Showing papers in "Journal of Interferon and Cytokine Research in 2009"
TL;DR: This review will discuss the biological processes and the structure and function of CCL2, one of the key chemokines that regulate migration and infiltration of monocytes/macrophages.
Abstract: Chemokines constitute a family of chemoattractant cytokines and are subdivided into four families on the basis of the number and spacing of the conserved cysteine residues in the N-terminus of the protein. Chemokines play a major role in selectively recruiting monocytes, neutrophils, and lymphocytes, as well as in inducing chemotaxis through the activation of G-protein-coupled receptors. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. Both CCL2 and its receptor CCR2 have been demonstrated to be induced and involved in various diseases. Migration of monocytes from the blood stream across the vascular endothelium is required for routine immunological surveillance of tissues, as well as in response to inflammation. This review will discuss these biological processes and the structure and function of CCL2.
3,050 citations
TL;DR: Current knowledge on the VACV genes encoding proteins acting as decoy receptors to block the activity of type I and type II IFNs, targeting cytokines and chemokines, and antagonizing intracellular signaling pathways are analyzed.
Abstract: Vaccinia virus (VACV), a prototype member of the poxvirus family, has been used from the early times after interferons (IFN) were discovered, as a model virus cell system to analyze the mode of action of IFN. This large DNA-containing virus (around 200 kb) replicates entirely in the cytoplasm of the cell, taking rapidly over the host cell machinery for virus multiplication. In the presence of IFN, this virus exhibits sensitivity or resistance depending on the virus–host model. With the discovery of IFN-induced enzymes, the sensitivity of VACV to IFN was correlated with dsRNA activation of the protein kinase PKR and 2 ′–5 ′-OAS/RNaseL systems leading to a translational block by the phosphorylation of the eIF2 α factor and RNA breakdown. Following sequencing of the VACV genome and generation of deletion mutants, the resistance phenomenon to IFN was shown to be exerted through inhibition of multiple pathways. This review analyzes current knowledge on the VACV genes encoding proteins acting as decoy receptors to block the activity of type I and type II IFNs, targeting cytokines and chemokines, and antagonizing intracellular signaling pathways (pattern recognition receptors [PRRs] signaling). The molecular dissection of how VACV prevents the IFN response is providing important insights on our understanding of antiviral action and immune surveillance.
169 citations
TL;DR: The structure of the VP35 dsRNA-binding domain, which has recently become available, is expected to provide insight into how VP35 IFN-antagonist and ds RNA-binding functions are related.
Abstract: The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), cause frequently lethal viral hemorrhagic fever. These infections induce potent cytokine production, yet these host responses fail to prevent systemic virus replication. Consistent with this, filoviruses have been found to encode proteins VP35 and VP24 that block host interferon (IFN)-α/β production and inhibit signaling downstream of the IFN-α/β and the IFN-γ receptors, respectively. VP35, which is a component of the viral nucleocapsid complex and plays an essential role in viral RNA synthesis, acts as a pseudosubstrate for the cellular kinases IKK-e and TBK-1, which phosphorylate and activate interferon regulatory factor 3 (IRF-3) and interferon regulatory factor 7 (IRF-7). VP35 also promotes SUMOylation of IRF-7, repressing IFN gene transcription. In addition, VP35 is a dsRNA-binding protein, and mutations that disrupt dsRNA binding impair VP35 IFN-antagonist activity while leaving its RNA replication functions intact. The phenotypes of reco...
150 citations
TL;DR: Understanding of the mechanisms by which restriction factors interfere with retroviral replication, and how their effects are avoided by certain retroviruses, is accruing, but far from complete, which could allow for novel forms of therapeutic intervention in pathogenic Retroviral infections, as well as the development of animal models of human disease.
Abstract: Recent discoveries have revealed previously unappreciated complexity with which retroviruses interact with their hosts. In particular, we have become aware that many mammals, including humans, are equipped with genes encoding so-called “restriction factors,” that provide considerable resistance to retroviral infection. Such antiretroviral genes are sometimes constitutively expressed, and sometimes interferon-induced. Thus they can be viewed as comprising an intrinsic immune system that provides a pre-mobilized defense against retroviral infection or, alternatively, as a specialized extension of conventional innate immunity. Antiretroviral restriction factors have evolved at an unusually rapid pace, particularly in primates, and some startling examples of evolutionary change are present in genes encoding restriction factors. Our understanding of the mechanisms by which restriction factors interfere with retroviral replication, and how their effects are avoided by certain retroviruses, is accruing, but far ...
143 citations
TL;DR: The results indicate that REM sleep deprivation induced an inflammatory response, and IL-17A appears to play a pivotal role in coordinating the inflammation.
Abstract: Sleep deprivation is a major health problem in modern society. Deprivation of rapid eye movement (REM) sleep is particularly damaging to cognition and to spatial memory; however, the mechanisms that mediate these deteriorations in function are not known. We explored the possibility that REM sleep deprivation may provoke major changes in the immune system by inducing inflammation. Rats were subjected to 72 h of REM sleep deprivation, and the plasma levels of proinflammatory cytokines (IL-1, IL-1beta, IL-6, IL-17A, and TNF-alpha), an anti-inflammatory cytokine (IL-10), the inflammatory markers homocysteine, corticosterone, and hyperthermia were measured immediately after the deprivation period, and 7 days later. The results indicate that REM sleep deprivation induced an inflammatory response. The levels of the proinflammatory cytokines and markers were significantly elevated in sleep-deprived rats as compared to control rats. After 7 days of recovery, the levels of some markers, including hyperthermia, remained higher in sleep-deprived rats versus the control animals. IL-17A appears to play a pivotal role in coordinating the inflammation. These data shed new light on the mechanism of sleep deprivation-induced inflammation.
