title: IFN-α-Induced Downregulation of miR-221 in Dendritic Cells: Implications for HCV Pathogenesis and Treatment.
abstract: 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.
authors.affiliation: 1 Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Mohit
authors.initials: M
authors.lastname: Sehgal
authors.affiliation: 2 Weill Cornell Medical College , New York, New York.
authors.forename: Marija
authors.initials: M
authors.lastname: Zeremski
authors.affiliation: 3 School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Talal
authors.affiliation: 1 Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Rashida
authors.initials: R
authors.lastname: Ginwala
authors.affiliation: 4 Emory Vaccine Center , Atlanta, Georgia .
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Elrod
authors.affiliation: 4 Emory Vaccine Center , Atlanta, Georgia .
authors.forename: Arash
authors.initials: A
authors.lastname: Grakoui
authors.affiliation: 5 Duke University Medical Center , Durham, North Carolina.
authors.forename: Qi-Ging
authors.initials: QG
authors.lastname: Li
authors.affiliation: 6 Immunotope, Inc., Pennsylvania Biotechnology Center , Doylestown, Pennsylvania.
authors.forename: Ramila
authors.initials: R
authors.lastname: Philip
authors.affiliation: 1 Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Zafar K
authors.initials: ZK
authors.lastname: Khan
authors.affiliation: 1 Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Pooja
authors.initials: P
authors.lastname: Jain
mesh_terms: D017209:Apoptosis / Q000502:physiology; D003713:Dendritic Cells / Q000378:metabolism* / Q000821:virology*; D015536:Down-Regulation / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity; D016174:Hepacivirus / Q000472:pathogenicity*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000378:metabolism / Q000821:virology; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics / Q000378:metabolism / Q000821:virology; D035683:MicroRNAs / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D015850:Interleukin-6; D053612:Janus Kinases; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; C525709:MIR221, human; C108944:SOCS1 protein, human; C494086:STAT3 protein, human