Interferon-α and -β differentially regulate osteoclastogenesis: Role of differential induction of chemokine CXCL11 expression

Coelho, Luiz Felipe Leomil; Almeida, Gabriel Marchesan; Mennechet, Franck J. D.; Blangy, Anne; Uzé, Gilles

doi:10.1073/pnas.0502188102

Cited by 106 publications

(74 citation statements)

References 41 publications

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“…For example, IFN-␤, but not IFN-␣ or IFN-, was able to induce the phosphorylation of an IFNAR1-associated subunit (1,62) later identified as IFNAR-2c (15). The TYK2-deficient cell line U1A was responsive to IFN-␤ but not to IFN-␣ 2 (25,63), and IFN-␤ has been shown to be 100-fold more potent than IFN-␣ 2 at inhibiting the differentiation of human monocytes into osteoclasts (11). These differences persist even within a single IFN subfamily.…”

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confidence: 78%

Longitudinal system-based analysis of transcriptional responses to type I interferons

Pappas

Coppola

Gabatto

et al. 2009

Physiological Genomics

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Type I interferons (IFNs) are pleiotropic cytokines that modulate both innate and adaptive immune responses. They have been used to treat autoimmune disorders, cancers, and viral infection and have been demonstrated to elicit differential responses within cells, despite sharing a single receptor. The molecular basis for such differential responses has remained elusive. To identify the mechanisms underlying differential type I IFN signaling, we used whole genome microarrays to measure longitudinal transcriptional events within human CD4 ϩ T cells treated with IFN-␣2b or IFN-␤1a. We identified differentially regulated genes, analyzed them for the enrichment of known promoter elements and pathways, and constructed a network module based on weighted gene coexpression network analysis (WGCNA). WGCNA uses advanced statistical measures to find interconnected modules of correlated genes. Overall, differential responses to IFN in CD4 ϩ T cells related to three dominant themes: migration, antigen presentation, and the cytotoxic response. For migration, WGCNA identified subtypespecific regulation of pre-mRNA processing factor 4 homolog B and eukaryotic translation initiation factor 4A2, which work at various levels within the cell to affect the expression of the chemokine CCL5. WGCNA also identified sterile ␣-motif domain-containing 9-like (SAMD9L) as critical in subtype-independent effects of IFN treatment. RNA interference of SAMD9L expression enhanced the migratory phenotype of activated T cells treated with IFN-␤ compared with controls. Through the analysis of the dynamic transcriptional events after differential IFN treatment, we were able to identify specific signatures and to uncover novel genes that may underpin the type I IFN response.human; T cell; cytokines; gene regulation INTERFERONS (IFNs) are pleiotropic molecules implicated in a wide range of cellular responses (44) and are Federal Drug Administration-approved therapeutics for the treatment of cancer, infection, and autoimmunity (49). Based on sequence homology and structure, IFNs are divided into three classes: types I, II, and III. Type I IFNs include IFN-␣ (15 known ␣-subtypes), IFN-␤, and IFN-, whereas type II IFN consists only of IFN-␥ and type III IFN consists only of IFN-. All type I IFNs activate a common cell surface receptor [the IFN receptor (IFNR)], which exists as two separate polypeptides (IFNAR1 and IFNAR2) with no intrinsic dimerization capacity (12). Binding of type I IFNs to IFNAR2, recruitment of IFNAR1, and stabilization of a heterotrimeric ligand/receptor complex activate members of the Jak1/tyrosine kinase 2 (Tyk2) and JAK/STAT pathways (12, 45). Phosphorylated STAT1/ STAT2 heterodimers form transcriptional activation complexes with IFN regulatory factor (IRF)9/p48, translocate to the nucleus, and drive the expression of numerous genes, including myxovirus resistance protein 1 (MX1), 2Ј,5Ј-oligoadenylate synthetase 1, and double-stranded RNA-activated protein kinase (EIF2AK2).Although type I IFNs share the same cognate receptor and und...