120 citations
TL;DR: The virus and host processes that regulate the RIG-I pathway during HCV infection are described and an understanding of these HCV-host interactions could lead to more effective therapies for HCV designed to reactivate the host immune response followingHCV infection.
Abstract: Hepatitis C virus (HCV) is a global public health problem that mediates a persistent infection in nearly 200 million people. HCV is efficient in establishing chronicity due in part to the inefficiency of the host immune system in controlling and counteracting HCV-mediated evasion strategies. HCV persistence is linked to the ability of the virus to suppress the RIG-I pathway and interferon production from infected hepatocytes, thus evading innate immune defenses within the infected cell. This review describes the virus and host processes that regulate the RIG-I pathway during HCV infection. An understanding of these HCV–host interactions could lead to more effective therapies for HCV designed to reactivate the host immune response following HCV infection.
116 citations
TL;DR: The current understanding of viral proteins encoded by HSV-1 involved in the evasion of the IFN response is identified and summarized.
Abstract: The interferon (IFN) family of cytokines constitutes potent inducers of innate antiviral responses that also influence adaptive immune processes. Despite eliciting such formidable cellular defense responses, viruses have evolved ways to interfere with the IFN response. Herpes simplex virus 1 (HSV-1) is an enveloped, dsDNA virus and a member of the herpesvirus family. Like other herpesvirus family members, HSV-1 has become highly specialized for its host and establishes a lifelong infection by undergoing latency within neurons. A leading reason for the success of HSV-1 as a pathogen results from its ability to evade the IFN response. Specifically, HSV-1 encodes several proteins that function to inhibit both IFN production and subsequent signal transduction. This review will identify and summarize the current understanding of viral proteins encoded by HSV-1 involved in the evasion of the IFN response.
112 citations
TL;DR: In this article, the authors applied transcriptome profiling to identify genes synergistically upregulated by IFN-γ and TNF in macrophages which are potentially involved in the defense against intracellular pathogens.
Abstract: Interferon-γ (IFN-γ) and tumor necrosis factor (TNF) are essential cytokines for successful clearance of microbial infections. Activation of macrophages by synergistic effects of these cytokines leads to induction of antimicrobial effector systems like reactive oxygen and reactive nitrogen intermediates. Strikingly, IFN-γR−/− and TNFRp55−/− mice are considerably more susceptible to infections than inducible nitric oxide synthase−/− and p47phox−/− mice. Thus we applied transcriptome-profiling studies to identify genes synergistically upregulated by IFN-γ and TNF in macrophages which are potentially involved in the defense against intracellular pathogens. From a total of 234 regulated genes we found 35 genes that were upregulated by combined effects of IFN-γ and TNF and were at least 2-fold induced. The majority of these genes are involved in signal transduction and transcriptional regulation. However, we found several genes were poorly characterized with regard to immunological functions. As a prototypic T...
106 citations
TL;DR: The data showed that the OASL gene is rapidly induced in response to viral infection and that this induction is mediated by IFN regulatory factor 3 (IRF-3), and the induction of the Oas1 gene by virus infection was lower, and did require a functional type I IFN response.
Abstract: The 2′-5′ oligoadenylate synthetase (OAS) family consist of three genes encoding active OAS enzymes (OAS1-3) and an OAS-Like (OASL) gene encoding an inactive protein. The transcription of all four members of this family is actively induced by interferon (IFN), but so far no attempt to systematically analyze the expression of these genes during viral infection has been made. We analyzed the expression of the human OAS1 and OASL genes in response to infection with Sendai virus or Influenza A virus. Surprisingly, we found a marked difference in the expression pattern of these genes. Our data showed that the OASL gene is rapidly induced in response to viral infection and that this induction is mediated by IFN regulatory factor 3 (IRF-3). In contrast to the OASL gene, the induction of the OAS1 gene by virus infection was lower, and did require a functional type I IFN response. The pronounced difference in gene regulation between the OAS1 and OASL genes agrees with a functional difference between these genes, w...
99 citations
TL;DR: The data suggest IL-1beta modulates TNF-alpha-mediated inflammatory lung diseases by enhancing epithelial cell TNF receptor surface expression.
