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Moll H.P.,Medical University of Vienna | Maier T.,Medical University of Vienna | Zommer A.,Medical University of Vienna | Lavoie T.,PBL InterferonSource | Brostjan C.,Medical University of Vienna
Cytokine | Year: 2011

IFN-α proteins have been described to originate from 14 individual genes and allelic variants. However, the exceptional diversity of IFN-α and its functional impact are still poorly understood. To characterize the biological activity of IFN-α subtypes in relation to the cellular background, we investigated the effect of IFN-α treatment in primary fibroblasts and endothelial cells of vascular or lymphatic origin. The cellular response was evaluated for 13 distinct IFN-α proteins with respect to transcript regulation of the IFN-stimulated genes (ISGs) IFIT1, ISG15, CXCL10, CXCL11 and CCL8. The IFN-α proteins displayed a remarkably consistent potency in gene induction irrespective of target gene and cellular background which led to the classification of IFN-α subtypes with low (IFN-α1), intermediate (IFN-α2a, -4a, -4b, -5, -16, -21) and high (IFN-α2b, -6, -7, -8, -10, -14) activity. The differential potency of IFN-α classes was confirmed at the ISG protein level and the functional protection of cells against influenza virus infection. Differences in IFN activity were only observed at subsaturating levels of IFN-α proteins and did not affect the time course of ISG regulation.Cell-type specific responses were apparent for distinct target genes independent of IFN-α subtype and were based on different levels of basal versus inducible gene expression. While fibroblasts presented with a high constitutive level of IFIT1, the expression in endothelial cells was strongly induced by IFN-α. In contrast, CXCL10 and CXCL11 transcript levels were generally higher in endothelial cells despite a pronounced induction by IFN-α in fibroblasts.In summary, the divergent potency of IFN-α proteins and the cell-type specific regulation of individual IFN target genes may allow for the fine tuning of cellular responses to pathogen defense. © 2010 Elsevier Ltd.

Liao A.P.,Brigham and Womens Hospital | Liao A.P.,Harvard University | Salajegheh M.,Brigham and Womens Hospital | Salajegheh M.,Harvard University | And 8 more authors.
Clinical Immunology | Year: 2010

To determine the potential consequences of plasmacytoid dendritic cell (pDC) accumulation in tissue sites observed in several autoimmune diseases, we measured type 1 interferon production from circulating human pDCs as a function of pDC concentration. The effects of interferon-alpha and blockade of the type 1 interferon receptor (IFNAR) on human pDC type 1 interferon and interferon-inducible transcription and protein production were measured. Human pDCs became far more efficient producers of interferon-alpha at concentrations beyond those normally present in blood, through an IFNAR-dependent mechanism. Extracellular interferon-alpha increased pDC production of type 1 interferons. The accumulation of pDCs in diseased tissue sites allows marked non-linear amplification of type 1 interferon production locally. The role of the IFNAR-dependent mechanism of interferon production by human pDCs is greater than previously suggested. IFNAR blockade has potential for diminishing type 1 interferon production by all human cells. © 2010 Elsevier Inc. All rights reserved.

Liao A.P.,Harvard University | Salajegheh M.,Harvard University | Nazareno R.,Harvard University | Kagan J.C.,Harvard University | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objectives: To determine whether type 1 interferon (IFN) proteins in blood are associated with downstream type 1 IFN-inducible gene expression in blood from patients with myositis. Methods: IFNα, IFNβ and IFNω concentrations were measured by ELISA in 129 blood samples (from 93 patients with dermatomyositis (DM), inclusion body myositis, polymyositis and other muscle diseases and from 36 healthy volunteers). Their concentrations were correlated with their ability to stimulate type 1 IFN-inducible gene transcription in a functional assay for 123 of these samples and the type 1 IFN-inducible blood gene expression from 70 of the same samples. Results: Blood IFNβ concentration was uniquely associated with DM (p=0.0004), detectable in 64% of samples from patients with untreated or minimally treated DM and 35% of all DM samples compared with 6% of other inflammatory myopathy and 6% of healthy volunteer samples. Blood IFNβ, but not IFNα or IFNω, correlated with high blood type 1 IFN-inducible gene expression (p=0.01). Healthy volunteer samples with a high ELISA signal for IFNα and IFNω lacked functional bioassay activity and such a signal was confirmed as artefactual. Conclusion: Elevated blood IFNβ protein concentration is associated with DM. Systemic and local production of IFNβ might contribute to, but may not fully explain, the marked overproduction of type 1 IFN-inducible transcripts and proteins seen in DM muscle and blood.

Wan S.,Johnson University | Pestka S.,Johnson University | Jubin R.G.,PBL InterferonSource | Lyu Y.L.,Johnson University | And 2 more authors.
PLoS ONE | Year: 2012

Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT), a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I) expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β) and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-naïve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1) or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine) similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through T cell cytotoxicity during metronomic chemotherapy, as well as increased efficacy of combined chemo- (or radio-)/immuno-therapy. © 2012 Wan et al.

Lavoie T.B.,PBL InterferonSource | Kalie E.,Weizmann Institute of Science | Crisafulli-Cabatu S.,PBL InterferonSource | Abramovich R.,Weizmann Institute of Science | And 4 more authors.
Cytokine | Year: 2011

Vertebrates have multiple genes encoding Type I interferons (IFN), for reasons that are not fully understood. The Type I IFN appear to bind to the same heterodimeric receptor and the subtypes have been shown to have different potencies in various experimental systems. To put this concept on a quantitative basis, we have determined the binding affinities and rate constants of 12 human Alpha-IFN subtypes to isolated interferon receptor chains 1 and 2. Alpha-IFNs bind IFNAR1 and IFNAR2 at affinities of 0.5-5μM and 0.4-5nM respectively (except for IFN-alpha1 - 220nM). Additionally we have examined the biological activity of these molecules in several antiviral and antiproliferative models. Particularly for antiproliferative potency, the binding affinity and activity correlate. However, the EC 50 values differ significantly (1.5nM versus 0.1nM for IFN-alpha2 in WISH versus OVCAR cells). For antiviral potency, there are several instances where the relationship appears to be more complicated than simple binding. These results will serve as a point of reference for further understanding of this multiple ligand/receptor system. © 2011 Elsevier Ltd.

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