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At least 685 records · Page 38Linked to original sources
PubMed2001

An essential role for Daxx in the inhibition of B lymphopoiesis by type I interferons.

Interferon-alpha and -beta inhibit the interleukin-7-mediated growth and survival of T and B lymphoid progenitors via an unknown, STAT1-independent pathway. Gene expression profile analysis of interferon-beta-treated progenitor B cells revealed enhanced Daxx expression, with concomitant Daxx protein increase and nuclear body translocation. The interferon effects included downregulation of cell cycle regulating genes and cell cycle arrest, followed by Bcl-2 downregulation and apoptosis. Daxx antisense oligonucleotides rescued the interferon-treated pro-B cells from growth arrest and apoptosis in parallel with the reduction of nuclear Daxx. These findings implicate the gene repressor function of Daxx in interferon-induced apoptosis of lymphoid progenitors.

3T3 Cells↗
PubMed2000

Therapeutic potential for orally administered type 1 interferons.

Interferons (IFNs), with annual global sales valued at more than US$4 billion, have therapeutic value in the treatment of viral, neoplastic and autoimmune diseases. Parenteral administration by high-dose injection can, however, cause serious side effects. Significant improvement in the therapeutic index of IFNs could be achieved with oral administration. Using this route, dose-related side effects are not seen, and efficacy is maintained in both animal studies and human clinical trials. Oral IFN administration appears to mimic a natural innate immune response. As such, it may represent an alternative delivery strategy to make better use of these critical cytokines.

Journal Article↗
PubMed2002

Discovery of 8-hydroxyadenines as a novel type of interferon inducer.

9-Benzyl-8-hydroxyadenine (6) was found to possess interferon-inducing activity in vitro as a lead compound. Although replacement of the 9-benzyl group of 6 did not improve the activity, the introduction of a substituent such as alkyl, alkylthio, alkylamino, and alkoxy groups into the 2-position of the adenine ring resulted in a remarkable increase in the activity. The 2-alkylthio (30-32), 2-butylamino (41), and 2-butoxy (47) analogues indicated the highest activities by oral administration to mice.

Adenine↗
PubMed1989

Induction of class I major histocompatibility complex antigen expression by West Nile virus on gamma interferon-refractory early murine trophoblast cells.

Primary murine trophoblast giant cells (TGC) do not express detectable major histocompatibility complex (MHC) antigens and are refractory to the MHC-increasing effects of alpha and beta (virus-induced) interferons and gamma (immune type) interferon during early implantation (postcoital days 3.5-6). West Nile virus infection of primary TGC monolayers from postcoital-day-3.5 preimplantation blastocysts induced paternal MHC antigen expression within 16 hr, as detected by immunogold labeling for electron microscopy. Induction is unlikely to have been mediated by secreted virus-induced interferons or other factors, as it occurred in the presence of high concentrations of anti-alpha/beta interferon antibodies and was not induced by virus-inactivated supernatants from MHC-induced primary TGC cultures. Attempts to induce MHC antigen expression with poly(I.C) or recombinant tumor necrosis factor alpha in primary TGC cultures also failed. Thus, the apparent inhibition of MHC antigen expression in primary TGC during early implantation and their refractoriness to induction of de novo MHC antigen expression is not absolute. This may represent a maternal-and/or species-protective evolutionary device. As such, manipulation of this phenomenon may allow a conclusive assessment of the significance of inhibition of MHC antigen expression on trophoblast cells in the implanting semiallogeneic embryo.

Animals↗
PubMed1998

Induction of the pro-myelocytic leukaemia gene by type I and type II interferons.

The physiological role of the pro-myelocytic leukaemia (PML) gene product is poorly defined. Among other functions, PML is involved in haematopoietic differentiation and in control of cell growth and tumorigenesis. We investigated the regulation of human PML expression by interferons (IFNs) and IL-1 in various human haematopoietic lines (U937, THP1, HL60, NB4), in human diploid fibroblasts and in human peripheral blood leukocytes. Cytokine-induced modulation of PML expression was assessed by Northern blot analyses, flow cytometry studies and in situ immunolabelling. Our data show that IFNs and IL-1 upregulate PML transcript and protein expression in a time and dose-dependent manner. In situ immunolabelling revealed that upregulation of protein expression by IFN-alpha is a consequence of a marked increase in both the number and the intensity of the staining of so-called PML nuclear bodies. Our data suggest that stimulation of PML expression by interferons and IL-1 may account for upregulation of PML proteins observed in inflammatory tissues and in proliferative states.