Abstract: Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) mediate the development of numerous inflammatory lung diseases. Since IL-1β is typically activated in situations where TNF-α is produced, it was hypothesized that IL-1β alters TNF-α–induced proinflammatory epithelial cell function by altering TNF receptor shedding and surface abundance. In this study, the impact of IL-1β on TNF-α–mediated chemokine production as well as TNF receptor surface expression and shedding were investigated from mouse pulmonary epithelial cells (MLE-15). Interleukin-1β rapidly and persistently enhanced soluble and surface TNFR2. These effects were dependent on TNFR1 expression. TNFR2 small-interfering RNA (siRNA) shifted IL-1β responses, significantly increasing surface and shed TNFR1 implying IL-1β selectively modifies TNF receptors depending on cellular receptor composition. mRNA expression of both receptors was unaltered by IL-1β up to 24 h or in combination with TNF-α indicating effects were post-transcriptional. Interleukin-1β pretreatment enhanced TNF-α–induced macrophage inflammatory protein (MIP)-2 and KC mRNA expression as well as MIP-2 and KC protein levels at the same time point analyzed. Experiments utilizing siRNA against the TNF receptors and a TNFR1 neutralizing antibody demonstrated TNF-α induced MIP-2 through TNFR1, whereas both receptors may have contributed to KC production. These data suggest IL-1β modulates TNF-α–mediated inflammatory lung diseases by enhancing epithelial cell TNF receptor surface expression.
97 citations
TL;DR: The maintenance and regulation of the barrier function of the epithelial lining of the intestine are important homeostatic events, serving to allow selective absorption from the gut lumen while simultaneously limiting the access of bacteria into the mucosa.
Abstract: The maintenance and regulation of the barrier function of the epithelial lining of the intestine are important homeostatic events, serving to allow selective absorption from the gut lumen while simultaneously limiting the access of bacteria into the mucosa. Interferon-gamma is a pleiotrophic cytokine produced predominantly by natural kill cells and CD4+ T cells that under normal circumstances, and particularly during infection or inflammation, will be a component of the intestinal milieu. Use of colon-derived epithelial cell lines and, to a less extent, murine in vivo analyses, have revealed that interferon-gamma (IFN-gamma) can increase epithelial permeability as gauged by markers of paracellular permeability and bacterial transcytosis, with at least a portion of the bacteria using the transcellular permeation pathway. In this review, we describe the main characteristics of epithelial permeability and then focus on the ability of IFN-gamma to increase epithelial permeability, and the mechanism(s) thereof.
TL;DR: How paramyxoviruses limit the production of PAMPs and inhibit the cellular responses to PAMps is discussed, by interfering with the activities of the pattern recognition receptors (PRRs), mda-5, and RIG-I, as well as downstream components in the type I IFN induction cascades.
Abstract: α/β), and havused as agents in the commercial production of human IFN- α. However, in the last few years it has become clear that viruses in general mount a major challenge to the IFN system, and paramyxoviruses are no exception. Indeed, most paramyxoviruses encode mechanisms to inhibit both the production of, and response to, type I IFN. Here we review our knowledge of the type I IFN-inducing signals (by so-called pathogen-associated molecular patterns, or PAMPs) produced during paramyxovirus infections, and discuss how paramyxoviruses limit the production of PAMPs and inhibit the cellular responses to PAMPs by interfering with the activities of the pattern recognition receptors (PRRs), mda-5, and RIG-I, as well as downstream components in the type I IFN induction cascades.
TL;DR: Members of the family Reoviridae have evolved a variety of mechanisms to subvert the host's innate protective response.
Abstract: The mammalian reoviruses and rotaviruses have evolved specific mechanisms to evade the Type I interferon (IFN) antiviral response. Rotavirus likely represses the IFN response by at least 4 mechanisms. First, the rotavirus protein NSP1, most likely functioning as an E3 ligase, can induce proteasome-dependent degradation of the transcription factors IRF3, IRF5, and IRF7 to prevent their induction of IFN. Second, NSP1 can induce proteasome-dependent degradation of the ubiquitin ligase complex protein beta-TrCP, resulting in stabilization of I kappaB and concomitant failure of virus to activate NF-kappaB for induction of IFN. Third, rotavirus may sequester NF-kappaB in viroplasms. And fourth, rotavirus can prevent STAT1 and STAT2 nuclear translocation. The predominant mechanism for rotavirus inhibition of the IFN response is likely both rotavirus strain-specific and cell type-specific. The mammalian reoviruses also display strain-specific differences in their modulation of the IFN response. Reovirus activates RIG-I and IPS-1 for phosphorylation of IRF3. Reovirus-induced activation of MDA5 also participates in induction if IFN-beta, perhaps through activation of NF-kappaB. Reovirus likely inhibits the IFN response by at least 3 virus strain-specific mechanisms. First, the reovirus mu2 protein can induce an unusual nuclear accumulation of IRF9 and repress IFN-stimulated gene (ISG) expression, most likely by disrupting IRF9 function as part of the heterotrimeric transcription factor complex, ISGF3. Second, the reovirus sigma 3 protein can bind dsRNA and prevent activation of the latent antiviral effector protein PKR. And third, genetic approaches have identified the reovirus lambda 2 and sigma 2 proteins in virus strain-specific modulation of the IFN response, but the significance remains unclear. In sum, members of the family Reoviridae have evolved a variety of mechanisms to subvert the host's innate protective response.
TL;DR: Both CXCL1 and CXCR2 play an important role in chemokine expression and neutrophil infiltration following adenoviral corneal infection, but have a redundant role in the development of keratitis.
