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Results for “Type I interferon”

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PubMed1996

Mycoplasma fermentans-derived lipid inhibits class II major histocompatibility complex expression without mediation by interleukin-6, interleukin-10, tumor necrosis factor, transforming growth factor-beta, type I interferon, prostaglandins or nitric oxide.

Mycoplasma cause several diseases in man and animals. Some strains can chronically infect humans, leading to fever or inflammatory syndromes such as arthritis, particularly in immunosuppressed patients. A set of pathogenicity factors shared by many mollicutes may be membrane components that activate macrophages to secrete cytokines and other inflammatory mediators. Mycoplasma-derived high molecular weight material (MDHM) is a macrophage-activating amphiphilic lipid which was purified from Mycoplasma fermentans. We studied the influence of MDHM on the expression of major histocompatibility complex (MHC) class II molecules by mouse resident peritoneal macrophages with an ELISA. Highly purified MDHM at 4 ng/ml and 0.8 microgram/ml crude heat-killed M. fermentans (concentrations chosen to give maximal responses) suppressed interferon (IFN)-gamma-dependent class II MHC induction when added simultaneously with IFN-gamma. MDHM was not toxic and did not result in loss of adherent cells. Kinetic data showed that MDHM first up-regulated, then down-regulated the expression of preformed class II MHC molecules, while expression of Mac-1 and F4/80 antigens remained constant. MDHM-dependent suppression of class II MHC molecule expression resulted in impaired antigen presentation to the helper T cell line D10.G4.1. We further attempted to identify hypothetical products of MDHM-stimulated macrophages as secondary mediators of class II MHC suppression such as were described for lipopolysaccharide (LPS)-stimulated macrophages. Type I IFN, prostaglandins and nitric oxide, all reported to cause down-regulation of class II MHC, could be excluded in this context. Of the cytokines tumor necrosis factor, interleukin (IL)-6, IL-10 and transforming growth factor-beta, only IL-10 inhibited class II MHC expression, although less effectively than MDHM. The involvement of IL-10 was ruled out, as no evidence for its MDHM-dependent formation could be found. Our data suggest that MDHM interferes with class II MHC expression by up-regulating its turnover, and at the same time, inhibits the formation of new class II MHC molecules.

Animals↗

PubMed2007

In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance.

Liver gene transfer is a highly sought goal for the treatment of inherited and infectious diseases. Lentiviral vectors (LVs) have many desirable properties for hepatocyte-directed gene delivery, including the ability to integrate into nondividing cells. Unfortunately, upon systemic administration, LV transduces hepatocytes relatively inefficiently compared with nonparenchymal cells, and the duration of transgene expression is often limited by immune responses. Here, we investigated the role of innate antiviral responses in these events. We show that administration of LVs to mice triggers a rapid and transient IFNalphabeta response. This effect was dependent on functional vector particles, and in vitro challenge of antigen-presenting cells suggested that plasmacytoid dendritic cells initiated the response. Remarkably, when LVs were administered to animals that lack the capacity to respond to IFNalphabeta, there was a dramatic increase in hepatocyte transduction, and stable transgene expression was achieved. These findings indicate that, even in the setting of acute delivery of replication-defective vectors, IFNs effectively interfere with transduction in a cell-type-specific manner. Moreover, because disabling a single component of the innate/immune network was sufficient to establish persistent xenoantigen expression, our results raise the hope that the immunologic barriers to gene therapy are less insurmountable than expected.

Animals↗

PubMed1994

Virus induction of NF-kappa B/Rel proteins and type I interferon gene expression in myelomonoblastic cells.

The correlation between virus induced NF-kappa B DNA binding activity and interferon gene expression was examined in the myelomonoblastic PLB-985 cell line. Previous studies have shown that chronic HIV-1 infection of PLB-985 cells (PLB-IIIB) leads to the selection of cells with a more differentiated monocytic phenotype and with constitutive NF-kappa B DNA-binding activity. In this report we demonstrate that the kinetics of HIV-1 and Sendai virus infection of PLB-985 cells directly correlates with induction of NF-kappa B DNA binding activity. Based on UV cross-linking and immunoprecipitation analysis, p50, the strong transcriptional activator p65 and c-Rel represent the major constituents of this NF-kappa B DNA-binding activity. We also demonstrate an alteration in the kinetics of type I IFN gene transcription following secondary Sendai virus infection of PLB-IIIB cells compared to PLB-985. The results of our studies suggest that HIV infected individuals may respond differently to secondary viral or bacterial infections by augmenting the synthesis of NF-kappa B regulated immune response modifiers, which could alter the onset or progression of AIDS.

