Showing papers on "Interferon published in 2006"
TL;DR: Members of the Toll-like receptor family have emerged as key sensors that recognize viral components such as nucleic acids and induce type I interferon responses via distinct signaling pathways.
Abstract: Induction of the antiviral innate immune response depends on recognition of viral components by host pattern-recognition receptors. Members of the Toll-like receptor family have emerged as key sensors that recognize viral components such as nucleic acids. Toll-like receptor signaling results in the production of type I interferon and inflammatory cytokines and leads to dendritic cell maturation and establishment of antiviral immunity. Cells also express cytoplasmic RNA helicases that function as alternative pattern-recognition receptors through recognition of double-stranded RNA produced during virus replication. These two classes of pattern-recognition receptor molecules are expressed in different intracellular compartments and induce type I interferon responses via distinct signaling pathways.
1,743 citations
TL;DR: The findings suggest that the beneficial effect on graft‐versus‐host disease induced by in vivo coinfusion with the graft of MSCs may be due to the activation of the immunomodulatory properties of M SCs by T cell– derived IFN‐γ.
Abstract: Mesenchymal stem cells (MSCs) inhibit the proliferation of HLA-unrelated T lymphocytes to allogeneic stimulation, but the mechanisms responsible for this activity are not fully understood. We show here that MSCs suppress the proliferation of both CD4+ and CD8+ T lymphocytes, as well as of natural killer (NK) cells, whereas they do not have an effect on the proliferation of B lymphocytes. The antiproliferative effect of MSCs was not associated with any effect on the expression of cell-activation markers, induction of cell apoptosis, or mimicry/enhancement of T regulatory cell activity. The suppressive activity of MSCs was not contact-dependent and required the presence of interferon (IFN)-gamma produced by activated T cells and NK cells. Accordingly, even activated B cells became susceptible to the suppressive activity of MSCs in the presence of exogenously added IFN-gamma. The suppressive effect of IFN-gamma was related to its ability to stimulate the production by MSCs of indoleamine 2,3-dioxygenase activity, which in turn inhibited the proliferation of activated T or NK cells. These findings suggest that the beneficial effect on graft-versus-host disease induced by in vivo coinfusion with the graft of MSCs may be due to the activation of the immunomodulatory properties of MSCs by T cell- derived IFN-gamma.
1,204 citations
TL;DR: Evidence is presented that cytosolic DNA activates a potent type I interferon response to the invasive bacterium Listeria monocytogenes, and a unique but overlapping gene-expression program activated by cytOSolic DNA compared to TLR9- and RIG-I/MDA5-dependent responses.
978 citations
TL;DR: It is demonstrated that cells lacking TRAF3, a member of the TNF receptor-associated factor family, are defective in type I IFN responses activated by several different TLRs, suggesting that TRAF 3 serves as a critical link between TLR adaptors and downstream regulatory kinases important for IRF activation.
Abstract: Type I interferon (IFN) production is a critical component of the innate defence against viral infections. Viral products induce strong type I IFN responses through the activation of Toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as protein kinase R (PKR). Here we demonstrate that cells lacking TRAF3, a member of the TNF receptor-associated factor family, are defective in type I IFN responses activated by several different TLRs. Furthermore, we show that TRAF3 associates with the TLR adaptors TRIF and IRAK1, as well as downstream IRF3/7 kinases TBK1 and IKK-epsilon, suggesting that TRAF3 serves as a critical link between TLR adaptors and downstream regulatory kinases important for IRF activation. In addition to TLR stimulation, we also show that TRAF3-deficient fibroblasts are defective in their type I IFN response to direct infection with vesicular stomatitis virus, indicating that TRAF3 is also an important component of TLR-independent viral recognition pathways. Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response.
888 citations
TL;DR: The capture of apoptotic cells by mDCs and of nucleic acid-containing immune complexes by plasmacytoid DCs and B cells amplifies the autoimmune reaction leading to disease manifestations.
881 citations
TL;DR: The current view on the balancing act between virus-induced IFN responses and the viral counterplayers is discussed.
667 citations
TL;DR: In this paper, the authors show that several classes of viruses induce expression of IFN-λ1 and -λ2/3 in similar patterns, and they identify type III IFNs as IFN stimulated genes.
