB p65, which was absent following exercise in the VWR/HFD group. In summary, in an obesogenic mouse model of NAFLD physical exercise improves fatty acid and glucose homeostasis and protects from macrophage-associated hepatic inflammation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado/imunologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/metabolismo , Insulina/imunologia , Resistência à Insulina/imunologia , Estilo de Vida , Lipogênese/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/imunologia , Obesidade/metabolismo , Comportamento Sedentário
8.
J Virol ; 93(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602604

RESUMO

Gammaherpesviruses are ubiquitous viruses that establish lifelong infections. Importantly, these viruses are associated with numerous cancers and lymphoproliferative diseases. While risk factors for developing gammaherpesvirus-driven cancers are poorly understood, it is clear that elevated viral reactivation from latency often precedes oncogenesis. Here, we demonstrate that the liver X receptor alpha isoform (LXRα) restricts gammaherpesvirus reactivation in an anatomic-site-specific manner. We have previously demonstrated that deficiency of both LXR isoforms (α and ß) leads to an increase in fatty acid and cholesterol synthesis in primary macrophage cultures, with a corresponding increase in gammaherpesvirus replication. Interestingly, expression of fatty acid synthesis genes was not derepressed in LXRα-deficient hosts, indicating that the antiviral effects of LXRα are independent of lipogenesis. Additionally, the critical host defenses against gammaherpesvirus reactivation, virus-specific CD8+ T cells and interferon (IFN) signaling, remained intact in the absence of LXRα. Remarkably, using a murine gammaherpesvirus 68 (MHV68) reporter virus, we discovered that LXRα expression dictates the cellular tropism of MHV68 in the peritoneal cavity. Specifically, LXRα-/- mice exhibit reduced latency within the peritoneal B cell compartment and elevated latency within F4/80+ cells. Thus, LXRα restricts gammaherpesvirus reactivation through a novel mechanism that is independent of the known CD8+ T cell-based antiviral responses or changes in lipid synthesis and likely involves changes in the tropism of MHV68 in the peritoneal cavity.IMPORTANCE Liver X receptors (LXRs) are nuclear receptors that mediate cholesterol and fatty acid homeostasis. Importantly, as ligand-activated transcription factors, LXRs represent potential targets for the treatment of hypercholesterolemia and atherosclerosis. Here, we demonstrate that LXRα, one of the two LXR isoforms, restricts reactivation of latent gammaherpesvirus from peritoneal cells. As gammaherpesviruses are ubiquitous oncogenic agents, LXRs may represent a targetable host factor for the treatment of poorly controlled gammaherpesvirus infection and associated lymphomagenesis.


Assuntos
Linfócitos B/virologia , Gammaherpesvirinae/imunologia , Gammaherpesvirinae/fisiologia , Infecções por Herpesviridae/imunologia , Receptores X do Fígado/imunologia , Cavidade Peritoneal/virologia , Latência Viral/imunologia , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Feminino , Infecções por Herpesviridae/virologia , Interações Hospedeiro-Patógeno/imunologia , Interferons/imunologia , Lipogênese/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritônio/imunologia , Peritônio/virologia , Transdução de Sinais/imunologia , Tropismo/imunologia , Ativação Viral/imunologia , Replicação Viral/imunologia
9.
J Invest Dermatol ; 135(9): 2219-2227, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25880702

RESUMO

Protease-activated receptor-2 (PAR-2) functions as innate biosensor for proteases and regulates numerous functions of the skin. However, the expression and physiological role of PAR-2 in sebocytes remain to be elucidated. Here, we identified PAR-2 expression in SZ95 sebocytes at both mRNA and protein levels. Intracellular Ca(2+) mobilization by PAR-2 agonist peptide (PAR-2 AP) or Propionibacterium acnes (P. acnes) culture supernatant was detected, indicating that P. acnes is a potent activator of PAR-2 on sebocytes. The small interfering RNA (siRNA)-mediated PAR-2 knockdown in sebocytes resulted in defective differentiation and lipogenesis. PAR-2 AP treatment enhanced lipogenesis and sterol response element-binding protein-1 (SREBP-1) expression, suggesting a role of PAR-2 in the differentiation and lipogenesis of sebocytes. Moreover, PAR-2 AP induced cytokines and human ß-defensin-2 (hBD-2) transcription in sebocytes. PAR-2 expression was increased in sebaceous glands of acne lesions. PAR-2 silencing by siRNA abrogated the increase in sebaceous lipogenesis and SREBP-1 expression by P. acnes supernatant. PAR-2 knockdown also inhibited the P. acnes supernatant-induced expression of cytokines and hBD-2. In conclusion, PAR-2 is expressed in SZ95 sebocytes and mediates differentiation, lipogenesis, inflammation, and innate immunity in response to P. acnes. Therefore, PAR-2 might be a therapeutic target for sebaceous gland disorders such as acne.