Abstract: Epidemic keratoconjunctivitis (EKC), caused by human adenovirus (HAdV), is one of the most common ocular infections and results in corneal inflammation and subepithelial infiltrates. Adenoviral keratitis causes significant morbidity to the patients, and is characterized by infiltration of leukocytes in the corneal stroma, and expression of chemokines. The exact role of these chemokines in adenoviral infection has not been studied due to lack of animal models. Here, we have characterized the role of chemokine CXCL1/KC and receptor CXCR2 in adenoviral keratitis using a novel mouse model. Analysis of chemokine expression, leukocyte infiltration, and development of keratitis was performed by ELISA, flow cytometry, and histopathology, respectively. Deficiency of CXCL1 and CXCR2 resulted in delayed infiltration of neutrophils, but not inflammatory monocytes in HAdV-37 corneal infection. CXCL1−/− mice showed decreased expression of CXCL2/MIP-2, but not CCL2/MCP-1. CXCR2−/− mice showed increased expression of CXC...
TL;DR: This review will summarize the current understanding of how mammalian cells recognize flaviviruses to induce an inhibitory IFN response and the countermeasures this group of viruses has evolved to antagonize this response.
Abstract: Virus survival and the ability to cause disease in mammalian hosts depend on their ability to avoid recognition and control by the interferon signal transduction and effector pathways. Flaviviruses comprise a large family of nonsegmented positive sense enveloped cytoplasmic RNA viruses, many of which are globally important human pathogens. Although the mechanistic details are still being dissected, new insight has emerged as to how a flavivirus minimizes the antiviral activity of type I interferon (IFN) to establish productive and potentially lethal infection. This review will summarize our current understanding of how mammalian cells recognize flaviviruses to induce an inhibitory IFN response and the countermeasures this group of viruses has evolved to antagonize this response.
TL;DR: The molecular mechanisms employed are different from those of the paramyxovirus P gene products serving similar functions, and illustrate evolution of IFN antagonists to specifically support virus survival in the natural niches.
Abstract: The family Rhabdoviridae contains important pathogens of humans, livestock, and crops, including the insect-transmitted vesicular stomatitis virus (VSV) and the neurotropic rabies virus (RV), which is directly transmitted between mammals. In spite of a highly similar organization of RNA genomes, proteins, and virus particles, cell biology of VSV and RV is divergent in several aspects, particularly with respect to their interplay with the cellular host defense. While infection with both rhabdoviruses is recognized via viral triphosphate RNAs by the cytoplasmic RNA helicase/translocase RIG-I, the viral counteractions to limit the response are contrasting. VSV infection is characterized by a rapid general shutdown of host gene expression and severe cytopathic effects, due to multiple activities of the matrix (M) protein affecting host polymerase functions and mRNA nuclear export, and by rapid and high-level virus replication. In contrast, RV spread and transmission relies on preserving the integrity of host ...
TL;DR: Diverse members of this large virus family effectively suppress STAT signaling by the actions of their V proteins, or the related proteins derived from alternate viral mRNAs, resulting in a variety of negative effects on STATs and their signal transduction.
Abstract: RNA viruses in the paramyxovirus family have evolved a number of strategies to escape host cell surveillance and antiviral responses. One mechanism exploited by a number of viruses in this family is direct targeting of cytokine-inducible transcription regulators in the STAT family. Diverse members of this large virus family effectively suppress STAT signaling by the actions of their V proteins, or the related proteins derived from alternate viral mRNAs. These viral proteins have distinct means of targeting STATs, resulting in a variety of negative effects on STATs and their signal transduction. Recent developments in understanding STAT targeting will be reviewed.
TL;DR: Viral double-stranded RNA-binding proteins are required to prevent the shutoff of protein synthesis by protein kinase R, further demonstrating the vital importance of evading the IFN response at multiple levels during infection.
Abstract: Human cytomegalovirus (HCMV), which infects the majority of the population worldwide, causes few, if any, symptoms in otherwise healthy people but is responsible for considerable morbidity and mortality in immuno-compromised patients and in congenitally infected newborns. The evolutionary success of HCMV depends in part on its ability to evade host defense systems. Here we review recent progress in elucidating the remarkable assortment of mechanisms employed by HCMV and the related β-herpesviruses, murine cytomegaloviruses (MCMV) and rhesus cytomegaloviruses (RhCMV), for counteracting the host interferon (IFN) response. Very early after infection, cellular membrane sensors such as the lymphotoxin β receptor initiate the production of antiviral cytokines including type I IFNs. However, virion factors, such as pp65 (ppUL83) and viral proteins made soon after infection including the immediate early gene 2 protein (pUL122), repress this response by interfering with steps in the activation of IFN regulatory factor 3 and NF-κB. CMVs then exert a multi-pronged attack on downstream IFN signaling. HCMV infection results in decreased accumulation and phosphorylation of the IFN signaling kinases Jak1 and Stat2, and the MCMV protein pM27 mediates Stat2 down-regulation, blocking both type I and type II IFN signaling. The HCMV immediate early gene 1 protein (pUL123) interacts with Stat2 and inhibits transcriptional activation of IFN-regulated genes. Infection also causes reduction in the abundance of p48/IRF9, a component of the ISGF3 transcription factor complex. Furthermore, CMVs have multiple genes involved in blocking the function of IFN-induced effectors. For example, viral double-stranded RNA-binding proteins are required to prevent the shutoff of protein synthesis by protein kinase R, further demonstrating the vital importance of evading the IFN response at multiple levels during infection.