Abstract: Type III interferons (IFNs) (interleukin-28/29 or lambda interferon [IFN-λ]) are cytokines with IFN-like activities. Here we show that several classes of viruses induce expression of IFN-λ1 and -λ2/3 in similar patterns. The IFN-λs were—unlike alpha/beta interferon (IFN-α/β)—induced directly by stimulation with IFN-α or -λ, thus identifying type III IFNs as IFN-stimulated genes. In vitro assays revealed that IFN-λs have appreciable antiviral activity against encephalomyocarditis virus (EMCV) but limited activity against herpes simplex virus type 2 (HSV-2), whereas IFN-α potently restricted both viruses. Using three murine models for generalized virus infections, we found that while recombinant IFN-α reduced the viral load after infection with EMCV, lymphocytic choriomeningitis virus (LCMV), and HSV-2, treatment with recombinant IFN-λ in vivo did not affect viral load after infection with EMCV or LCMV but did reduce the hepatic viral titer of HSV-2. In a model for a localized HSV-2 infection, we further found that IFN-λ completely blocked virus replication in the vaginal mucosa and totally prevented development of disease, in contrast to IFN-α, which had a more modest antiviral activity. Finally, pretreatment with IFN-λ enhanced the levels of IFN-γ in serum after HSV-2 infection. Thus, type III IFNs are expressed in response to most viruses and display potent antiviral activity in vivo against select viruses. The discrepancy between the observed antiviral activity in vitro and in vivo may suggest that IFN-λ exerts a significant portion of its antiviral activity in vivo via stimulation of the immune system rather than through induction of the antiviral state.
591 citations
TL;DR: In vivo evidence is provided that the cytosolic viral signaling pathway through MAVS is specifically required for innate immune responses against viral infection.
585 citations
TL;DR: Dose- and time-dependent HCV inhibition and kinetics of IFN-λ-mediated signal transducers and activators of transcription (STAT) activation and induction of potential effector genes were distinct from those ofIFN-α.
557 citations
TL;DR: Interestingly, the fish type I IFNs possess the same exon/intron structure as theIFN-lambdas, but show most sequence similarity to IFN-alpha.
524 citations
TL;DR: It is suggested that natural killer cells kill activated hepatic stellate cells via retinoic acid early inducible 1/NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent mechanisms, thereby ameliorating liver fibrosis.
TL;DR: IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses, and is the critical role of IPS-1 in antiviral responses in vivo.
Abstract: IFN-β promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor κB activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.
TL;DR: The role of TLRs and RLHs in the antiviral innate immune response is reviewed, located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA.
Abstract: Viral infection is detected by the host innate immune system. Innate immune cells such as dendritic cells and macrophages detect nucleic acids derived from viruses through pattern recognition receptors (PRRs). Viral recognition by PRRs initiates the activation of signaling pathways that lead to production of type I interferon and inflammatory cytokines, which are important for the elimination of viruses. Two types of PRRs that recognize viral nucleic acids, Toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH), have been identified. Of the TLRs, TLR3 recognizes viral double-stranded (ds) RNA, TLR7 and human TLR8 identify viral single-stranded (ss) RNA and TLR9 detects viral DNA. TLRs are located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA. Here we review the role of TLRs and RLHs in the antiviral innate immune response.
TL;DR: The recently identified adaptor protein MAVS is essential for antiviral innate immunity, but it also serves as a target of Hepatitis C virus, which employs a viral protease to cleave MAVS off the mitochondria, thereby allowing HCV to escape the host immune system.
Abstract: Recent studies have uncovered two signaling pathways that activate the host innate immunity against viral infection. One of the pathways utilizes members of the Toll-like receptor (TLR) family to detect viruses that enter the endosome through endocytosis. The TLR pathway induces interferon production through several signaling proteins that ultimately lead to the activation of the transcription factors NF-κB, IRF3 and IRF7. The other antiviral pathway uses the RNA helicase RIG-I as the receptor for intracellular viral double-stranded RNA. RIG-I activates NF-κB and IRFs through the recently identified adaptor protein MAVS, a CARD domain containing protein that resides in the mitochondrial membrane. MAVS is essential for antiviral innate immunity, but it also serves as a target of Hepatitis C virus (HCV), which employs a viral protease to cleave MAVS off the mitochondria, thereby allowing HCV to escape the host immune system.
TL;DR: In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity, which formally distinguish them from classical NK cells.