Amino Acid Sequence↗

PubMed1995

Secretion of bovine uterine proteins in response to type I interferons.

Bovine interferon-tau (bIFN-tau) is secreted by the developing conceptus and initiates antiluteolytic events by interacting with uterine membrane receptors. We have identified three endometrial proteins (approximately 8, 16, and 28 kDa; P8, P16, and P28; respectively) that are secreted in response to recombinant (r) bIFN-tau. The objective of this study was to determine whether or not secretion of these proteins was a unique response to IFN-tau during early pregnancy. Three experiments were designed to examine secretion of endometrial proteins as a function of time in culture (0, 3, 6, 12, 18, 24 h), stage of the estrous cycle and pregnancy (Days 15, 18, 0/21), and dose of Type I IFN (0, 0.5, 5, and 25 nM; rbIFN-tau, rbIFN-alpha, and roIFN-tau). Endometrium was cultured for times specified with L-[3H]leusine to generate radiolabeled proteins. Secreted proteins were quantitated by using one-dimensional (1D)-PAGE, fluorography, and densitometry. Secretion of P8, P16, and P28 increased over time (p < 0.0001) in culture and in response to 25 nM rbIFN-tau (p < 0.05). Secretion of P8 in response to rbIFN-tau was higher (p < 0.05). Secretion of P8 in response to rbIFN-tau was higher (p < 0.0005) in endometrium collected from pregnant than nonpregnant heifers, but did not differ across the days examined. Although secretion of P8 was higher (p < 0.0001) in the presence than in the absence of rbIFN-tau, it was not affected by rbIFN-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

trans activation of type 1 interferon promoters by simian virus 40 T antigen.

A human transient expression system was used to measure the influence of simian virus 40 T antigen and adenovirus E1a proteins on the activation of alpha interferon subtype 1 (IFN-alpha 1) and IFN-beta promoters linked to the reporter chloramphenicol acetyltransferase gene. Large T-antigen production, amplified by expression plasmid replication in transfected 293 cells, was able to trans activate the IFN-beta promoter 5- to 10-fold, increasing both the constitutive and Sendai virus-induced levels of expression. Surprisingly, the previously quiescent transfected IFN-alpha 1 promoter in T-antigen-expressing cells displayed a level of inducibility similar to IFN-beta. The endogenous IFN-alpha 1 gene was also inducible to a limited extent in cells expressing T antigen. A truncated IFN-beta promoter deleted to position -37 relative to the CAP site was neither inducible nor trans activated by T antigen, suggesting that sequences required for efficient induction were also needed for trans activation. Since 293 cells express adenoviral E1a proteins, experiments were also performed in HeLa cells to assess the relative contribution of T antigen and E1a proteins to IFN trans activation. In HeLa cells, T-antigen coexpression increased the constitutive level of IFN-beta and IFN-alpha 1 promoter activity without augmenting relative inducibility. Coexpression of T antigen and E1a proteins did not have a cooperative effect on type 1 IFN expression.

Adenovirus Early Proteins↗

PubMed1977

Effect of interferon on antibody formation.

Virus-type interferon is capable of suppressing the antibody response both in vivo and in vitro. Interferon induced by antigen or mitogen (immune interferon) primarily in T lymphocytes also appears capable of suppressing the antibody response. Cyclic AMP has a regulatory effect on the induction of both virus-type and immune interferon. The immunosuppressive effects of virus-type and immune interferon may differ at the cellular or subcellular level.

Animals↗

PubMed2002

Expression of type I interferon receptor in liver and peripheral blood mononuclear cells in chronic hepatitis C patients.