TL;DR: This article highlights the recent progress in the understanding of key interactions of influenza viruses with the type I IFN defense, which are central to viral virulence.
Abstract: Virus research of the past decades showed that the vertebrate type I interferon (IFN) system is in principle capable of slowing down the replication and spread of most if not all viruses at early stages of infection. However, influenza viruses and other viral pathogens have evolved gene products to subvert this innate defense to enable efficient reproduction and thereby cause disease. Inhibition of type I IFN also impairs adaptive immune reactions as those cytokines function in the development of pathogen-specific cellular immunity. This article highlights the recent progress in our understanding of key interactions of influenza viruses with the type I IFN defense, which are central to viral virulence. A main focus is on corruptions of IFN-dependent antiviral functions mediated by the cellular receptors RIG-I and PKR and their blockade by the viral NS1 protein.
TL;DR: The novel evasion mechanisms by which Kaposi's sarcoma-associated herpesvirus, through its vIRFs, circumvents IFN-mediated innate immune responses and deregulates the cell growth control mechanism are summarized.
Abstract: Upon viral infection, the major defensive strategy employed by the host immune system is the activation of the interferon (IFN)-mediated antiviral pathway, which is overseen by IFN regulatory factors (IRFs). In order to complete their life cycles, viruses must find a way to modulate the host IFN-mediated immune response. Kaposi's sarcoma-associated herpesvirus (KSHV), a human tumor-inducing herpesvirus, has developed a unique mechanism for antagonizing cellular IFN-mediated antiviral activity by incorporating viral homolog of the cellular IRFs, called vIRFs, into its genome. Here, we summarize the novel evasion mechanisms by which KSHV, through its vIRFs, circumvents IFN-mediated innate immune responses and deregulates the cell growth control mechanism.
TL;DR: Cells containing complete HPV genomes that are able to undergo productive replication upon differentiation are sensitive to interferon-induced growth arrest, while cells from high-grade cancers that only express E6 and E7 are resistant.
Abstract: Human papillomaviruses (HPV) are small DNA viruses that target stratified keratinocytes for infection. A subset of HPV types infect epithelia in the genital tract and are the causative agents of cervical as well as other anogenital cancers. Interferon treatment of existing genital HPV lesions has had mixed results. While HPV proteins down-regulate the expression of interferon-inducible genes, interferon treatment ultimately induces their high-level transcription after a delay. Cells containing complete HPV genomes that are able to undergo productive replication upon differentiation are sensitive to interferon-induced growth arrest, while cells from high-grade cancers that only express E6 and E7 are resistant. Recent studies indicate this sensitivity is dependent upon the binding of the interferon-inducible factor, p56, to the E1 replication protein. The response to interferon by HPV proteins is complex and results from the action of multiple viral proteins.
TL;DR: The role of some members of the interferon regulatory factor family more deeply involved in the differentiation of hematopoietic cells and in immune regulation is addressed, with a specific focus on T cells and dendritic cells.
Abstract: Members of the interferon regulatory factor (IRF) family are transcription factors implicated in the regulation of a variety of biological processes. Originally identified as intracellular mediators of the induction and biological activities of interferons, their central role in host resistance to pathogens has recently been confirmed by the recognition of their involvement in the regulation of gene expression in responses triggered by Toll-like receptors and other pattern recognition receptors (PRRs). Their function in regulating the development as well as the activity of hematopoietic cells puts them at the interface between innate and adaptive immune responses. IRFs also regulate cell growth and apoptosis in several cell types, thereby affecting susceptibility to and the progression of cancer. In this review the role of some members of the family more deeply involved in the differentiation of hematopoietic cells and in immune regulation is addressed, with a specific focus on T cells and dendritic cells.
TL;DR: Analysis of patients who developed PAF after 1 day post-CABG revealed a higher level of IL-10 and IFN-gamma at 24 h post- CABG compared with patients without PAF.
Abstract: Recently, inflammation has been considered as a risk factor of postoperative atrial fibrillation (PAF). The main purpose of this study was to estimate the connections between occurrence of PAF and cytokine release. Thirty-three patients who qualified for cardiopulmonary bypass graft (CABG) were included in the study. Blood was taken from all of them before CABG, then 3 h, 24 h, and 72 h afterwards. Cytokine (IL-6, IL-2, IL-4, IL-10, IFN-γ, TNF-α) concentration was measured at every time point. Eleven patients developed atrial fibrillation after the CABG. Five of them developed PAF until 1 day post-CABG and six of them after 1 day post-CABG. Patients who developed PAF before 1 day post-CABG were characterized by a higher level of IL-2 in sera before 24 h and 72 h post-CABG compared with patients without PAF. Moreover, the PAF before 1 day post-CABG group was also characterized by the higher level of IFN-γ and IL-10 at 24 h after intervention. Analysis of patients who developed PAF after 1 day post-CABG rev...
TL;DR: Results show for the first time that the IFN-gamma modulation of TJ protein and TJ barrier function is regulated by a cross-talk between PI3-K and NF-kappaB pathways.