Abstract: Natural killer (NK) cells and dendritic cells (DCs) are, respectively, central components of innate and adaptive immune responses. We describe here a third DC lineage, termed interferon-producing killer DCs (IKDCs), distinct from conventional DCs and plasmacytoid DCs and with the molecular expression profile of both NK cells and DCs. They produce substantial amounts of type I interferons (IFN) and interleukin (IL)-12 or IFN-gamma, depending on activation stimuli. Upon stimulation with CpG oligodeoxynucleotides, ligands for Toll-like receptor (TLR)-9, IKDCs kill typical NK target cells using NK-activating receptors. Their cytolytic capacity subsequently diminishes, associated with the loss of NKG2D receptor (also known as Klrk1) and its adaptors, Dap10 and Dap12. As cytotoxicity is lost, DC-like antigen-presenting activity is gained, associated with upregulation of surface major histocompatibility complex class II (MHC II) and costimulatory molecules, which formally distinguish them from classical NK cells. In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity. By virtue of their capacity to kill target cells, followed by antigen presentation, IKDCs provide a link between innate and adaptive immunity.
TL;DR: A critical role of IRF‐1 is found in the regulation of constitutive and IFN‐γ‐induced expression of B7‐H1 in cancer cells, and AG490, a Janus activated kinase/signal transducer and activator of transcription inhibitor, greatly abolished the responsiveness of A549 cells to IFN-γ by reducing the IRF•1 transcription.
TL;DR: Evidence is provided that VP35 possesses double-stranded RNA (dsRNA)-binding activity, which supports the hypothesis that dsRNA binding may contribute to VP35 IFN antagonist function, and that additional mechanisms of inhibition, at a point proximal to the IRF-3 kinases, most likely also exist.
Abstract: Activation of alpha/beta interferon (IFN-α/β) production is a key step in the innate immune response to viral infection. Double-stranded RNA (dsRNA) has long been used as an experimental inducer of IFN-α/β and is potentially synthesized during the replication of many viruses. Thus, viral dsRNA has been hypothesized to be a trigger of cellular antiviral responses (29). A number of cellular dsRNA recognition proteins have been implicated in the IFN-induced antiviral response to infection. These include the dsRNA-dependent protein kinase PKR, the 2′,5′-oligoadenylate synthase, and ADAR1 (20, 44, 59, 63). More recently, two IFN-induced, caspase recruiting domain (CARD)-containing, DExD/H family helicases, the retinoic acid-inducible gene I (RIG-I) protein and the melanoma differentiation-associated gene 5 (MDA-5) protein, have been implicated as key sensors of viral infection (1, 30, 56, 66, 67). These proteins are activated by viral infection, possibly through recognition of dsRNA or of ribonucleoprotein complexes produced during infection, and transduce downstream signaling to activate the IFN-α/β responses (34).
The transcription factor interferon regulatory factor 3 (IRF-3) plays a critical role in the activation of the IFN-α/β gene. A cytoplasmic protein in its inactive state, IRF-3 becomes hyperphosphorylated on serine and threonine residues, dimerizes, and accumulates in the nucleus, where it participates in initial IFN-α/β gene expression (37, 68, 69). RIG-I and MDA-5 activate IRF-3 in response to dsRNA or to viral infection upstream of the IRF-3 kinases TBK-1 and IKKɛ (18, 30, 54, 66). This signaling appears to involve the homotypic interaction of the CARDs of the helicases with another CARD-containing protein termed alternatively IPS-1, MAVS, VISA, or Cardif (31, 41, 53, 65).
Viruses have evolved a variety of mechanisms to avoid recognition or to block the antiviral responses mediated by IFNs (2, 19). Several such proteins also exhibit dsRNA-binding activity. Examples of dsRNA-binding proteins that counteract cellular antiviral responses include the NS1 proteins of influenza A (NS1A) and B (NS1B) viruses, the E3L protein of vaccinia virus, the σ3 protein of reovirus, and the pTRS1 protein of human cytomegalovirus (5, 11, 12, 14, 16, 17, 22, 27, 57). Although dsRNA binding appears to contribute to IFN antagonist function, NS1A, NS1B, and E3L possess additional dsRNA-binding-independent mechanisms to inhibit the cellular antiviral response.
The Ebola virus (EBOV) VP35 protein has been found to inhibit IFN-α/β production and the activation of IRF-3 (3, 4, 9, 23, 48). Recently, it was suggested that VP35 may contain a dsRNA-binding motif similar to that found in the NS1 protein of influenza A virus (23). It was further suggested that this dsRNA-binding activity may be required for the ability of VP35 to inhibit IFN production (23). Here, we provide evidence that VP35 has dsRNA-binding activity that may contribute to IFN antagonism. It is likely that VP35 also possesses a dsRNA-binding-independent mechanism(s) that targets a point at or downstream of the IRF-3 kinases TBK-1 and IKKɛ.
