Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Virus-induced activation of the beta interferon (IFN-beta) gene requires orderly recruitment of chromatin-remodeling complexes and time-regulated acetylation of histone residues K8H4 and K14H3 on the promoter region. We have previously shown that transcription factor Yin Yang 1 (YY1) binds the murine IFN-beta promoter at two sites (-122 and -90) regulating promoter transcriptional capacity with a dual activator/repressor role. In this work we demonstrate that both YY1 -122 and -90 sites are required for CBP recruitment and K8H4/K14H3 acetylation to take place on the IFN-beta promoter region after virus infection. A single point mutation introduced at either one of these two sites inhibiting YY1 binding completely disrupted CBP recruitment and K8H4/K14H3 acetylation independently of HMGI or IRF3 binding to the promoter. We have previously demonstrated that YY1 represses the transcriptional capacity of the IFN-beta promoter through its -90 site via histone deacetylation. Here we demonstrate that, in vivo, the binding of YY1 to the -90 site is constant all through virus infection whereas the binding of YY1 to the -122 site is activated after infection. We discuss here the capacity of YY1 to either repress (through histone deacetylase recruitment) or activate (through CBP recruitment) IFN-beta gene expression according to the occupancy of either only its -90 site or both its -122 and -90 sites.
Mol Cell Biol 2006 Nov
PMID:Binding of YY1 to the proximal region of the murine beta interferon promoter is essential to allow CBP recruitment and K8H4/K14H3 acetylation on the promoter region after virus infection. 1695 76

Tyk2, a member of the Jak family of protein tyrosine kinases, is critical for the biological actions of alpha/beta interferon (IFN-alpha/beta). Although Tyk2(-/-) mice are phenotypically normal, they exhibit abnormal responses to inflammatory challenges in a variety of cells isolated from Tyk2(-/-) mice. The reported phenotypic alterations in both Tyk2-null cells and mice are consistent with the possibility that the expression of this tyrosine kinase may regulate mitochondrial function. We report here that Tyk2-null pro-B cells are markedly deficient in basal oxygen consumption and exhibit a significant decrease in steady-state cellular ATP levels compared to wild-type cells. Tyk2-null cells also exhibit impaired complex I, III, and IV function of the mitochondrial electron transport chain. Reconstitution of Tyk2-null pro-B cells with either the wild type or a kinase-inactive mutant of Tyk2 restores basal mitochondrial respiration. By contrast, the kinase activity of Tyk2 is required for maintenance of both complex I-dependent mitochondrial respiration as well as induction of apoptosis in cells incubated with IFN-beta. Consistent with the role of Tyk2 in the regulation of tyrosine phosphorylation of Stat3, expression of a constitutively active Stat3 can restore the mitochondrial respiration in Tyk2-null cells treated with IFN-beta. Finally, Tyk2(-/-) mice show decreased exercise tolerance compared to wild-type littermates. Our results implicate a novel role for Tyk2 kinase and Stat3 phosphorylation in mitochondrial respiration.
Mol Cell Biol 2006 Nov
PMID:Tyk2 tyrosine kinase expression is required for the maintenance of mitochondrial respiration in primary pro-B lymphocytes. 1698 90

Retinoic acid-inducible gene I (RIG-I) has recently been identified as one of the key intracellular sensors of virus infection. RIG-I binds to cytosolic double-stranded RNA and initiates a signaling cascade that leads to the activation of transcription factors required for expression of type I interferon (IFN-I). Previous evidence suggests that nonstructural protein 1 (NS1) encoded by influenza A virus (IAV) suppresses IFN-I secretion in virus-infected cells by an unknown mechanism. In the present study, we demonstrate that RIG-I is required for induction of IFN-I in an IAV-infected human lung epithelial cell line. Knockdown of RIG-I expression by RNA interference greatly impairs production of IFN-beta in cells infected with different strains of wild-type IAV. Furthermore, co-expression of IAV NS1 down-regulates production of IFN-beta induced by RIG-I agonists, and ectopic expression of RIG-I inhibits the replication of IAV. These results provide further information on the mechanism by which IAV NS1 antagonizes the host antiviral response.
Am J Respir Cell Mol Biol 2007 Mar
PMID:NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I. 1705 3