Cell Nucleus↗
PubMed1999

The type I interferon receptor: structure, function, and evolution of a family business.

Recent results indicate that coherent models of how multiple interferons (IFN) are recognized and signal selectively through a common receptor are now feasible. A proposal is made that the IFN receptor, with its subunits IFNAR-1 and IFNAR-2, presents two separate ligand binding sites, and this double structure is both necessary and sufficient to ensure that the different IFN are recognized and can act selectively. The key feature is the duplication of the extracellular domain of the IFNAR-1 subunit and the configurational geometry that this imposes on the intracellular domains of the receptor subunits and their associated tyrosine kinases.

Amino Acid Sequence↗
PubMed1998

Prolonged allograft survival in cynomolgus monkeys treated with a monoclonal antibody to the human type I interferon receptor and low doses of cyclosporine.

A monoclonal antibody (mAb) directed against the extracellular domain of the IFNAR1 chain of the human interferon-alpha (IFN-alpha) receptor (IFN-alphaR), which inhibits activation of the Jak-Stat signal transduction pathway, administered together with a subeffective dose of cyclosporine induced prolonged survival of skin allografts in major histocompatibility complex (MHC) divergent cynomolgus monkeys. Skin biopsies from animals treated with anti-IFN-alphaR mAb and cyclosporine revealed very low levels of MHC class I and class II antigen expression and the absence of histologic signs of rejection. Monkey antibodies (IgG) to the mouse antihuman IFN-alphaR mAb were not detected in the serum of any of the animals treated with the anti-IFN-alphaR mAb either alone or together with cyclosporine. The anti-IFN-alphaR mAb abrogated activation of the Jak-Stat signal transduction pathway in IFN-treated cells. These results, which show that selective and long-lasting immunosuppression can be obtained by short-term administration of an IFN-alpha antagonist together with a subeffective dose of cyclosporine, may have important implications for the therapy of human allograft rejection.

Animals↗
PubMed1997

A protein-arginine methyltransferase binds to the intracytoplasmic domain of the IFNAR1 chain in the type I interferon receptor.

The intracytoplasmic domain (IC) of cytokine receptors provides docking sites for proteins which mediate signal transduction. Thus, in interferon-alpha,beta receptors (IFNAR1 and 2), the IC region binds protein-tyrosine and -serine/threonine kinases which phosphorylate the receptor and the associated Stat transcription factors. A two-hybrid screening was carried out to identify additional proteins which could interact with the IC domain of the IFNAR1 chain of the IFN-alpha,beta receptor. Several positive clones representing a protein sequence designated IR1B4 were recovered from a human cDNA library. IR1B4 was identified as the human homolog of PRMT1, a protein-arginine methyltransferase from rat cells. Flag-IR1B4 fusion proteins bind to the isolated IFNAR1 intracytoplasmic domain produced in Escherichia coli, as well as to the intact IFNAR1 chain extracted by detergent from human U266 cell membranes. S-Adenosylmethionine-dependent methyltransferase activity was precipitated by anti-IFNAR1 antibodies from untreated human cells. IR1B4/PRMT1 is involved in IFN action since U266 cells rendered deficient in this methyltransferase by antisense oligonucleotides become more resistant to growth inhibition by IFN. Methylation of proteins by enzymes which can attach to the IC domains of receptors may be a signaling mechanism complementing protein phosphorylation. Among substrates methylated by PRMT1 are RNA-binding heterogeneous nuclear ribonucleoproteins (hnRNPs) which are involved in mRNA processing, splicing and transport into the cytoplasm.

Animals↗
PubMed1992

Type I interferons inhibit hepatitis B virus replication and induce hepatocellular gene expression in cultured liver cells.

