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PubMed1985

NK-cell stimulating properties of a membrane proteoglycane from non-capsulated Klebsiella pneumoniae biotype a.

Upon testing the individual fractions of a composite bacterial vaccine for biological activities, a potent immuno-stimulatory capacity could be demonstrated within a crude membrane proteoglycan preparation from Klebsiella pneumoniae. One of its characteristic features was the capacity to induce alpha-type interferon and increased NK activity in vivo in mice, following intraperitoneal or oral administration. A highly purified fraction from the crude preparation was obtained using alkaline hydrolysis, delipidation and size fractionation. This fraction was shown to be a very potent inducer of NK cells in vivo or in vitro, where in the latter systems concentrations as low as 0.1 microgramme per ml were highly efficient.

Adjuvants, Immunologic↗

PubMed1981

Natural interferon-producing cells in mice.

When mouse lymphoid cells derived from untreated C57BL/6 mice were cocultivated in liquid cultures with L-cell monolayers for 3 h, overlaid with soft agar, and then further incubated for 12 h, protected foci of L cells against vesicular stomatitis virus infection were formed. Many strains of mice have been found to have the protected focus-forming cells on the L-cell monolayers. The formation of the protected foci was completely suppressed by addition of cycloheximide into soft agar. When anti-interferon (type I) antiserum was added to soft agar, there was a decrease in focus counts of about 80%. These experimental results indicated that the formation of protected foci by untreated mouse lymphoid cells was mediated for the most part by type I interferon that was produced without addition of special inducer. We have designated these focus-forming cells as natural interferon-producing cells (NIPC). NIPC belong to the glass-adherent fraction, and Thy-1 antigen, immunoglobulin, and Ia antigen could not be detected on the surface of the NIPC. NIPC were detected in congenitally athymic nude mice. These findings suggest that NIPC belong to the Ia-negative macrophages. Mouse lymphoid cells obtained from germfree mice could form the protected foci on L-cell monolayers and could produce interferon without the addition of a special inducer. NIPC are considered to be a cellular background for spontaneous interferon production.

Animals↗

PubMed1985

[Multidisciplinary therapy of urogenital cancer].

At present there is no effective chemotherapeutic agent for the treatment of renal carcinoma. In Japan there have been reports concerning group studies employing alpha and beta-type interferon (IFN) with effective results of being obtained. The treatment of advanced renal cell carcinoma is exceptionally difficult but Kato and his co-workers at Akita university have achieved good results with a chemo-embolization method employing MMC-mc. In cases of bladder cancer, there have been several reports in the international and Japanese reports concerning the relationship between prognosis and the loss of ABO blood antigens on the cellular membrane. We consider that, in it's negative cases, aggressive multidisciplinary treatment is necessary even in early stage cases. The treatment of prostate cancer is primarily based on hormone treatment but in cases of recurrence or hormone resistant cases chemotherapy including adriamycin, cyclophosphamide and cis-platin is employed but complete response is difficult to obtain. Therefore the problem is how to control such cases for as long as possible.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1984

Natural human interferon-gamma. Complete amino acid sequence and determination of sites of glycosylation.

Fresh human peripheral blood lymphocytes were induced with desacetylthymosin -alpha 1 and staphylococcal enterotoxin B. The induced gamma interferon (or IFN-gamma, immune interferon, type II interferon) was purified to homogeneity utilizing controlled-pore glass, concanavalin A-Sepharose, Bio-Gel P100, or Sephacryl S-200, and reversed phase high performance liquid chromatography. This procedure resulted in two active species with apparent Mr = 20,000 and 25,000 as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Both species were found to have identical amino acid sequences with a pyroglutamate residue as NH2-terminus. In both cases six different COOH termini were found. They are, at least qualitatively, identical in both species. There are two possible Asn-X-Ser/Thr glycosylation sites. Both carry carbohydrates in the Mr = 25,000 species whereas in the Mr = 20,000 species only one site is glycosylated. This likely explains the difference in apparent molecular weight between the two species and the expected molecular weight based upon the amino acid sequence.