Assuntos
Acne Vulgar/imunologia , Imunidade Inata/genética , Inflamação/genética , Lipogênese/genética , Receptor PAR-2/genética , Glândulas Sebáceas/citologia , Glândulas Sebáceas/metabolismo , Acne Vulgar/microbiologia , Biópsia por Agulha , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Imunidade Inata/fisiologia , Imuno-Histoquímica , Inflamação/imunologia , Lipogênese/imunologia , Propionibacterium acnes/imunologia , RNA Interferente Pequeno/análise , Sensibilidade e Especificidade , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
11.
J Hepatol ; 62(2): 412-20, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25234945

RESUMO

BACKGROUND & AIMS: Innate immune activation has been postulated as a central mechanism for disease progression from hepatic steatosis to steatohepatitis in obesity-related fatty liver disease. Arginase 2 competes with inducible nitric oxide synthase (iNOS) for its substrate and the balance between these two enzymes plays a crucial role in regulating immune responses and macrophage activation. Our aim was to test the hypothesis that arginase 2 deficiency in mice favours progression from isolated hepatic steatosis, induced by high fat feeding, to steatohepatitis. METHODS: Arginase 2-knockout (Arg2(-/-)) mice were studied for changes in liver histology and metabolic phenotype at baseline and after a short term course (7 week) feeding with a high fat (HFAT) diet. In additional experiments, Arg2(-/-) mice received tail vein injections of liposome-encapsulated clodronate (CLOD) over a three-week period to selectively deplete liver macrophages. RESULTS: Unexpectedly, Arg2(-/-) mice showed profound changes in their livers at baseline, characterized by significant steatosis as demonstrated with histological and biochemical analysis. These changes were independent of systemic metabolic parameters and associated with marked mRNA level increases of genes involved in hepatic de novo lipogenesis. Liver injury and inflammation were present with elevated serum ALT, marked infiltration of F4/80 positive cells, and increased mRNA levels of inflammatory genes. HFAT feeding exacerbated these changes. Macrophage depletion after CLOD injection significantly attenuated lipid deposition and normalized lipogenic mRNA profile of livers from Arg2(-/-) mice. CONCLUSIONS: This study identifies arginase 2 as a novel link between innate immune responses, hepatic lipid deposition, and liver injury.


Assuntos
Arginase/metabolismo , Fígado Gorduroso/imunologia , Hiperargininemia/complicações , Imunidade Inata , Células de Kupffer/imunologia , Metabolismo dos Lipídeos , Lipogênese/imunologia , Animais , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Hiperargininemia/imunologia , Hiperargininemia/metabolismo , Immunoblotting , Células de Kupffer/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
J Immunol ; 192(7): 3190-9, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24567531

RESUMO

Fatty acids (FAs) are essential constituents of cell membranes, signaling molecules, and bioenergetic substrates. Because CD8(+) T cells undergo both functional and metabolic changes during activation and differentiation, dynamic changes in FA metabolism also occur. However, the contributions of de novo lipogenesis to acquisition and maintenance of CD8(+) T cell function are unclear. In this article, we demonstrate the role of FA synthesis in CD8(+) T cell immunity. T cell-specific deletion of acetyl coenzyme A carboxylase 1 (ACC1), an enzyme that catalyzes conversion of acetyl coenzyme A to malonyl coenzyme A, a carbon donor for long-chain FA synthesis, resulted in impaired peripheral persistence and homeostatic proliferation of CD8(+) T cells in naive mice. Loss of ACC1 did not compromise effector CD8(+) T cell differentiation upon listeria infection but did result in a severe defect in Ag-specific CD8(+) T cell accumulation because of increased death of proliferating cells. Furthermore, in vitro mitogenic stimulation demonstrated that defective blasting and survival of ACC1-deficient CD8(+) T cells could be rescued by provision of exogenous FA. These results suggest an essential role for ACC1-mediated de novo lipogenesis as a regulator of CD8(+) T cell expansion, and may provide insights for therapeutic targets for interventions in autoimmune diseases, cancer, and chronic infections.