A hepatoblastoma cell line transfected with hepatitis B virus (HBV) DNA (Hep G2.2.15) was used to investigate the effects of interferons (IFNs) on HBV replication and hepatocellular gene expression. IFN-alpha 2b or -beta inhibited HBV replication transiently. In parallel, there was a decrease in the amount of HBV mRNA. Hepatitis B surface antigen and early antigen secretion were not influenced; however, their intracellular levels diminished during treatment. The cellular 2',5'-oligoadenylate synthetase activity was increased 9- to 18-fold during treatment of cells with IFN-gamma, -alpha, or -beta. The number of IFN-alpha and -beta receptors was down-regulated, while the number of IFN-gamma receptors remained constant. The expression of major histocompatibility complex class I antigens was stimulated by addition of IFN-alpha or -beta. These data show that both IFN-alpha and -beta can effectively inhibit HBV replication and induce a cellular IFN response in Hep G2.2.15 cells similar to that seen in humans.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Transcriptional activation of human (2'-5')oligoadenylate synthetase gene expression by the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate in type-I-interferon-treated HL-60 and HeLa cells.

(2'-5')Oligoadenylate [(2'-5')(A)n] synthetase is a key enzyme in the interferon-elicited antiviral response whose controlled expression in interferon-treated cells has been only partially elucidated. In this investigation, we have compared the modulation of the (2'-5')(A)n synthetase gene by interferon alone and by the combination of interferon and a second cellular effector, 12-O-tetradecanoyl-phorbol 13-acetate (TPA). Although TPA alone had no effect on (2'-5')(A)n synthetase, it potentiated the induction of (2'-5')(A)n of synthetase by interferon in HL-60 and HeLa cells by increasing content of its mRNA and an immunoreactive 40-kDa isoenzyme. Since TPA activates protein kinase C (PKC), other PKC-activating phorbol-ester analogues were tested and found to be effective, whereas the PKC inhibitor staurosporine reduced the potentiative activity of TPA. By using the (2'-5')(A)n synthetase gene promoter linked to a reporter gene, chloramphenicol acetyltransferase (CAT), TPA and interferon were found to result in a doubling of CAT activity compared to cells treated with interferon alone. Moreover, when nuclear extracts prepared from control cells or cells treated with TPA and interferon (IFN), separately or together, were incubated with radioactively labeled oligodeoxynucleotides containing the interferon-responsive element (IRE), TPA was shown to down-regulate an IFN-inducible IRE/protein complex. These data further suggest that TPA regulates (2'-5')(A)n synthetase gene expression at the level of transcription.

2',5'-Oligoadenylate Synthetase↗
PubMed1980

At least three human type alpha interferons: structure of alpha 2.

The sequence of a human leukocyte-derived complementary DNA (cDNA), Hif-2h, which directs the formation in Escherichia coli of a polypeptide, IFN-alpha 1, with interferon (IFN) activity has been described. A second IFN cDNA, Hif-SN206, which also elicits synthesis of a biologically active IFN, IFN-alpha 2, is described in this article. Whereas IFN-alpha 2 is twice as active on human as on bovine cells, IFN-alpha 1 is 10 to 20 times more active on bovine than on human cells. As deduced from the cDNA's, the messenger RNA's for the two IFN's differ in length and in 20 percent of the nucleotides; the mature IFN polypeptides differ in 17 percent of the amino acids. Both IFN-alpha 1 and IFN-alpha 2 differ from the lymphoblastoid IFN described by others. Therefore, at least three different IFN-alpha genes are expressed in man; studies on genomic DNA reveal the presence of at least eight IFN-related genes.

Amino Acid Sequence↗
PubMed2000

Cocaine causes increased type I interferon secretion by both L929 cells and murine macrophages.

Cocaine has been demonstrated to have a number of different effects on immune cell functions. We have reported alterations of cellular functions by macrophages (Mphi) exposed to cocaine in vitro, including the inhibition of mouse hepatitis virus replication. Here, we present evidence that cocaine stimulates the secretion of an antiviral product that is neutralized by anti-interferon (anti-IFN). A dose-dependent increase in the secretion of IFN by both Mphi and L929 cells incubated with cocaine, with a concomitant decrease in virus replication, is also reported. The increase in IFN secretion was most pronounced when cells were cultured in the presence of the IFN inducer poly(I.C). The effect of cocaine on IFN production was found to be primarily at the transcript level in both Mphi and L929 cells. These findings further support our previous research demonstrating an antiviral activity of cocaine in vitro. The relevance of this activity to viral infections in general remains to be determined.

Animals↗