Amino Acid Sequence↗

PubMed1993

Differential expression of distinct mRNAs for ovine trophoblast protein-1 and related sheep type I interferons.

An antiluteolytic substance secreted by the ovine conceptus and primarily responsible for maternal recognition of pregnancy is ovine trophoblast protein-1 (oTP-1), a new type I interferon (IFN). The objectives of this research were 1) to investigate whether multiple, distinct genes encode oTP-1 and other type I IFNs in the ovine genome and 2) to examine expression of oTP-1 and other IFN mRNAs during conceptus development. Genes for type I IFNs were isolated from a subgenomic library constructed from Day 25 (Day 0 = estrus) ovine conceptus high-molecular-weight DNA. Six clones were isolated and nucleotide-sequenced from -1000 to +900 (bases relative to cap site). Comparisons of inferred amino acid sequences demonstrated that four clones were distinct oTP-1 genes and that two clones, defined as o9 and o12, were related type 1 IFNs (deduced aa homology of o9 and o12 to oTP-1 was 71% and 54%, respectively). The presence of mRNAs encoded by oTP-1 and type I IFN genes was examined quantitatively via reverse transcription-polymerase chain reaction (RT-PCR) analysis of total cellular RNA (tcRNA) extracted from Day 13-45 concepti. Total cellular RNA obtained from Day 75 placenta and adult lymphocytes was also analyzed by RT-PCR, coupled with Southern blot hybridization of the PCR reaction products with specific DNA probes. PCR products were sequenced in order to confirm primer specificity, and mRNAs corresponding to two of the four oTP-1 genes and to both related IFN clones (o9 and o12) were identified. Furthermore, quantitation of the PCR products revealed that of the two oTP-1 genes examined, one was highly expressed on Days 13-20 and transcripts were weakly detectable on Days 30 and 45. In contrast, the other oTP-1 gene examined was weakly expressed on Days 13-20 only. Densitometric analysis of hybridization signals revealed that IFN o9 mRNA was detected in Day 75 placenta but only weakly detected in conceptus (Days 13-45) and adult lymphocytes. IFN o12 mRNA was abundant in lymphocytes relative to the other tissues examined. Collectively, these results demonstrate the existence of distinct oTP-1 and related type I IFN genes. The data suggest that these genes display differential, tissue-specific expression and developmental regulation during pregnancy.

Amino Acid Sequence↗

PubMed2000

Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice.

Type I interferons (IFNs) are cytokines exhibiting antiviral and antitumor effects, including multiple activities on immune cells. However, the importance of these cytokines in the early events leading to the generation of an immune response is still unclear. Here, we have investigated the effects of type I IFNs on freshly isolated granulocyte/macrophage colony-stimulating factor (GM-CSF)-treated human monocytes in terms of dendritic cell (DC) differentiation and activity in vitro and in severe combined immunodeficiency mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID) mice. Type I IFNs induced a surprisingly rapid maturation of monocytes into short-lived tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-expressing DCs endowed with potent functional activities, superior with respect to the interleukin (IL)-4/GM-CSF treatment, as shown by FACS((R)) analyses, mixed leukocyte reaction assays with allogeneic PBLs, and lymphocyte proliferation responses to HIV-1-pulsed autologous DCs. Type I IFN induced IL-15 production and strongly promoted a T helper cell type 1 response. Notably, injection of IFN-treated HIV-1-pulsed DCs in SCID mice reconstituted with autologous PBLs resulted in the generation of a potent primary immune response, as evaluated by the detection of human antibodies to various HIV-1 antigens. These results provide a rationale for using type I IFNs as vaccine adjuvants and support the concept that a natural alliance between these cytokines and monocytes/DCs represents an important early mechanism for connecting innate and adaptive immunity.

Adjuvants, Immunologic↗

PubMed2006

Promoters of type I interferon genes from Atlantic salmon contain two main regulatory regions.

