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J Interferon Cytokine Res ; 35(9): 698-709, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26090579

RESUMO

Although interferon (IFN)-α is known to exert immunomodulatory and antiproliferative effects on dendritic cells (DCs) through induction of protein-coding IFN-stimulated genes (ISGs), little is known about IFN-α-regulated miRNAs in DCs. Since several miRNAs are involved in regulating DC functions, it is important to investigate whether IFN-α's effects on DCs are mediated through miRNAs as well. In this study, we examined miRNA expression patterns in myeloid DCs (mDCs) and plasmacytoid DCs after exposing them to IFN-α. We report that IFN-α downregulates miR-221 in both DC subsets via inhibition of STAT3. We validated proapoptotic proteins BCL2L11 and CDKN1C as miR-221 targets suggesting that IFN-α can induce DC apoptosis via miR-221 downregulation. In addition, we validated another miR-221 target, SOCS1, which is known to be a negative regulator of JAK/STAT signaling. Consistent with this, miR-221 overexpression in mDCs enhanced the secretion of proinflammatory cytokines IL-6 and TNF-α. In peripheral blood mononuclear cells (PBMCs) of HIV-1/HCV co-infected individuals undergoing IFN-α-based treatment the baseline miR-221 expression was lower in non-responders compared with responders; and miR-221 expression directly correlated with DC frequency and IL-6/TNF-α secretion. In addition to PBMCs, we isolated total liver cells and kupffer cells from HCV-infected individuals and individuals with alcoholic cirrhosis. We found that both total liver cells and kupffer cells from HCV-infected individuals had significantly higher miR-221 levels compared with individuals with cirrhosis. Overall, we demonstrate that IFN-α exerts both antiproliferative and immunomodulatory effects on mDCs via miR-221 downregulation; and IFN-miR-221 axis can play important role in HCV pathogenesis and treatment.


Assuntos
Células Dendríticas/metabolismo , Células Dendríticas/virologia , Regulação para Baixo/genética , Hepacivirus/patogenicidade , Interferon-alfa/metabolismo , MicroRNAs/genética , Apoptose/fisiologia , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/patogenicidade , Hepatite C/genética , Hepatite C/metabolismo , Hepatite C/virologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Células de Kupffer/metabolismo , Células de Kupffer/virologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Fígado/metabolismo , Fígado/virologia , Cirrose Hepática Alcoólica/genética , Cirrose Hepática Alcoólica/metabolismo , Cirrose Hepática Alcoólica/virologia , Fator de Transcrição STAT3/metabolismo , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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