To assess whether peripheral blood mononuclear cells (PBMCs) can be substituted for liver tissue in monitoring the hepatic expression of interferon receptors (IFNAR1 and/or IFNAR2) in chronic hepatitis C, we quantified the mRNA of both subunits, using the competitive polymerase chain reaction, in the liver specimens from 37 chronic hepatitis C patients and in PBMCs from 29 of 37 patients. PBMCs from 10 healthy subjects were also quantified for both subunits. Hepatic expression of IFNAR1 and IFNAR2 were more frequent than PBMCs: IFNAR1, 23/27 (85%) vs 7/19 (37%), P = 0.0021, IFNAR2, 34/37 (92%) vs 19/29 (66%), P = 0.0182. Neither subunits was detected in PBMCs from control subjects. The expression level of IFNAR2 in the liver was related to that in PBMCs (r = 0.613, P = 0.0052). These results suggest that hepatitis C virus infection may up-regulate the expression of the type I interferon receptor and that the measurement of IFNAR2 expression in PBMCs may be useful for monitoring its expression in liver.

Adult↗

PubMed2026

Cell type-dependent induction of type I interferon and PARP1 activation in astrocytes and neurons during chikungunya virus infection.

Chikungunya virus, a mosquito-borne alphavirus, causes fever, rash, arthritis, and neurological disorders. Its non-structural protein 3 harbors a macrodomain, a key neurovirulence factor that removes adenosine diphosphate ribose from ADP-ribosylated substrates. Notably, chikungunya virus infection results in distinct ADP-ribosylation patterns and non-structural protein 3 macrodomain-mediated replication dynamics in astrocytes and neurons. Understanding the connection between ADP-ribosylation and the activation of innate immunity, particularly interferon release, is key to elucidating how the cellular immunological state influences ADP-ribosylation, an understudied post-translational modification during viral infection. Here, murine astrocytic (C8-D1A) and neuronal (NSC-34) cells were infected with chikungunya virus to profile transcript and protein expression of innate immune mediators and type I IFNs. The role of PARP1 in global ADP-ribosylation patterns was assessed using PARP-specific inhibitors and genetic depletion approaches. Our investigations revealed that neuronal chikungunya virus infection induces ADP-ribosylation through PARP1 activation, driven by caspase-3-mediated apoptosis, without transcriptionally activating PARPs. In contrast, astrocytic infections showed minimal ADP-ribosylation despite transcriptional activation of interferon-stimulated PARPs. Neurons exhibited limited innate immune response gene transcriptional activity, whereas astrocytes demonstrated strong upregulation of genes essential for pattern recognition receptor activation, thus enhancing double-stranded RNA sensing and increasing type I interferon production during infection. We posit that PARP1 activation and type I IFN response differentially regulate ADP-ribosylation in chikungunya virus-infected neural cells in a cell type-dependent manner.IMPORTANCEChikungunya virus is an emergent mosquito-borne alphavirus increasingly associated with neurological infection and subsequent long-term disabilities. Its continued global spread and recurrent outbreaks underscore its significant pandemic potential and the urgent need for effective countermeasures. Chikungunya virus showcases distinct, cell-type dependent replication dynamics within astrocytes and neurons, two major permissive cerebral cell types. However, understanding of the immunological basis of such cell type-specific infection dynamics remains limited, yet is necessary to elucidate virus pathogenesis within the brain and thus identification of downstream drug targets. Our study characterized two distinctly activated innate immunological pathways in chikungunya virus-infected astrocytes versus neurons, thus significantly contributing to molecular understanding cell type-specific chikungunya virus neurovirulence on a molecular level.

Animals↗

PubMed2006

Type-I but not type-II interferon receptor knockout mice are susceptible to biliary atresia.