Recognition of viral nucleic acids by vertebrate host cells results in the synthesis and secretion of type I interferons (IFN-alpha/beta), which induce an antiviral state in neighboring cells. We have cloned the genes and promoters of two type I IFNs from Atlantic salmon. Both genes have the potential to encode IFN transcripts with either a short or a long 5'-untranslated region, apparently controlled by two distinct promoter regions, PR-I and PR-II, respectively. PR-I is located within 116 nucleotides upstream of the short transcript and contains a TATA-box, two interferon regulatory factor (IRF)-binding motifs, and a putative nuclear factor kappa B (NFkappaB)-binding motif. PR-II is located 469-677 nucleotides upstream of the short transcript and contains three or four IRF-binding motifs and a putative ATF-2/c-Jun element. Complete and truncated versions of the promoters were cloned in front of a luciferase reporter gene and analyzed for promoter activity in salmonid cells. Constructs containing PR-I were highly induced after treatment with the dsRNA poly(I:C), and promoter activity appeared to be dependent on NFkappaB. In contrast, constructs containing exclusively PR-II showed poor poly(I:C)-inducible activity. PR-I is thus the main control region for IFN-alpha/beta synthesis in salmon. Two pathogenic RNA viruses, infectious pancreatic necrosis virus and infectious salmon anemia virus, were tested for their ability to stimulate the minimal PR-I, but only the latter was able to induce promoter activity. The established IFN promoter-luciferase assay will be useful in studies of host-virus interactions in Atlantic salmon, as many viruses are known to encode proteins that prevent IFN synthesis by inhibition of promoter activation.

Animals↗

PubMed2005

Type I interferons as regulators of the differentiation/activation of human dendritic cells: methods for the evaluation of IFN-induced effects.

Recent studies have revealed that type I interferons (IFNs) are powerful inducers of the differentiation and activation of dendritic cells (DCs). These findings emphasize the importance of these cytokines in linking innate and adaptive immunity, suggesting that effects of type I IFN on DCs can play a role in the antitumor and antiviral activity observed in some IFN-treated patients. Thus, the evaluation of the effects of IFN on the differentiation/activation of DCs has become an important approach for testing novel biologically important IFN activities, and the description of some reference methods are urgently needed. In this chapter, we describe some methods for testing the effects of IFNs on the differentiation and activation of human DCs from the peripheral blood monocytes and for the characterization of the DCs generated after IFN treatment.

Animals↗

PubMed2006

Determination of the human type I interferon receptor binding site on human interferon-alpha2 by cross saturation and an NMR-based model of the complex.

Type I interferons (IFNs) are a family of homologous helical cytokines that exhibit pleiotropic effects on a wide variety of cell types, including antiviral activity and antibacterial, antiprozoal, immunomodulatory, and cell growth regulatory functions. Consequently, IFNs are the human proteins most widely used in the treatment of several kinds of cancer, hepatitis C, and multiple sclerosis. All type I IFNs bind to a cell surface receptor consisting of two subunits, IFNAR1 and IFNAR2, associating upon binding of interferon. The structure of the extracellular domain of IFNAR2 (R2-EC) was solved recently. Here we study the complex and the binding interface of IFNalpha2 with R2-EC using multidimensional NMR techniques. NMR shows that IFNalpha2 does not undergo significant structural changes upon binding to its receptor, suggesting a lock-and-key mechanism for binding. Cross saturation experiments were used to determine the receptor binding site upon IFNalpha2. The NMR data and previously published mutagenesis data were used to derive a docking model of the complex with an RMSD of 1 Angstrom, and its well-defined orientation between IFNalpha2 and R2-EC and the structural quality greatly improve upon previously suggested models. The relative ligand-receptor orientation is believed to be important for interferon signaling and possibly one of the parameters that distinguish the different IFN I subtypes. This structural information provides important insight into interferon signaling processes and may allow improvement in the development of therapeutically used IFNs and IFN-like molecules.

Amino Acid Sequence↗

PubMed2005

Specialization, kinetics, and repertoire of type 1 interferon responses by human plasmacytoid predendritic cells.