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confidence: 78%

Longitudinal system-based analysis of transcriptional responses to type I interferons

Pappas

Coppola

Gabatto

et al. 2009

Physiological Genomics

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“…Given the increased expression of IFN-b in pSjS serum, we hypothesized that this cytokine was mainly responsible for the type I IFN effect seen in these patients. To test this, expression of genes differentially regulated by IFN-a (pyridoxal kinase (PDXK) and vascular endothelial growth factor-C (VEGF-C) [19]) and IFN-b (CXCL11 and BCL2-associated transcription factor-1 (BCLAF-1) [20]) was tested. Expression of CXCL11 was significantly increased in pSjS, with BCLAF-1 following the same trend (Fig.…”

Section: Gene Expression Profile In Psjs Monocytesmentioning

confidence: 99%

Systemic increase in type I interferon activity in Sjögren's syndrome: A putative role for plasmacytoid dendritic cells

et al. 2008

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In the salivary glands of primary Sjögren's syndrome (pSjS) patients, type I IFN activity is increased, but systemic levels of type I IFN proteins are rarely detected. This study focused on the systemic activity of type I IFN in pSjS, as well as the role of peripheral plasmacytoid dendritic cells (pDC). Monocytes obtained from pSjS patients showed an increased expression of 40 genes. Twenty-three of these genes (58%), including IFI27, IFITM1, IFIT3 and IFI44, were inducible by type I IFN. pSjS serum had an enhanced capability of inducing IFI27, IFITM1, IFIT3 and IFI44 in the monocytic cell line THP-1, likely due to the action of IFN-b. This effect could be inhibited by blocking the type I IFN receptor, supporting a high type I IFN bioactivity in pSjS serum. In addition, circulatory pDC showed increased expression of CD40. This expression was correlated to the expression level of the type I IFN-regulated genes IFI27 and IFITM1 in monocytes of the same individual. This study indicates that the increased type I IFN activity observed in pSjS patients is not only a local but also a systemic phenomenon and points to pDC as a possible source of this activity.

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“…Apart from the fact that it is rapidly induced, of all the type I IFN isotypes, IFN-␤ is the most potent activator of the type I IFN receptor (14,15) that amplifies type I IFN responses via feed forward mechanisms (11). To resolve the complexity of the IFN system and to track the cells that initiate the type I IFN signaling cascade, we generated a versatile reporter mouse that allows conditional deletion of IFN-␤ and undisturbed detection of IFN-␤ induction in vivo using firefly luciferase as a reporter.…”

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confidence: 99%

Novel Reporter Mouse Reveals Constitutive and Inflammatory Expression of IFN-β In Vivo

Lienenklaus

Cornitescu²,

Zie̜tara³

et al. 2009

The Journal of Immunology

215

250

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Type I IFN is a major player in innate and adaptive immune responses. Besides, it is involved in organogenesis and tumor development. Generally, IFN responses are amplified by an autocrine loop with IFN-β as the priming cytokine. However, due to the lack of sensitive detection systems, where and how type I IFN is produced in vivo is still poorly understood. In this study, we describe a luciferase reporter mouse, which allows tracking of IFN-β gene induction in vivo. Using this reporter mouse, we reveal strong tissue-specific induction of IFN-β following infection with influenza or La Crosse virus. Importantly, this reporter mouse also allowed us to visualize that IFN-β is expressed constitutively in several tissues. As suggested before, low amounts of constitutively produced IFN might maintain immune cells in an activated state ready for a timely response to pathogens. Interestingly, thymic epithelial cells were the major source of IFN-β under noninflammatory conditions. This relatively high constitutive expression was controlled by the NF Aire and might influence induction of tolerance or T cell development.

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Interferon-α and -β differentially regulate osteoclastogenesis: Role of differential induction of chemokine CXCL11 expression

Cited by 106 publications

References 41 publications

Longitudinal system-based analysis of transcriptional responses to type I interferons

Longitudinal system-based analysis of transcriptional responses to type I interferons

Systemic increase in type I interferon activity in Sjögren's syndrome: A putative role for plasmacytoid dendritic cells

Novel Reporter Mouse Reveals Constitutive and Inflammatory Expression of IFN-β In Vivo

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