TL;DR: It is demonstrated that the EBOV VP24 protein functions as an inhibitor ofIFN-α/β and IFN-γ signaling, and is likely to be an important virulence determinant that allows E BOV to evade the antiviral effects of IFNs.
Abstract: Ebola virus (EBOV) infection blocks cellular production of alpha/beta interferon (IFN-α/β) and the ability of cells to respond to IFN-α/β or IFN-γ. The EBOV VP35 protein has previously been identified as an EBOV-encoded inhibitor of IFN-α/β production. However, the mechanism by which EBOV infection inhibits responses to IFNs has not previously been defined. Here we demonstrate that the EBOV VP24 protein functions as an inhibitor of IFN-α/β and IFN-γ signaling. Expression of VP24 results in an inhibition of IFN-induced gene expression and an inability of IFNs to induce an antiviral state. The VP24-mediated inhibition of cellular responses to IFNs correlates with the impaired nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1), a key step in both IFN-α/β and IFN-γ signaling. Consistent with this proposed function for VP24, infection of cells with EBOV also confers a block to the IFN-induced nuclear accumulation of PY-STAT1. Further, VP24 is found to specifically interact with karyopherin α1, the nuclear localization signal receptor for PY-STAT1, but not with karyopherin α2, α3, or α4. Overexpression of VP24 results in a loss of karyopherin α1-PY-STAT1 interaction, indicating that the VP24-karyopherin α1 interaction contributes to the block to IFN signaling. These data suggest that VP24 is likely to be an important virulence determinant that allows EBOV to evade the antiviral effects of IFNs.
TL;DR: Emerging evidence suggests that viruses not only interfere with the interferon system involving PKR but also manipulate the programs emanating from the ER in a complex way, which may facilitate viral replication or pathogenesis.
Abstract: Viral infection induces endoplasmic reticulum (ER) stress and interferon responses. While viral double-stranded RNA intermediates trigger interferon responses, viral polypeptides synthesized during infection stimulate ER stress. Among the interferon-regulated gene products, the double-stranded RNA-dependent protein kinase (PKR) plays a key role in limiting viral replication. Thus, to establish productive infection, viruses have evolved mechanisms to overcome the deleterious effects of PKR. It has become clear that ER stress causes translational attenuation and transcriptional upregulation of genes encoding proteins that facilitate folding or degradation of proteins. Notably, prolonged ER stress triggers apoptosis. Therefore, viruses are confronted with the consequences of ER stress. Emerging evidence suggests that viruses not only interfere with the interferon system involving PKR but also manipulate the programs emanating from the ER in a complex way, which may facilitate viral replication or pathogenesis. This review highlights recent progress in these areas.
TL;DR: IL‐29 and IFN‐α stimulate identical antiviral responses despite their utilization of different receptors, which suggests that IL‐29 may have therapeutic value against chronic viral hepatitis in human patients.
TL;DR: Results demonstrate that D2S10 causes a more relevant disease in mice and that TNF-α may be one of several key mediators of severe DEN-induced disease in mouse, and it begins to provide mechanistic insights into DEN- induced disease in vivo.
Abstract: Lack of an appropriate animal model for dengue virus (DEN), which causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), has impeded characterization of the mechanisms underlying the disease pathogenesis. The cardinal feature of DHF/DSS, the severe form of DEN infection, is increased vascular permeability. To develop a murine model that is more relevant to DHF/DSS, a novel DEN strain, D2S10, was generated by alternately passaging a non-mouse-adapted DEN strain between mosquito cells and mice, thereby mimicking the natural transmission cycle of the virus between mosquitoes and humans. After infection with D2S10, mice lacking interferon receptors died early without manifesting signs of paralysis, carried infectious virus in both non-neuronal and neuronal tissues, and exhibited signs of increased vascular permeability. In contrast, mice infected with the parental DEN strain developed paralysis at late times after infection, contained detectable levels of virus only in the central nervous system, and displayed normal vascular permeability. In the mice infected with D2S10, but not the parental DEN strain, significant levels of serum tumor necrosis factor alpha (TNF-) were produced, and the neutralization of TNF- activity prevented early death of D2S10-infected mice. Sequence analysis comparing D2S10 to its parental strain implicated a conserved region of amino acid residues in the envelope protein as a possible source for the D2S10 phenotype. These results demonstrate that D2S10 causes a more relevant disease in mice and that TNF- may be one of several key mediators of severe DEN-induced disease in mice. This report represents a significant advance in animal models for severe DEN disease, and it begins to provide mechanistic insights into DEN-induced disease in vivo.