The etiology of biliary atresia (BA) is not yet understood, but recent studies have shown inflammation with an up-regulated interferon (IFN) activity in the intra- and extrahepatic bile ducts of patients with BA. These findings support an inflammatory/infectious cause of BA as mimicked in our infective murine model. To study the role of the IFN receptors in our model, we used mice with inactivated INF-alpha/beta receptor A129, with inactivated IFN-gamma receptor G129, or inactivation of both interferon receptors AG129 as well as the wild type controls W129. Mice were infected with rotavirus within 48h of birth and 7 d postpartum. The incidence of BA in each group was determined during a 3 wk period. In the second week the virus load was measured. BA incidence was 76% in A129 and 67% in AG129 animals, whereas in the G129 group only 33% of the pups developed BA. The wild type presented with a BA-incidence of 15%, while 7 d old mice failed to develop BA. There was no significant difference in the virus load of the livers between the groups independent of clinical symptoms. In conclusion, inactivation of type I INF-receptor significantly increases the incidence of BA following postpartal rotavirus infection. This effect is independent of the presence of type II-INF-receptors. Thus, in our model a type I IFN-linked deregulation of the innate immune system appears to be crucial for the induction of biliary atresia.

Animals↗

PubMed2000

Structure-function study of the extracellular domain of the human type I interferon receptor (IFNAR)-1 subunit.

Despite accumulating information about the different effector molecules and signaling cascades that are invoked on interferon-alpha (IFN-alpha) binding to the type 1 IFN receptor, little is known about the specifics of the binding interactions between the ligand and the receptor complex. The IFN-alpha/beta receptor (IFNAR)-2 subunit of the IFN receptor is considered the primary binding chain of the receptor, yet it is clear that both receptor subunits, IFNAR-1 and IFNAR-2, cooperate in the high-affinity binding of IFN to the receptor complex. Earlier results from our laboratory suggested that an association of IFNAR-1 with membrane Galalpha1-4Gal-containing glycolipids facilitates receptor-mediated signaling. The data implicated amino acid residues in the SD100 domain of IFNAR-1 in the glycosphingolipid (GSL) modification of the type 1 IFN receptor. Interestingly, the human and murine counterparts of IFNAR-1 exhibit remarkable species specificity despite their considerable amino acid sequence identity. Certainly, those amino acid residues that effect GSL modification of IFNAR-1 are conserved between species, yet specific regions of IFNAR-1 that confer species specificity have not been defined. To delineate further the role of the IFNAR-1 SD100A domain in receptor function, a chimeric cDNA was assembled, in which the SD100A domain of the murine IFNAR-1 chain was replaced with the human sequence. This construct was expressed in IFNAR-1-/- mouse embryonic fibroblasts, and stable transfectants were established. Transfectants are fully sensitive to murine IFN-alpha4 treatment with respect to the induction of IFN-stimulated gene factor 3 (ISGF3) and sis-inducing factor (SIF) signal transducer and activator of transcription factor (Stat) complexes, exhibiting comparable levels of Stat activation to those observed in IFNAR-1-/- cells reconstituted with intact MuIFNAR-1. Similar results were obtained with IFN-induced antiviral and growth inhibitory responses. Viewed together, these data suggest that the SD100A domain of IFNAR-1 does not contribute to species-specific IFN binding.

Amino Acid Sequence↗

PubMed2006

Rinderpest virus blocks type I and type II interferon action: role of structural and nonstructural proteins.

Rinderpest virus (RPV) is a paramyxovirus closely related to the human pathogen Measles virus. It causes severe disease in cattle, buffalo, and some wild animals; although it can infect humans, it does not cause disease. Here, we demonstrate that RPV blocks the action of both type I (alpha) and type II (gamma) interferons (IFNs) by blocking the phosphorylation and nuclear translocation of STAT1 and STAT2 and that this block is not related to species specificity. In addition, both wild-type virulent and vaccine strains of the virus blocked IFN action. Unlike the case with some other paramyxoviruses, neither STAT1 nor STAT2 is degraded upon virus infection. STAT1 is bound by both the viral structural protein P, and thereby recruited to concentrations of viral protein in the cell, and the nonstructural protein V. Although both P and V proteins bind to STAT1 and can block IFN action when expressed in transfected cells, the IFN antagonist activity of the P protein is weaker than that of the V protein. The viral C protein also seems to weakly block IFN-induced activation of STAT1 in transfection experiments. However, studies with knockout viruses showed that the viral V protein appears to be the dominant inhibitor of IFN signaling in the context of virus infection, since prevention of viral V expression restored the IFN sensitivity of infected cells. Although a change in the distribution pattern of STAT2 was observed in virus-infected cells, STAT2 was not bound by any viral protein.