Inflammation is an important factor in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease or multiple sclerosis, and during microbial infections of the nervous system. Glial cells were thought to be the main contributor for cytokine and chemokine production and Toll-like receptor (TLR) expression in the brain. Here, we report that human neurons express TLR-3, a major receptor in virus-mediated innate immune response. We established that these cells can mount a strong inflammatory response characterized by the expression of inflammatory cytokines (TNF-alpha, IL-6), chemokines (CCL-5 and CXCL-10), and antiviral molecules (2'5'OAS and IFN-beta) after treatment with dsRNA - a by-product of viral infection and ligand of TLR-3. This work firmly establishes that human neurons, in absence of glia, have the intrinsic machinery to trigger robust inflammatory, chemoattractive, and antiviral responses.
J Mol Neurosci 2006
PMID:The innate immune facet of brain: human neurons express TLR-3 and sense viral dsRNA. 2934 18

Suppressor of cytokine signaling (SOCS) 1 is an essential physiologic regulator of the IFN-gamma signaling that is crucial to lead appropriate immune responses, and impaired IFN-gamma production is considered a hallmark of atopic diseases. Recent study has shown that SOCS1 is also crucial in attenuating type 1 IFN signaling and in limiting the host response to viral infection. Clinical and experimental evidence suggest an important role for respiratory viral infections in the development of asthma. To assess genetic functional variants of SOCS1 related to susceptibility and clinical phenotypes in adult asthma in a Japanese population, we conducted association and haplotype analyses of 462 subjects with adult asthma and 639 control subjects. After screening for polymorphisms, we identified a total of 13 variants and characterized the linkage disequilibrium (LD) mapping of the gene. Three variants were selected for genotyping with regard to the LD pattern, and we found a significant association between an SOCS1 promoter polymorphism -1478CA > del and adult asthma (P = 0.0063). The three-locus haplotype of SOCS1 using these three polymorphisms also showed a positive association with a haplotype T-C-del (-5388T, -3969C, and -1478 del; P = 0.0097). Furthermore, reporter gene analysis revealed that related promoter variant -1478 del enhanced the transcriptional level of SOCS1 in human lung epithelial cells, and induced higher levels of protein expression of SOCS1 and lower phosphorylation of STAT1 stimulated with IFN-beta. These findings suggest that the SOCS1 gene might be involved in the development of adult asthma through functional genetic polymorphism.
Am J Respir Cell Mol Biol 2007 Apr
PMID:Functional polymorphism in the suppressor of cytokine signaling 1 gene associated with adult asthma. 1709 41

The 1,25(OH)(2)D(3) analog, TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)), has an interesting dissociation profile between its potent immunomodulatory and its calcemic effects in vivo. The strong immunomodulatory potency of TX527 is reflected by its ability to attenuate experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). At present most MS patients are being treated with systemic IFN-beta administration. The aim of this study was to investigate whether combining IFN-beta with TX527 could empower its EAE-protective effects. We evaluated also combinations with the standard immunosuppressant cyclosporin A (CsA). EAE was induced in SJL mice by PLP immunization, treatment was started 3 days before disease induction. The TX527+IFN-beta combination resulted in significant disease protection which was superior to the effect of both treatment separately. No disease amelioration, even aggravation, was obtained with the IFN-beta+CsA combination. By adding TX527 to the IFN-beta+CsA combination near complete protection from EAE was achieved (100% protection from paralysis, mean maximal score of 1.8+/-1.5, both p<0.05 versus controls and all individual treatments). From these data we conclude that adding TX527 to an IFN-beta and/or CsA treatment results in clear additional immunomodulatory effects in EAE prevention and is therefore a potentially interesting candidate to be considered in clinical intervention trials in MS.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Novel insights in the immune function of the vitamin D system: synergism with interferon-beta. 1725 71