TL;DR: A novel bidirectional interaction between hepatocytes and lymphocytes modulated by PD-L1 expression in hepatocytes is suggested, which may contribute to the unique immunological properties of the liver.
TL;DR: The results indicate that the influenza A virus NS1 protein is a bifunctional viral immunosuppressor which inhibits innate immunity by preventing type I IFN release and inhibits adaptive immunity by attenuating human DC maturation and the capacity of DCs to induce T-cell responses.
Abstract: Both antibodies and T cells contribute to immunity against influenza virus infection. However, the generation of strong Th1 immunity is crucial for viral clearance. Interestingly, we found that human dendritic cells (DCs) infected with influenza A virus have lower allospecific Th1-cell stimulatory abilities than DCs activated by other stimuli, such as lipopolysaccharide and Newcastle disease virus infection. This weak stimulatory activity correlates with a suboptimal maturation of the DCs following infection with influenza A virus. We next investigated whether the influenza A virus NS1 protein could be responsible for the low levels of DC maturation after influenza virus infection. The NS1 protein is an important virulence factor associated with the suppression of innate immunity via the inhibition of type I interferon (IFN) production in infected cells. Using recombinant influenza and Newcastle disease viruses, with or without the NS1 gene from influenza virus, we found that the induction of a genetic program underlying DC maturation, migration, and T-cell stimulatory activity is specifically suppressed by the expression of the NS1 protein. Among the genes affected by NS1 are those coding for macrophage inflammatory protein 1β, interleukin-12 p35 (IL-12 p35), IL-23 p19, RANTES, IL-8, IFN-α/β, and CCR7. These results indicate that the influenza A virus NS1 protein is a bifunctional viral immunosuppressor which inhibits innate immunity by preventing type I IFN release and inhibits adaptive immunity by attenuating human DC maturation and the capacity of DCs to induce T-cell responses. Our observations also support the potential use of NS1 mutant influenza viruses as live attenuated influenza virus vaccines.
TL;DR: The data provide a new dimension by which IFN-α mediates its antiviral activity and suggest a means to render the host nonpermissive for viral replication.
Abstract: Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G), a cytidine deaminase, is a recently recognized innate intracellular protein with lethal activity against human immunodeficiency virus (HIV). Packaged into progeny virions, APOBEC3G enzymatic activity leads to HIV DNA degradation. As a counterattack, HIV virion infectivity factor (Vif) targets APOBEC3G for proteasomal proteolysis to exclude it from budding virions. Based on the ability of APOBEC3G to antagonize HIV infection, considerable interest hinges on elucidating its mechanism(s) of regulation. In this study, we provide the first evidence that an innate, endogenous host defense factor has the potential to promote APOBEC3G and rebuke the virus-mediated attempt to control its cellular host. We identify interferon (IFN)-α as a potent inducer of APOBEC3G to override HIV Vif neutralization of APOBEC3 proteins that pose a threat to efficient macrophage HIV replication. Our data provide a new dimension by which IFN-α mediates its antiviral activity and suggest a means to render the host nonpermissive for viral replication.
TL;DR: The inhibition of NF‐κB and STATs offers a strategy for treatment of a variety of malignancies and can convert inflammation‐induced tumor growth into inflammation-induced tumor regression.
Abstract: It has been estimated that >20% of all malignancies are initiated or exacerbated by inflammation. Until recently, the molecular basis of this process has not been clarified. However, recent studies have uncovered the molecular mechanism of intracellular signaling pathways of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6. Three major transcription factors including NF-κB, STAT1 and STAT3 have been shown to play major roles in transmitting inflammatory cytokine signals to the nucleus. One function of NF-κB and STAT3 in tumor cells is the promotion of cell growth and cell survival through the induction of target genes, whose products promote cell division and inhibit apoptosis. In addition, NF-κB and STAT1 are important transcription factors that induce inflammatory mediators from inflammatory cells, especially macrophages, while STAT3 often antagonizes this process. STAT1 is generally believed to be an anti-oncogene because it promotes apoptosis through p53, but it could promote inflammation-mediated tumor development by enhancing tissue injury, remodeling, fibrosis and inflammation. Hence, the inhibition of NF-κB and STATs offers a strategy for treatment of a variety of malignancies and can convert inflammation-induced tumor growth into inflammation-induced tumor regression. (Cancer Sci 2006; 97)
TL;DR: Results indicate that LGP2 can inhibit antiviral signaling independently of dsRNA or virus infection intermediates by engaging in a protein complex with IPS-1, and provide the first demonstration of protein interaction as an element of negative-feedback regulation of intracellular antiviral signaled by L GP2.