Animals↗

PubMed1984

Factor determining the antigenic type of interferons produced in human lymphoblastoid cell lines.

The factor that determines the antigenic type of IFN produced in human lymphoblastoid cell lines was examined using live Sendai virus, ultraviolet (UV)-irradiated virus, HANA spikes exposed on L cells persistently infected with Sendai virus (L-HVJ) and poly-inosinic acid poly-cytidylic acid (poly I: C). When Sendai virus was irradiated with UV-light for 300 sec, its abilities to infect chicken eggs and induce IFN were diminished, but its HA activity was unaffected. HANA spikes exposed on L-HVJ could not induce IFN in human lymphoblastoid cell lines, although they induced IFN in mouse spleen cells. These results suggest that the induction of IFN in human lymphoblastoid cells is closely related to viral nucleic acid. Poly I: C also induced IFN in some human lymphoblastoid cell lines in which IFN production is induced by Sendai virus. The antigenic types of IFN induced by poly I: C were the same as those induced by Sendai virus. These results suggest that the antigenic type of IFN produced depends on the nature of the IFN producer cells rather than on the kind of IFN inducer.

Animals↗

PubMed2003

Role of Stat5 in type I interferon-signaling and transcriptional regulation.

Type I interferons are pleiotropic cytokines that transduce signals via activation of multiple downstream signaling cascades, including the Jak-Stat pathway. Although the roles of Stat1 and Stat2 in Type I interferon signaling are well established, the roles that other Stat-family members play in the induction of IFN-responses remain to be defined. In previous studies, we have shown that Stat5 associates with the CrkL adapter and forms a signaling complex that binds DNA. In the present study, we provide evidence that Stat5 is phosphorylated on serines 725/730 in an IFNalpha- and IFNbeta-dependent manner, providing direct evidence that serine phosphorylation of the protein is a component of an interferon signaling cascade. Such serine phosphorylation of Stat5 is Map kinase- and PI 3(')-kinase independent, while the activation of the serine kinase that phosphorylates Stat5 is regulated by upstream tyrosine kinase activity. Using mouse embryonic fibroblasts with targeted disruption of the Stat5a and Stat5b genes, we demonstrate that full activation of Stat5 is required for Type I interferon-dependent gene transcription via GAS elements. Altogether, our data provide evidence that Stat5 plays an important role in IFN-signaling and participates in the induction of Type I IFN-dependent responses. Furthermore, our results strongly suggest that, in addition to phosphorylation on tyrosine residues, phosphorylation on serine residues exhibits regulatory effects on the transcriptional capacity of Stat5.

Animals↗

PubMedDate not supplied

Studies on the capacity of human tonsillar lymphocyte subpopulations to produce interferon.

Tonsillar lymphocytes produced classical interferon (Type I) in response to NDV infection and produced immune interferon (Type II) in response to PHA, PPD or histo-incompatible antigens. Lymphocytes having higher specific gravity and having a greater proliferative response to mitogens or antigens produced more interferon than lymphocytes having lower specific gravity. There was no difference between heavy and light small tonsillar lymphocytes in regard to their sensitivity to the protective effects of interferon. As for the interferon produced in association with a cellular immune response, the peak of interferon production tended to appear earlier than the peak of 3H-TdR incorporation. It is suggested that tonsillar lymphocytes play an important role in human host defense against virus infections.

Animals↗

PubMed2001

Experimental reproduction of winter dysentery in lactating cows using BCV -- comparison with BCV infection in milk-fed calves.