Abstract: Interferon-gamma (IFN-gamma) is an important proinflammatory cytokine that plays a central role in the intestinal inflammatory process of inflammatory bowel disease. IFN-gamma induced disturbance of the intestinal epithelial tight junction (TJ) barrier has been postulated to be an important mechanism contributing to intestinal inflammation. The intracellular mechanisms that mediate the IFN-gamma induced increase in intestinal TJ permeability remain unclear. The aim of this study was to examine the role of the phosphatidylinositol 3-kinase (PI3-K) pathway in the regulation of the IFN-gamma induced increase in intestinal TJ permeability using the T84 intestinal epithelial cell line. IFN-gamma caused an increase in T84 intestinal epithelial TJ permeability and depletion of TJ protein, occludin. The IFN-gamma induced increase in TJ permeability and alteration in occludin protein was associated with rapid activation of PI3-K; and inhibition of PI3-K activation prevented the IFN-gamma induced effects. IFN-gamma also caused a delayed but more prolonged activation of nuclear factor-kappaB (NF-kappaB); inhibition of NF-kappaB also prevented the increase in T84 TJ permeability and alteration in occludin expression. The IFN-gamma induced activation of NF-kappaB was mediated by a cross-talk with PI3-K pathway. In conclusion, the IFN-gamma induced increase in T84 TJ permeability and alteration in occludin protein expression were mediated by the PI3-K pathway. These results show for the first time that the IFN-gamma modulation of TJ protein and TJ barrier function is regulated by a cross-talk between PI3-K and NF-kappaB pathways.
TL;DR: In this article, the influence of a commercially available bovine colostrum protein concentrate (CPC) to stimulate cytokine production by human peripheral blood mononuclear cells (PBMCs) was investigated.
Abstract: Bovine colostrum has been shown to influence the cytokine production of bovine leukocytes. However, it remains unknown whether processed bovine colostrum, a supplement popular among athletes to enhance immune function, is able to modulate cytokine secretion of human lymphocytes and monocytes. The aim of this investigation was to determine the influence of a commercially available bovine colostrum protein concentrate (CPC) to stimulate cytokine production by human peripheral blood mononuclear cells (PBMCs). Blood was sampled from four healthy male endurance athletes who had abstained from exercise for 48 h. PBMCs were separated and cultured with bovine CPC concentrations of 0 (control), 1.25, 2.5, and 5% with and without lipopolysaccharide (LPS) (3 microg/mL) and phytohemagglutinin (PHA) (2.5 microg/mL). Cell supernatants were collected at 6 and 24 h of culture for the determination of tumor necrosis factor (TNF), interferon (IFN)-gamma, interleukin (IL)-10, IL-6, IL-4, and IL-2 concentrations. Bovine CPC significantly stimulated the release of IFN-gamma, IL-10, and IL-2 (p < 0.03). The addition of LPS to PBMCs cocultured with bovine CPC significantly stimulated the release of IL-2 and inhibited the early release of TNF, IL-6, and IL-4 (p < 0.02). Phytohemagglutinin stimulation in combination with bovine CPC significantly increased the secretion of IL-10 and IL-2 at 6 h of culture and inhibited IFN-gamma and TNF (p < 0.05). This data show that a commercial bovine CPC is able to modulate in vitro cytokine production of human PBMCs. Alterations in cytokine secretion may be a potential mechanism for reported benefits associated with supplementation.
TL;DR: This special issue of the Journal is dedicated to the topic of “Viral Evasion of the Interferon System”; it has been edited by Gale and Sen, and the individual articles have been contributed by authors who are experts on specific viruses and their host responses.
Abstract: This special issue of the Journal is dedicated to the topic of “Viral Evasion of the Interferon System”; it has been edited by Gale and Sen, and the individual articles have been contributed by authors who are experts on specific viruses and their host responses.
The actions of type I interferons (IFNs) provide our first barrier of defense against virus infection and are the foundation of innate immunity. Upon virus infection host pathogen recognition receptors, including the Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and/or various other factors including protein kinase R (PKR), 2′-5′ oligoadenylate synthetase (OAS), and other nucleic acid-binding proteins that may serve as pathogen recognition receptors, function to discriminate self from nonself macromolecule ligands within the cell, and their engagement of nonself viral products triggers intracellular signaling cascades that drive the production of IFN and its secretion from the infected cell. The secreted IFN plays a major role in immunity by binding to the IFN receptors on the infected cell and on the neighboring bystander cells wherein signaling is initiated through the Jak-STAT pathway to drive the expression of hundreds of IFN-stimulated genes. It is the products of the IFN-stimulated genes (ISG) that confer the antiviral, immunomodulatory, and overall actions of IFN that limit virus replication and spread, and that enhance the adaptive immune response to infection. Curiously, along with IFNs, many of the IFN-stimulated genes are also induced directly by virus infection, probably to confer resistance to the infected cell itself.
Virus recognition as nonself occurs when a pathogen recognition receptor of the host cell may physically bind to a viral ligand. Virus infection typically triggers pathogen recognition receptor signaling and IFN production, though it is becoming increasingly clear that these processes and their outcome are cell-type specific in vivo, thus offering insights into the uniqueness of viral tropism and disease. In order to replicate and spread, viruses have to overcome local and even systemic IFN defenses, and virtually all pathogenic viruses have evolved the means to evade and/or suppress IFN defenses as a means of supporting virus growth. Many viruses encode pathogen recognition receptor antagonists and/or IFN antagonists within their genome. Such factors may direct blockades of intracellular signaling programs that otherwise trigger IFN production, confer signaling through the IFN receptor, or directly alter the function of IFN-stimulated gene products. Viral disruption of IFN production and action is tightly linked with virulence.