Recent studies suggest plasmacytoid predendritic cells (pDCs) and myeloid dendritic cells (mDCs) have the functional plasticity to produce similar amounts of type 1 interferons (IFNs) and interleukin-12 (IL-12), challenging the concept and existence of DC subsets with distinct function. In this study, we demonstrate that previous studies showed human pDCs produce large amounts of IL-12 because of contaminating mDCs. Using highly purified human DC subsets, we found that although pDCs make 300 times more IFN-alpha than mDCs and mDCs make 13 times more IL-12 p70 than pDCs in response to all the toll-like receptor ligands and CD40 ligands, pDCs rapidly make large amounts of IFN-alpha within the first 12 hours of activation and become refractory to further stimulation. pDCs preferentially expressed the transcriptional factors critical for type 1 IFN, but not for IL-12 transcription, and they dedicated 60% of new transcriptional activity to make 19 type 1 IFN subtypes. This study provides formal proof that the plasticity of DC subsets is limited and that different DC subsets evolve to perform distinct functions in linking innate and adaptive immunity.

CD40 Ligand↗

PubMed2004

Effectiveness of Type I interferons in the treatment of multidrug resistant osteosarcoma cells.

P-glycoprotein overexpression is an important adverse prognostic marker for osteosarcoma (OS) patients, which is associated with higher risk for developing metastases as a consequence of the limited responsiveness to standard treatments of P-glycoprotein overexpressing OS cells. The use of cytokines has been advocated as a possible therapeutic approach to overcome multidrug resistance (MDR), being active on cell lines that are resistant to conventional drugs. In this study, we evaluated in vitro effects of interferons (IFNs) on MDR P-glycoprotein overexpressing OS cells. Type I IFNs, but not IFNgamma, showed tangible inhibitory effects on OS cell growth, which were higher in MDR cell lines compared to parental cells. The higher sensitivity of P-glycoprotein overexpressing cells to Type I IFNs correlates with higher expression of the activator of the transcription (STAT)-2 and (STAT)-3, two intracellular mediators of the IFNalpha and IFNbeta signaling pathways, whereas no differences were observed with respect to the expression or activation of the Type I IFN receptor and STAT-1. Exposure of OS MDR cells to Type I IFN decreased the expression of P-glycoprotein. This effect resulted in a significantly increased chemosensitivity of MDR cells to doxorubicin. Therefore, our data support the use of IFNalpha or IFNbeta in the treatment of osteosarcoma patients who overexpress P-glycoprotein in their primary tumors, and respond insufficiently to current therapeutic regimens.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Cationic liposome-mediated efficient induction of type I interferons by a low dose of poly I:poly C in mouse cell lines.

Double-stranded polyriboinosinic acid:polyribocytidylic acid (poly I:poly C) is a powerful inducer of type I interferons (IFNs). However, the dose of poly I:poly C required for efficient IFN induction is so high as occasionally to be cytotoxic. In this work, we examined the IFN-inducibility of poly I:poly C complexed with several cationic reagents in mouse fibroblast L cells and found that Lipofectin and LipofectACE can induce the production of a substantial amount of type I IFNs (mostly beta-type) even at a two-order lower dose compared with poly I:poly C alone. Such effects of poly I:poly C were optimal at 0.1 microgram/ml for 2-10 microgram/ml of Lipofectin and LipofectACE. These conditions caused no significant cytotoxicity in the recipient cells. Furthermore, a short treatment (less than 10 min) with the complexes was sufficient for the maximum induction. This IFN induction method was applicable to other cell types and other species including human. Hence, our observations may pave the way for clinical application of the IFN inducer.

Animals↗

PubMed2005

Functional cartography of the ectodomain of the type I interferon receptor subunit ifnar1.