Assuntos
Acetil-CoA Carboxilase/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Ácidos Graxos/imunologia , Homeostase/imunologia , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Ácidos Graxos/metabolismo , Citometria de Fluxo , Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno/imunologia , Antígenos Comuns de Leucócito/imunologia , Antígenos Comuns de Leucócito/metabolismo , Lipogênese/genética , Lipogênese/imunologia , Listeria monocytogenes/genética , Listeria monocytogenes/imunologia , Listeria monocytogenes/fisiologia , Listeriose/genética , Listeriose/imunologia , Listeriose/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/genética , Ovalbumina/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
J Biol Chem ; 289(10): 7011-7024, 2014 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-24469453

RESUMO

Bacterially derived lipopolysaccharide (LPS) stimulates naive B lymphocytes to differentiate into immunoglobulin (Ig)-secreting plasma cells. Differentiation of B lymphocytes is characterized by a proliferative phase followed by expansion of the intracellular membrane secretory network to support Ig production. A key question in lymphocyte biology is how naive B cells reprogram metabolism to support de novo lipogenesis necessary for proliferation and expansion of the endomembrane network in response to LPS. We report that extracellularly acquired glucose is metabolized, in part, to support de novo lipogenesis in response to LPS stimulation of splenic B lymphocytes. LPS stimulation leads to increased levels of endogenous ATP-citrate lyase (ACLY), and this is accompanied by increased ACLY enzymatic activity. ACLY produces cytosolic acetyl-CoA from mitochondrially derived citrate. Inhibition of ACLY activity in LPS-stimulated B cells with the selective inhibitor 2-hydroxy-N-arylbenzenesulfonamide (compound-9; C-9) blocks glucose incorporation into de novo lipid biosynthesis, including cholesterol, free fatty acids, and neutral and acidic phospholipids. Moreover, inhibition of ACLY activity in splenic B cells results in inhibition of proliferation and defective endomembrane expansion and reduced expression of CD138 and Blimp-1, markers for plasma-like B cell differentiation. ACLY activity is also required for LPS-induced IgM production in CH12 B lymphoma cells. These data demonstrate that ACLY mediates glucose-dependent de novo lipogenesis in response to LPS signaling and identify a role for ACLY in several phenotypic changes that define plasma cell differentiation.


Assuntos
ATP Citrato (pro-S)-Liase/fisiologia , Linfócitos B/imunologia , Glucose/metabolismo , Lipogênese/imunologia , Lipopolissacarídeos/imunologia , Ativação Linfocitária , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Animais , Linfócitos B/citologia , Diferenciação Celular , Camundongos , Camundongos Endogâmicos BALB C
14.
Diabetes Metab ; 40(1): 16-28, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24139247

RESUMO

Obesity-associated insulin resistance is a complex disorder involving a number of candidate molecules, pathways and transduction systems possessing potential causal actions. Inflammation in adipose tissue (AT) is one mechanism proposed to explain the development of insulin resistance, while identification of factors that lead to or cause AT dysfunction when it reaches its limit of expansion represents an important challenge. Pathological expansion of AT is characterized by changes in its blood flow, and the presence of enlarged and dysfunctional adipocytes that begin an inflammatory campaign of altered adipokine and cytokine secretions. Adipocyte senescence, necrosis and death are associated with increased immune cell and macrophage infiltration of AT in obesity. This can boost inflammation and reinforce fat cell dysfunction and death. In addition, pathological fat mass expansion is also related to limited recruitment of fat cell progenitors able to proliferate and differentiate into healthy small fat cells to compensate for cell death and preserve adipocyte numbers. Limiting vascular development and enhancing fibrotic processes worsen inflammation towards chronic irreversibility. The AT expandability hypothesis states that failure of AT expansion is one of the key factors linking positive energy balance and cardiometabolic risks, not obesity per se. Besides the usual treatment of obesity based on behavioral approaches (specific dietary/nutritional approaches together with increased physical activity), a number of questions remain concerning the possible recovery of metabolic health after inflammation-preventing interventions.