Infection models were developed for adult cows and for young calves using the same strain of bovine coronavirus (BCV), which for the first time allows experimental reproduction of winter dysentery (WD) in seronegative lactating cows. The cattle were infected through direct contact with an experimentally inoculated calf. All experimental cattle shed faecal BCV with development of diarrhoea, being profusely watery with small amounts of blood in the most severely affected animals, including both cows and calves. The cows, in contrast to the calves, showed depressed general condition and appetite leading to a marked decrease in milk yield. Further age-associated differences were a shorter incubation period in the two youngest calves, but with milder fever and milder decrease in white blood cell counts. These findings shed light on the apparent epidemiological differences between WD and calf BCV diarrhoea suggesting that, (1) the same strains of BCV cause natural outbreaks of calf diarrhoea and WD, (2) seronegative cows are more severely affected by the infection than seronegative conventionally reared calves, and (3) unaffected general condition in diarrhoeic calves may lead to underestimation of the occurrence of calf diarrhoea in WD outbreaks. In response to infection, all cattle produced early interferon type 1 in serum and, except for one calf, in nasal secretions. A finding not previously reported is the detection of interferon type 1 responses in bovine milk. All cattle developed high IgM antibody responses and long-lasting IgA antibody responses both systemically and locally. The serum IgM antibody responses came earlier in most of the calves than in the cows. Prolonged IgM antibody responses were detected in serum and milk, while those in nasal secretions were much shorter. BCV-specific IgA was present in nasal secretions from all cattle throughout the 6 months follow-up. The IgA antibody response in serum was detected up to 17 months post-infection and the duration showed an age-related variation indicating a more prominent IgA memory in the adult cattle and in the older calves than in the younger ones. BCV-specific IgG was detected in all cattle during the experimental period of up to 22 months. In conclusion, WD was reproduced in seronegative lactating cows. The cows showed a more severe general diseases than seronegative calves infected concurrently. Very long-lasting IgA antibody responses were detected both systemically and locally.

Age Factors↗

PubMed1986

Interferon-induced gene expression in wild-type and interferon-resistant human lymphoblastoid (Daudi) cells.

Interferon-induced gene expression was analyzed in wild-type and interferon-resistant Daudi cells. Two classes of alpha-interferon-induced mRNAs and proteins were observed: those that were similarly induced in both types of cell and those that were induced only in the wild-type cells. Furthermore, the level of c-myc mRNA decreased in the wild-type but not in the resistant cells. This differential control in the wild-type and resistant cells indicates that there must be either functionally distinct alpha-interferon receptors or more than one pathway leading to altered gene expression triggered by a single receptor.

Cell Division↗

PubMed1989

The influence of interferon alpha and gamma, singly or in combination on human natural cell mediated cytotoxicity.

The influence of interferon alpha and gamma alone or in combination on the augmentation of human natural cytotoxicity was studied. Treatment of peripheral blood lymphocytes with IFN- alpha led to a rapid augmentation of NK activity, in contrast to IFN-gamma where target cell killing was observed only following 18 hrs exposure of lymphocytes to IFN-gamma. The results of the single cell assay paralleled those obtained using the Chromium release test, but neither interferon type caused an increase in the number of target binding lymphocytes. The combined effect of IFN-alpha and IFN-gamma in stimulating human natural cytotoxicity demonstrated individual lymphocyte responses to be variable. Exposure of lymphocytes to IFN-alpha and IFN-gamma for 18 hrs prior to assay for cytotoxicity usually decreased the level of cytotoxicity compared with control values, whereas other treatment regimes gave an additive and sometimes synergistic effect. Only treatment with IFN-alpha for 18 hrs and IFN-gamma for one hr produced a synergistic response in the majority of individuals tested. We conclude from this study that individual responses to IFN-alpha and IFN-gamma alone or in combination are variable and dependent upon timing of exposure of lymphocytes to individual interferon types, and possibly reflects the donor status at the time of sampling.

Cytotoxicity, Immunologic↗

PubMed1983

Interferon with novel characteristics produced by human mononuclear leukocytes.

Treatment of human peripheral blood mononuclear leukocytes with phytohaemmaglutinin and the tumour promoter teleocidin, results in the production of large amounts of interferon-gamma and significant amounts of a novel interferon-like substance which we tentatively class as interferon-delta. This novel interferon type possesses all the important characteristics of classical interferon but, of various cell types tested, has antiviral activity only in trisomy-21 human fibroblasts. It differs decisively from previously identified interferon types in its antigenic, biological and physicochemical properties.

Animals↗