Abstract: Antiviral innate immune responses can be triggered by accumulation of intracellular nucleic acids resulting from virus infections. Double-stranded RNA (dsRNA) can be detected by the cytoplasmic RNA helicase proteins RIG-I and MDA5, two proteins that share sequence similarities within a caspase recruitment domain (CARD) and a DExD/H box RNA helicase domain. These proteins are considered dsRNA sensors and are thought to transmit the signal to the mitochondrial adapter, IPS-1 (also known as MAVS, VISA, or CARDIF) via CARD interactions. IPS-1 coordinates the activity of protein kinases that activate transcription factors needed to induce beta interferon (IFN-β) gene transcription. Another helicase protein, LGP2, lacks the CARD region and does not activate IFN-β gene expression. LGP2 mRNA is induced by interferon, dsRNA treatments, or Sendai virus infection and acts as a feedback inhibitor for antiviral signaling. Results indicate that LGP2 can inhibit antiviral signaling independently of dsRNA or virus infection intermediates by engaging in a protein complex with IPS-1. Experiments suggest that LGP2 can compete with the kinase IKKi (also known as IKKe) for a common interaction site on IPS-1. These results provide the first demonstration of protein interaction as an element of negative-feedback regulation of intracellular antiviral signaling by LGP2.
TL;DR: IFNalpha in SLE plasma is a major stimulus of IFN target gene expression and is related to expression of those genes in PBMCs from SLE patients and to the titer of anti-RBP autoantibodies, providing additional support for the view that IFNalpha mediates immune system activation and dysregulation in Sle.
Abstract: Objective
Peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) have increased expression of genes typically induced by type I interferon (IFN). However, it has been difficult to identify and quantify the factors responsible for activation of the IFN pathway in SLE. To characterize these mediators, we developed an assay that measures the functional effects of plasma or serum components on the gene expression of cultured target cells.
Methods
WISH epithelial cell line cells were cultured with medium, with recombinant IFNα, IFNβ, or IFNγ, or with 50% plasma from SLE patients (n = 73), rheumatoid arthritis (RA) patients (n = 19), or healthy donors (n = 30). Real-time quantitative polymerase chain reaction was used to determine WISH cell expression of IFN target genes, including PRKR, IFIT1, IFI44, MX1, and C1orf29 (preferentially induced by IFNα) and CXCL9 (Mig) (preferentially induced by IFNγ).
Results
IFNα-regulated genes were induced by SLE plasma samples, but not by most of the RA or healthy control plasma samples. The activity in SLE plasma was inhibited >90% by anti-IFNα antibody, but not by anti-IFNβ or anti-IFNγ antibodies. The expression of each IFNα target gene induced by SLE plasma correlated with the expression of that gene studied ex vivo in PBMCs from the same patients and with the titer of anti–RNA binding protein (anti-RBP)–specific autoantibodies. Plasma activity paralleled PBMC expression of IFNα-inducible genes over time.
Conclusion
IFNα in SLE plasma is a major stimulus of IFN target gene expression and is related to expression of those genes in PBMCs from SLE patients and to the titer of anti-RBP autoantibodies. These data provide additional support for the view that IFNα mediates immune system activation and dysregulation in SLE.
TL;DR: It is suggested that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.
Abstract: Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon gamma-producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.
TL;DR: A regulatory function for STAT3 is identified in attenuating the inflammatory properties of type I IFNs and a mechanism of suppression of STAT1 function is provided that differs from previously described suppression of tyrosine phosphorylation.
TL;DR: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-α.
Abstract: Background: Interferon alpha (IFN-alpha) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-alpha therapy and to determine hepatic expression of factors inhibiting IFN-alpha signalling in obese and nonobese subjects with chronic HCV. Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-alpha or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. Results: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p = 30 kg/m(2) (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-alpha.