BRCA1 encodes a tumor suppressor gene that is mutated in the germ line of women with a genetic predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of important cellular functions including DNA damage repair, transcriptional regulation, cell cycle control, and ubiquitination. Using an Affymetrix U95A microarray, IRF-7 was identified as a BRCA1 transcriptional target and was also shown to be synergistically up-regulated by BRCA1 specifically in the presence of IFN-gamma, coincident with the synergistic induction of apoptosis. We show that BRCA1, signal transducer and activator of transcription (STAT)-1, and STAT2 are all required for the induction of IRF-7 following stimulation with IFN-gamma. We also show that the induction of IRF-7 by BRCA1 and IFN-gamma is dependent on the type I IFNs, IFN-alpha and IFN-beta. We show that BRCA1 is required for the up-regulation of STAT1, STAT2, and the type I IFNs in response to IFN-gamma. We show that BRCA1 is localized at the promoters of the molecules involved in type I IFN signaling leading to their up-regulation. Blocking this intermediary type I IFN step using specific antisera shows the requirement for IFN-alpha and IFN-beta in the induction of IRF-7 and apoptosis. Finally, we outline a mechanism for the BRCA1/IFN-gamma regulation of target genes involved in the innate immune response, which is dependent on type I IFN signaling.
Mol Cancer Res 2007 Mar
PMID:BRCA1 regulates IFN-gamma signaling through a mechanism involving the type I IFNs. 1737 31

Double-stranded RNA (dsRNA) and its mimic, polyinosinic acid:polycytidylic acid [poly(I):poly(C)], are recognized by toll-like receptor 3 (TLR3) that induces the production of IFN-beta in many cell types. In the present study, we investigated the effects of poly(I):poly(C) on mouse osteoblastic MC3T3-E1 (E1) cells. Poly(I):poly(C) markedly increased IFN-beta mRNA level in a dose-dependent manner. The increase in the IFN-beta mRNA level was apparent as early as 1 h after adding poly(I):poly(C) to the culture and peaked at 12 h. Stimulation with poly(I):poly(C) enhanced the expression of CXCL10 mRNA and TLR3 in E1 cells. Moreover, poly(I):poly(C) induced tyrosine phosphorylation of the transcription factor STAT1 in E1 cells. An anti-IFN-beta neutralizing antibody partially inhibited poly(I):poly(C)-induced CXCL10 mRNA, TLR3 mRNA and STAT1 phosphorylation. These results indicate that osteoblasts secrete IFN-beta in response to viral infection and that endogenous IFN-beta induces both CXCL10 and TLR3 production via an IFN-alpha/beta receptor-STAT1 pathway. It is suggested that osteoblasts are involved in host defense as well as bone metabolism.
Int J Mol Med 2007 May
PMID:Toll-like receptor 3 ligand-induced antiviral response in mouse osteoblastic cells. 1739 82

Toll-like receptor (TLR)3 recognizes dsRNA and activates the signaling cascade leading to production of IFN-beta via an adaptor protein, TICAM-1 (also called TRIF). The interface between ligand recognition and signal transduction by TLR3 remains largely unknown. The crystalized ectodomain of human TLR3 revealed a horseshoe-shaped solenoid assembled from 23 leucine-rich repeats (LRRs). Here, we constructed LRR deletion mutants and tested the participation of each LRR in the IFN-inducing ability of TLR3. Only 3 of the 23 LRRs (LRR4, LRR11 and LRR17) were dispensable for the TLR3 function. Among the 20 dysfunctional mutants, LRR20- and LRR22-deleted mutants acted as dominant-negative inhibitors of wild-type TLR3. The LRR20-deleted mutant lost the poly(I:C)-binding ability, while LRR22-deleted mutant possessed it. Strikingly, the LRR21-deleted mutant functioned as a constitutively active form. These three mutants formed homodimers regardless of their different functional features and reacted with TLR3.7, a function-blocking anti-human TLR3 mAb whose epitope resided in LRR10-LRR16, suggesting that the intact conformation around the central solenoid was retained in the C-terminal mutants. These results suggest that the extracellular domains are a crucial trigger of cytoplasmic IFN signaling in TLR3. The altered molecular topology resulting from the deletion of LRR20, LRR21 or LRR22 critically affects the functional assembly of cytoplasmic TLR3, resulting in dysregulation of receptor-receptor association and signal transmission from the outside ectodomain to the inside TIR domain.
Mol Immunol 2007 Jul
PMID:C-terminal LRRs of human Toll-like receptor 3 control receptor dimerization and signal transmission. 1752 32

IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-beta on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-beta delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-beta was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-beta-mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling-continuous delivery of IFN-beta. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy.
Mol Cancer Res 2007 Jun
PMID:Continuous delivery of IFN-beta promotes sustained maturation of intratumoral vasculature. 1757 15


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