RESUMO
Lambda interferons (IFNL, IFN-λ) are pro-inflammatory cytokines important in acute and chronic viral infection. Single-nucleotide polymorphisms rs12979860 and rs8099917 within the IFNL gene locus predict hepatitis C virus (HCV) clearance, as well as inflammation and fibrosis progression in viral and non-viral liver disease. The underlying mechanism, however, is not defined. Here we show that the rs12979860 CC genotype correlates with increased hepatic metallothionein expression through increased systemic zinc levels. Zinc interferes with IFN-λ3 binding to IFNL receptor 1 (IFNLR1), resulting in decreased antiviral activity and increased viral replication (HCV, influenza) in vitro. HCV patients with high zinc levels have low hepatocyte antiviral and inflammatory gene expression and high viral loads, confirming the inhibitory role of zinc in vivo. We provide the first evidence that zinc can act as a potent and specific inhibitor of IFN-λ3 signalling and highlight its potential as a target of therapeutic intervention for IFN-λ3-mediated chronic disease.
Assuntos
Interleucinas/metabolismo , Transdução de Sinais , Zinco/metabolismo , Adulto , Antivirais/farmacologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Hepatite C/genética , Humanos , Inflamação/genética , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Interferon-alfa/farmacologia , Interferons , Interleucinas/genética , Interleucinas/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Masculino , Metalotioneína/genética , Metalotioneína/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Anotação de Sequência Molecular , Receptores de Citocinas/metabolismo , Receptores de Interferon , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Transcriptoma/genética , Zinco/sangueRESUMO
Adiponectin demonstrates beneficial effects in various metabolic diseases, including diabetes, and in bowel cancer. Recent data also suggest a protective role in colitis. However, the precise molecular mechanisms by which adiponectin and its receptors modulate colitis and the nature of the adaptive immune response in murine models are yet to be elucidated. Adiponectin knock-out mice were orally administered dextran sulfate sodium for 7 days and were compared with wild-type mice. The severity of disease was analyzed histopathologically and through cytokine profiling. HCT116 colonic epithelial cells were employed to analyze the in vitro effects of adiponectin and AdipoR1 interactions in colonic injury following dextran sulfate sodium treatment. Adiponectin knock-out mice receiving dextran sulfate sodium exhibited severe colitis, had greater inflammatory cell infiltration, and an increased presence of activated B cells compared with controls. This was accompanied by an exaggerated proinflammatory cytokine profile and increased STAT3 signaling. Adiponectin knock-out mouse colons had markedly reduced proliferation and increased epithelial apoptosis and cellular stress. In vitro, adiponectin reduced apoptotic, anti-proliferative, and stress signals and restored STAT3 signaling. Following the abrogation of AdipoR1 in vitro, these protective effects of adiponectin were abolished. In summary, adiponectin maintains intestinal homeostasis and protects against murine colitis through interactions with its receptor AdipoR1 and by modulating adaptive immunity.
Assuntos
Adiponectina/metabolismo , Linfócitos B/imunologia , Colite/metabolismo , Receptores de Adiponectina/metabolismo , Fator de Transcrição STAT3/metabolismo , Doença Aguda , Adiponectina/genética , Animais , Apoptose , Proliferação de Células , Colite/prevenção & controle , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Células HCT116 , Homeostase , Humanos , Sistema Imunitário , Inflamação , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Endothelial cells (EC) form the inner lining of blood vessels and are positioned between circulating lymphocytes and tissues. Hypotheses have formed that EC may act as antigen presenting cells based on the intimate interactions with T cells, which are seen in diseases like multiple sclerosis, cerebral malaria (CM) and viral neuropathologies. Here, we investigated how human brain microvascular EC (HBEC) interact with and support the proliferation of T cells. We found HBEC to express MHC II, CD40 and ICOSL, key molecules for antigen presentation and co-stimulation and to take up fluorescently labeled antigens via macropinocytosis. In co-cultures, we showed that HBEC support and promote the proliferation of CD4(+) and CD8(+) T cells, which both are key in CM pathogenesis, particularly following T cell receptor activation and co-stimulation. Our findings provide novel evidence that HBEC can trigger T cell activation, thereby providing a novel mechanism for neuroimmunological complications of infectious diseases.
Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Microvasos/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Apresentação de Antígeno , Antígenos CD40/metabolismo , Linhagem Celular , Proliferação de Células , Invaginações Revestidas da Membrana Celular/imunologia , Técnicas de Cocultura , Células Endoteliais/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Isoantígenos/metabolismo , Ativação Linfocitária , Microvasos/citologia , Pinocitose/imunologiaRESUMO
Adiponectin (APN), a novel hormone/cytokine derived from adipocyte tissue, is involved in various physiological functions. Genetics, nutrition, and adiposity are factors contributing to circulating plasma concentrations of APN. Clinical correlation studies have shown that lower levels of serum APN are associated with increased malignancy of various cancers, such as breast and colon cancers, suggesting that APN has a role in tumorigenesis. APN affects insulin resistance, thus further influencing cancer development. Tumor cells may express receptors for APN. Cellular signaling is the mechanism by which APN exerts its host-protective responses. These factors suggest that serum APN levels and downstream signaling targets of APN may serve as potential diagnostic markers for malignancies. Further research is necessary to clarify the exact role of APN in cancer diagnosis and therapy.