Ligand-induced cross-linking of the type I interferon (IFN) receptor subunits ifnar1 and ifnar2 induces a pleiotrophic cellular response. Several studies have suggested differential signal activation by flexible recruitment of the accessory receptor subunit ifnar1. We have characterized the roles of the four Ig-like sub-domains (SDs) of the extracellular domain of ifnar1 (ifnar1-EC) for ligand recognition and receptor assembling. Various sub-fragments of ifnar1-EC were expressed in insect cells and purified to homogeneity. Solid phase binding assays with the ligands IFN(alpha)2 and IFN(beta) revealed that all three N-terminal SDs were required and sufficient for ligand binding, and that IFN(alpha)2 and IFN(beta) compete for this binding site. Cellular binding assays with different fragments, however, highlighted the key role of the membrane-proximal SD for the formation of an in situ IFN-receptor complex. Even substitution with the corresponding SD from homologous cytokine receptors did not restore high-affinity ligand binding. Receptor assembling analysis on supported lipid bilayers in vitro revealed that the membrane-proximal SD controls appropriate orientation of the receptor on the membrane, which is required for efficient association of ifnar1 into the ternary complex.

Amino Acid Sequence↗

PubMed2026

Trimethylamine-producing microbe Bacillus megaterium KCTC 3007 promotes antitumor immunity in endometrial cancer via type I interferon response pathways.

BACKGROUND: Endometrial cancer (ECa) is one of the most common gynecologic malignancies, with limited therapeutic responses in metastatic or recurrent cases. The bacterial microbiota has emerged as a key modulator of carcinogenesis and antitumor immunity. However, the role of endometrial microbiota in ECa pathogenesis and prognosis remains poorly understood. METHODS: We performed comprehensive multi-omics analysis integrating metatranscriptomics, transcriptomics, and targeted metabolomics from 60 ECa and 18 benign patients. RNA sequencing enabled simultaneous profiling of active tissue-resident microbiota and host gene expression. Serum metabolomics was conducted on all patients. Identified microbial-metabolite associations were validated through in vitro co-culture experiments using peripheral blood mononuclear cells (PBMCs), cancer cell lines, RNA sequencing, and live cell imaging. RESULTS: ECa patients exhibited significantly altered microbial diversity and composition compared to benign controls. Through integrated multi-omics analysis, we identified Bacillus megaterium (BM) KCTC 3007 as a beneficial microbe associated with prolonged recurrence-free survival. In an exploratory analysis of ECa subtypes, Cupriavidus taiwanensis and Marinomonas primoryensis showed potential links to poor prognosis, although these observations warrant caution due to the limited size of certain subgroups. Tissue BM abundance positively correlated with serum trimethylamine N-oxide (TMAO) levels, particularly in postmenopausal women. In vitro experiments demonstrated that BM KCTC 3007 enhanced antitumor immunity by promoting interleukin and type I interferon expression, expanding CD8 + T cell populations, and increasing immune cell-tumor cell interactions. RNA sequencing revealed activation of interferon alpha response and immune cell proliferation pathways, with IFNAR1 identified as a key upstream regulator. TMAO treatment recapitulated these immune-activating effects, enhancing CD8 + T cell responses and preferentially inducing pyroptotic cancer cell death. CONCLUSIONS: We provide the first evidence that tissue-resident BM KCTC 3007 promotes antitumor immunity in ECa through TMAO production and subsequent type I interferon-mediated immune activation. This integrated multi-omics approach establishes a complete microbe-metabolite-host mechanistic pathway and highlights the therapeutic potential of TMAO-producing probiotic strains for ECa treatment. Video Abstract.

Female↗

PubMed1999

Type I interferons (IFNs) regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on human T cells: A novel mechanism for the antitumor effects of type I IFNs.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a proapoptotic member of the TNF family of type II membrane proteins, which constitutes one component of T cell cytotoxicity. In this study, we investigated the expression and function of TRAIL in human peripheral blood T (PBT) cells. Although freshly isolated PBT cells did not express a detectable level of TRAIL on their surface, a remarkable TRAIL expression was rapidly induced on the surface of both CD4(+) and CD8(+) PBT cells upon stimulation with anti-CD3 monoclonal antibody and type I interferons (IFNs). This enhancement of TRAIL expression was a unique feature of type I IFNs (IFN-alpha and IFN-beta), and neither type II IFN (IFN-gamma) nor various other cytokines enhanced TRAIL expression on anti-CD3-stimulated PBT cells. Type I IFNs have been used for clinical treatment of renal cell carcinomas (RCCs), and we found that most RCC cell lines were susceptible to TRAIL-induced apoptosis. Type I IFNs substantially augmented cytotoxic activity of anti-CD3-stimulated PBT cells against RCC cell lines in a TRAIL-dependent manner. These results indicate a unique feature of type I IFNs to regulate TRAIL-mediated T cell cytotoxicity, which may be involved in the antitumor effects of type I IFNs against various tumors.