Assuntos
Adipócitos/patologia , Adipogenia , Tecido Adiposo/patologia , Inflamação/patologia , Resistência à Insulina , Obesidade/patologia , Adipócitos/imunologia , Adipogenia/imunologia , Adipocinas/metabolismo , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/imunologia , Metabolismo Energético , Feminino , Humanos , Inflamação/imunologia , Resistência à Insulina/imunologia , Lipogênese/imunologia , Lipólise/imunologia , Masculino , Obesidade/imunologia , Obesidade/fisiopatologia , Estresse Oxidativo
15.
J Invest Dermatol ; 132(12): 2700-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22763784

RESUMO

Acne vulgaris is the most common disease of the pilosebaceous unit. The pathogenesis of this inflammatory disease is complex, involving increased sebum production and perifollicular inflammation. To identify effective agents for factors that induce acne vulgaris, we explored the pharmacological potential of epigallocatechin-3-gallate (EGCG), which has been widely investigated as an anti-proliferative and anti-inflammatory agent. In this study, we demonstrated that topical application of EGCG to rabbit auricles reduced the size of the sebaceous glands. When applied to cultured human SZ95 sebocytes, EGCG strongly suppressed cell proliferation and lipogenesis. These actions of EGCG were reproduced in IGF-I-differentiated SZ95 sebocytes. To investigate the anti-inflammatory potential of EGCG, we evaluated pro-inflammatory cytokine synthesis in IGF-I-differentiated SZ95 sebocytes and found that expression of IL-1, IL-6, and IL-8 was decreased. These results provide early evidence that EGCG is an effective candidate for acne therapy whose mechanisms of action in IGF-I-differentiated SZ95 sebocytes include the inhibition of lipogenesis and inflammation.


Assuntos
Acne Vulgar/tratamento farmacológico , Catequina/análogos & derivados , Fator de Crescimento Insulin-Like I/farmacologia , Lipogênese/efeitos dos fármacos , Glândulas Sebáceas/citologia , Acne Vulgar/imunologia , Acne Vulgar/patologia , Administração Tópica , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Catequina/farmacologia , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Citocinas/imunologia , Citocinas/metabolismo , Pavilhão Auricular/citologia , Pavilhão Auricular/efeitos dos fármacos , Feminino , Humanos , Interleucina-1/imunologia , Interleucina-1/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Interleucina-8/imunologia , Interleucina-8/metabolismo , Lipogênese/imunologia , Coelhos , Glândulas Sebáceas/imunologia , Glândulas Sebáceas/metabolismo , Sebo/imunologia , Sebo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
16.
Arch Dermatol Res ; 300(6): 311-6, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18427822

RESUMO

Acne is a complex, chronic and common skin disorder of pilosebaceous units. Although it is known that exacerbation of acne results from emotional stress, the nature of the association between stress and acne remains unclear. This is due in part to the lack of substantial evidence regarding the participation of cutaneous neurogenic factors in the pathogenesis of acne. Culture of sebocytes provides a new insight into the participation of neuropeptides, notably substance P (SP), in the pathophysiology of acne. To examine the possible involvement of neurogenic factors in the pathogenesis of acne, we used immunohistochemistry and RT-PCR to compare the expression of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), peroxisome proliferators activated receptors-gamma (PPAR-gamma) on the cultured sebocytes stimulated by SP. IL-1 is primarily proinflammatory cytokines to stimulate the expression of genes associated with inflammation. IL-6 is a pleiotropic cytokine with a wide range of biological activities and regulates inflammation. TNF-alpha is a pleiotropic pro-inflammatory cytokine that exerts multiple biologic effects. PPAR-gamma is a nuclear hormone receptor and plays a unique role in stimulating sebocyte lipogenesis. More numerous immunoreactivity to IL-1, IL-6, TNF-alpha and PPAR-gamma and increased RNA amplification for IL-1, IL-6, TNF-alpha and PPAR-gamma were observed after addition of SP compared with the control. This study reveals that SP is involved in the pathogenesis of acne.


Assuntos
Acne Vulgar/imunologia , Células Epiteliais/metabolismo , PPAR gama/imunologia , Substância P/metabolismo , Acne Vulgar/metabolismo , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Células Epiteliais/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Inflamação , Lipogênese/imunologia , Neuroimunomodulação/imunologia , PPAR gama/metabolismo , Glândulas Sebáceas/citologia , Glândulas Sebáceas/imunologia , Glândulas Sebáceas/metabolismo , Sebo/imunologia , Sebo/metabolismo , Substância P/imunologia , Substância P/farmacologia
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