Understanding the molecular mechanisms by which viruses trigger and evade IFN actions are therefore of paramount importance for defining strategies aimed at controlling virus infection. The nature of viral pathogen-associated molecular patterns or the macromolecules that trigger IFN production is currently an intense area of study. While such work has shown that viral DNA or RNA can stimulate IFN production, it has also revealed that the exact nature of the pathogen-associated molecular pattern embedded within viral nucleic acid might be as diverse as the different viruses that trigger IFN production. Double-stranded RNA, B-form DNA, single-stranded RNA, polyuridine RNA, and various nucleic acid compositions have each been defined as pathogen-associated molecular patterns that are engaged by TLRs, RLRs, or other distinct pathogen recognition receptors. Ongoing and future studies should further define the nature of specific pathogen-associated molecular patterns within viral nucleic acid as well as viral proteins and virus-associated lipids.
Viruses are good at multitasking and they often impose multiple blockades within the infected cell to evade and limit IFN defenses. These range from disrupting TLR or RLR signaling to dysregulating Jak-STAT signaling and controlling ISG function. The use of multiple strategies to evade and counter IFN defenses could reflect the need to regulate innate immunity within a variety of different cell types as infection proceeds from the initial portal of entry to the target tissue/cell type of virus amplification in vivo. This underscores the distinctions by which various cell types recognize and respond to virus infection, whereby distinct cell types feature TLR versus RLR pathways of IFN production to express specific IFN-α subtypes and a cell-specific bioset of ISGs, possibly reflecting specialized organotypic functions of immunity.
An example of IFN as a major therapeutic for virus infection is found in the population of hepatitis C virus (HCV)-infected patients. Pharmacologic preparations of IFN-α 2a, IFN-α 2b, or consensus IFN, in conjunction with ribavirin, are the currently approved therapies for chronic HCV infection. Moreover, various forms of IFN are used as anticancer therapy and therapeutics for autoimmune diseases. Thus, an understanding of IFN actions, including mechanisms of viral and host response or resistance to IFN, is essential for refining and improving IFN-based therapy applications. In the example of HCV, only about 50% of treated patients overall respond to IFN therapy or relapse after therapy cessation. In this case HCV is shown to suppress pathogen recognition receptor signaling in the infected cell, but it is not clear if the virus itself may truly evolve into an IFN-resistant variant during therapy. This underscores a need to fully define the mechanisms of viral evasion of IFN actions and to understand the many aspects of cross talk between various cellular processes/signaling pathways and IFN-responsive cellular programs that regulate infection and immunity.
In this issue, the topic of viral evasion of the IFN system has been broadly addressed by a number of leaders of the field; the authors have strived to provide a state-of-the-art picture, rather than a comprehensive historical account of the subject matter. However, for interested readers, the reference lists are inclusive enough to trace all relevant important observations by various investigators. The article by George and others focuses on 2 dsRNA-binding enzymes, PKR and ADAR1, which are important nodes of evasion by many viruses. Horner and Gale provide an introduction to the RLR pathways of cytoplasmic innate immune signaling in the context of HCV and discuss how this virus evades these pathways. Rieder and Conzelmann focus on 2 prototypic rhabdoviruses, vesicular stomatitis virus and rabies virus, and compare and contrast their distinct evasion strategies. The article by Basler and Amarasinhe deals with the evasion strategies used by filoviruses; specifically, the highly pathogenic Marburg and Ebola viruses. Diamond discusses how different flaviviruses antagonize the IFN system. Because much of our early knowledge of how RNA viruses evade innate immune responses of the host has come from investigations of the paramyxoviruses, 2 articles have been devoted to them. Ramachandran and Horvath discuss how these viruses disrupt IFN signaling by interfering with the actions of STAT proteins, whereas Goodbourn and Randall deal with viral blockage of IFN induction as triggered by the RLH pathways. Wolff and Ludwig provide a balanced account of various mechanisms used by influenza viruses to evade specific aspects of the IFN system. Moving on to double-stranded RNA viruses, Sherry tells us how rotavirus and reovirus deal with the IFN response. The article by Neil and Bieniasz focuses on retroviruses, more specifically HIV-1, and educates us about several distinct restriction factors of HIV-1 replication, their relationship to the IFN system, and how various viral proteins can antagonize them. The pox-viruses employ a plethora of strategies to counteract both the innate and the adaptive arms of the immune system. In this context, Perdiguero and Esteban focus on the mechanisms used by vaccinia virus to evade the IFN system. There are 3 articles on herpesviruses: Paladino and Mossman tell us about the evading mechanisms used by herpes simplex virus-1, whereas Marshall and Geballe discuss multiple strategies employed by different cytomegaloviruses. Lee and others explore the world of viral IFN regulatory factors in the context of Kaposi's sarcoma-associated herpesvirus and tell us how they interfere with the IFN system and the P53 pathway. Finally, Beglin and others report how another clinically important virus family, the papilloma viruses, interfere with the functioning of the IFN system.