Antineoplastic Agents↗

PubMed1999

Involvement of receptor-bound protein methyltransferase PRMT1 in antiviral and antiproliferative effects of type I interferons.

Protein arginine N-methyltransferase (PRMT1) is one of the proteins that bind to the intracytoplasmatic domain of the IFNAR-1 chain of the type I interferon (IFN) receptor system. The attachment is specific and is not seen with PRMT2, another member of this protein family. Antisense PRMT1 cDNA constructs expressed under the early cytomegalovirus (CMV) promoter were transfected into HeLa cells, and stable transformants were selected. Antibodies to PRMT1 were used to identify clones with reduced PRMT1 expression. In such clones, IFN-beta inhibited three to five times less the replication of vesicular stomatitis virus (VSV) than in the original HeLa cells. The antiproliferative effect of IFN-beta was also reduced up to fivefold in the clones with low PRMT1 expression. No difference was seen when IFN-gamma was used alone to inhibit cell growth. The protein methylating enzyme, bound to IFNAR-1, appears to regulate positively the biologic activity of type I IFN.

Antisense Elements (Genetics)↗

PubMed2005

Type I interferon correlates with serological and clinical manifestations of SLE.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems triggered by the production of autoantibodies. Previous clinical studies in humans and murine models suggest that type I interferons (IFNs) are important for the initiation and potentiation of SLE activity. METHODS: 65 consecutive patients with SLE were identified from the University of California, San Francisco Lupus Clinic with moderate-severe disease activity. 94 serological samples were collected. Type I IFN levels and the ability of plasma to induce expression of several surface markers of dendritic cell maturation were measured. RESULTS: Type I IFN levels correlated with the presence of cutaneous manifestations, and there was a trend towards correlation with renal disease. No correlation was found between type I IFN levels and neurological disease. Type I IFN levels correlated positively with the SLEDAI score and anti-dsDNA levels and inversely with C3 levels. Interestingly, type I IFN levels were highest in African American patients. SLE plasma also induced the expression of MHC class I, CD38, and CD123 on monocytes, and was blocked by the addition of a monoclonal antibody to IFNAR1. CONCLUSIONS: The pathogenic role of type I IFN is suggested by the induction of cell surface markers for dendritic cell maturation. The potential therapeutic utility of antibodies directed to either type I IFN or IFNAR1/IFNAR2 may be of interest in further studies.

Adult↗

PubMed1993

A novel and atypical type one interferon gene expressed by trophoblast during early pregnancy.

Low stringency screening of day 14-15 pig conceptus cDNA library using an interferon (IFN)-omega probe has led to the isolation of a novel type one (type I) IFN gene physiologically expressed by trophoblast during the period of implantation in the uterus. It encodes a 170-amino acid preprotein with two potential N-glycosylation sites and a predicted N-terminal signal peptide of 21 residues. This protein was shorter and richer in Cys residues than other type I IFNs and distantly related to all of them including IFN-tau, the trophoblast IFNs of ruminants, with amino acid identities ranging between 27 and 42%. Moreover, its antiviral activity was resistant to neutralization by antisera directed against several IFN-alpha, -beta, -omega, and -tau family members. The pig genome contained only two intronless, non-allelic loci homologous to the cDNA, one of them corresponding to the cDNA. This gene had a single transcription initiation site. Its upstream putative regulatory regions had no similarity with those of other type I IFN genes and did not display the typical clustering of short sequence motifs thought to be involved in virus inducibility but, instead, a modular structure of 30-40-base pair direct repeats. These data highlight the very atypical characteristics of this gene and its product and suggest that it represents the first member of a yet unknown family of type I IFNs present in other mammalian species according to sequence divergence analysis.

Amino Acid Sequence↗