TL;DR: IKK-beta has a novel role in IFN-gamma-dependent activation of chemokine gene expression through its activation of IRF1 and p65.
Abstract: Activation of chemokine genes in response to interferon (IFN)-γ or NF-κB is an important aspect of inflammation Using the chemokine gene ip-10 in mouse embryonic fibroblast cells as an example, we show that the response to IFN-γ is long lasting but secondary: initial STAT1 activation drives IRF1 synthesis, and IRF1 then binds to IFN-stimulated regulatory elements (ISREs) in the ip-10 promoter The promoters of most IKK-β-dependent IFN-stimulated genes (ISGs) also contain ISREs In response to IFN-γ, inhibitor of NF-κB (IκB) kinase β (IKK-β) is required to activate both newly synthesized IRF1 and the p65 subunit of NF-κB, which contributes to ip-10 expression by binding to κB sites in the ip-10 promoter, with little or no activation of classical NF-κB In contrast to IFN-γ, IL-1β induces ip-10 expression rapidly but transiently, by activating classical NF-κB and increasing the synthesis of IRF1 Together, IL-1β and IFN-γ induce ip-10 synergistically IFN-γ does not affect the transient activation of class
TL;DR: Using a surrogate model, restoration of GRIM-19 levels reestablishes the control over STAT3-dependent gene expression and tumor growth in vivo and identifies another major novel molecular pathway inactivated during the development of human cervical cancer.
Abstract: Cervical cancer is the most common malignant disease responsible for the deaths of a large number of women in the developing world. Although certain strains of human papillomavirus (HPV) have been identified as the cause of this disease, events that lead to formation of malignant tumors are not fully clear. STAT3 is a major oncogenic transcription factor involved in the development and progression of a number of human tumors. However, the mechanisms that result in loss of control over STAT3 activity are not understood. Gene associated with Retinoid-Interferon-induced Mortality-19 (GRIM-19) is a tumor-suppressive protein identified using a genetic technique in the interferon/retinoid-induced cell death pathway. Here, we show that reduction in GRIM-19 protein levels occur in a number of primary human cervical cancers. Consequently, these tumors tend to express a high basal level of STAT3 and its downstream target genes. More importantly, using a surrogate model, we show that restoration of GRIM-19 levels reestablishes the control over STAT3-dependent gene expression and tumor growth in vivo. GRIM-19 suppressed the expression of tumor invasion- and angiogenesis-associated factors to limit tumor growth. This study identifies another major novel molecular pathway inactivated during the development of human cervical cancer.
TL;DR: PRBC supernatant potentiates proinflammatory LPS-induced cytokine secretion from PBMCs, which may partially explain the immune activation seen clinically after blood transfusion.
Abstract: Allogeneic blood transfusion has an immunomodulatory capacity on its recipients through accumulation of immunologically active substances with blood storage, and prestorage leukoreduction reduces many of these mediators. We investigated lipopolysaccharide (LPS)-induced cytokine response of peripheral blood mononuclear cells (PBMCs) exposed to packed red blood cell (PRBC) supernatants from leukoreduced (LR) or non-leukoreduced (NLR) units with variable duration of storage. PRBC units were collected with or without leukoreduction on Day 0 before routine storage. The plasma fraction (supernatant) was isolated from LR and NLR units after 1 day (D1) or 42 days (D42) of storage and exposed to PBMCs versus control media for 24 h, then with LPS for an additional 24 h. Cell supernatants were analyzed for IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha by cytokine bead array. IL-1beta, TNF-alpha, and IL-6 were significantly elevated in PRBC groups versus control. D42 NLR PRBC supernatant significantly increased secretion of IL-1beta and IL-6 compared to D1 NLR PRBC supernatant. LR significantly attenuated the cytokine response of IL-1beta. Thus, PRBC supernatant potentiates proinflammatory LPS-induced cytokine secretion from PBMCs. This response is accentuated with storage duration and partially attenuated with leukoreduction. These findings may partially explain the immune activation seen clinically after blood transfusion.
TL;DR: The study suggests that TNF-alpha and IL-10 gene polymorphisms seem to have some influence on the disease susceptibility and progression of OLP in this Chinese cohort with Han ethnicity.
Abstract: Cytokines have an important role in the pathogenesis and disease progression on oral lichen planus (OLP). The aim of this study is to investigate the impact of gene polymorphisms of T-helper cell subtype Th1/Th2 cytokines, tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) on OLP in a Chinese cohort with Han ethnicity. Three single-nucleotide polymorphisms (SNPs) of the IL-10 gene (IL-10) at positions -1082G/A, -819C/T, and -592C/A and one SNP of the TNF-α gene (TNFG) at position -308G/A were analyzed in 151 patients with OLP and 143 healthy controls using polymerase chain reaction with sequence-specific primers (PCR-SSP) method and polymerase chain reaction–restriction fragment length (PCR-RFLP) method. The data revealed that there was no difference between the OLP patients and healthy control groups in frequencies of both TNF-α and IL-10 alleles (P = 0.053) and genotypes (P = 0.197). However, the frequencies of TNF-α-308A allele (P = 0.013) in patients with erosive OLP were significantly greate...