Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “INTERFERON”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,117 records · Page 62Linked to original sources
PubMed2003

Upregulation of MHC class II, interferon-alpha and interferon-gamma receptor protein expression in HIV-associated nephropathy.

BACKGROUND: Renal cellular HIV infection has been linked to the pathogenesis of HIV-associated nephropathy (HIVAN), but mediators of its development are unknown. HIV infection is associated with disordered cytokine metabolism, and chemokine receptors are coreceptors for HIV immune cellular infection. Chemokines such as interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1) and RANTES, and interferons (IFNs) have been implicated in the progression of nephropathy. Renal major histocompatibility complex (MHC) protein expression is involved in antigen presentation and modulating tissue cellular immune responses. Their relative importance in HIVAN pathogenesis is unknown. METHODS: We measured levels of chemokines, IFN-alpha, IFN-gamma receptor and non-polymorphic MHC Class II protein by high performance capillary electrophoresis, and incubation with antibodies for quantification by chemiluminesce in renal tissue of patients with HIVAN, compared with tissue without HIV infection, in the presence and absence of nephropathy. Renal biopsy tissue protein levels were correlated with the number and type of infiltrating tissue immune cells. RESULTS: Mean renal interstitial and glomerular MCP-1, RANTES and IL-8 tissue levels were higher in patients with HIV infection compared with tissue without HIV infection, regardless of the presence of renal disease. In contrast, mean renal interstitial and glomerular non-polymorphic MHC Class II, IFN-alpha and IFN-gamma receptor protein were higher in patients with HIVAN compared with all other groups. Tissue MHC Class II and IFN-gamma receptor protein levels did not correlate with immune cellular infiltration in patients with HIV infection and renal disease. CONCLUSIONS: The data suggest an upregulated renal immune microenvironment, capable of antigen presentation, exists in HIVAN. MHC Class II proteins and IFNs, and the capacity to present antigen may be crucial in HIVAN pathogenesis.

AIDS-Associated Nephropathy↗
PubMed1998

Expression of interferon regulatory factors one and two in the ovine endometrium: effects of pregnancy and ovine interferon tau.

Availàble evidence suggests that interferon tau (IFNtau), the signal for pregnancy recognition in ruminants, suppresses transcription of the estrogen receptor (ER) gene in the endometrial lumenal epithelium (LE) and superficial glandular epithelium (sGE) to prevent oxytocin receptor (OTR) expression and pulsatile release of luteolytic prostaglandin F2alpha. The IFN regulatory factors one (IRF-1) and two (IRF-2) are transcription factors induced by type I IFNs that activate and silence gene expression, respectively. The objectives of these studies were to determine effects of pregnancy and IFNtau on expression of immunoreactive IRF-1 and IRF-2 proteins in the ovine endometrium. In study one, IRF-1 and IRF-2 were not detected in the LE or sGE of cyclic ewes. In pregnant ewes, IRF-1 expression was detected transiently in the LE and sGE only on Days 11 and 13, and IRF-2 was detected in these same epithelia on Days 13, 15, 17, and 20. In study two, 36 ewes were fitted with uterine catheters on Day 5 of the estrous cycle, and one uterine horn was double-ligated at the base. Uterine horns of each ewe received twice-daily injections of either recombinant ovine IFNtau or control proteins beginning on Day 11 until hysterectomy at 1, 3, 6, 12, 24, 48, 72, 96, or 120 h after initial injection. The IRF-1 was detected transiently in the endometrial LE and sGE only at 12 and 24 h in the uterine horn receiving IFNtau but not in those tissues receiving control proteins. The IRF-2 was expressed in the LE and sGE at 24 h and thereafter in the IFNtau-treated, but not control uterine horns. In control uterine horns, ER and OTR were first detected in the LE at 48 h and 72 h, respectively, and remained abundant thereafter. In horns receiving IFNtau, ER and OTR expression was not detected in the endometrial LE and sGE. Results suggest that IFNtau acts directly on the LE and sGE during pregnancy to sequentially induce IRF-1 and then IRF-2 gene expression, which is correlated temporally with an absence of ER and OTR. The ovine ER gene may contain an IFNtau-responsive element(s) that binds negative-acting, IFNtau-inducible transcription factors, such as IRF-2, which silences transcription of the ER gene in the endometrial epithelium during maternal recognition of pregnancy.

Animals↗
PubMed1999

Defective induction of the transcription factor interferon-stimulated gene factor-3 and interferon alpha insensitivity in human trophoblast cells.

During pregnancy, trophoblast cells of the placenta contact maternal immune cells and yet are protected from attack. One mechanism that may account for this is that trophoblasts show altered expression of major histocompatibility complex (MHC) antigens. The gene for human leukocyte antigen G (HLA-G), a nonclassical gene, is expressed at high levels in trophoblast. Unlike other MHC class I genes, the HLA-G gene lacks an interferon (IFN) response element. Moreover, we demonstrate here that IFN, which regulates classical MHC class I genes in other cell types, does not affect these genes in trophoblast, owing to inactivation of an IFNalpha signaling pathway. Trophoblast cells (JEG-3 and JAR) were found to be selectively refractory to IFN. Specifically, although IFNalpha induced the transcription factors STAT1, STAT2, and IFN regulatory factor-1, and a protective response against encephalomyocarditis virus, it failed to protect the cells from vesicular stomatitis virus, activate a transfected MHC class I gene promoter, and induce the transcription factor IFN-stimulated gene factor (ISGF)-3. The lack of ISGF3 DNA-binding activity apparently was due to diminished p48/ISGF3gamma subunit activity since ISGF3 DNA-binding activity and IFNalpha induction of MHC class I promoter activity were reconstituted by p48/ISGF3gamma supplementation. These data indicate that a specific IFN signaling pathway is inactive in JEG-3 trophoblast cells because of altered activity of p48/ISGF3gamma, and they suggest IFN insensitivity as a mechanism that may help promote feto-placental survival.

Choriocarcinoma↗
PubMed1992

Treatment of hairy cell leukemia with granulocyte colony-stimulating factor and recombinant consensus interferon or recombinant interferon-alpha-2b.

Patients with hairy cell leukemia and neutropenia (absolute neutrophil count less than 1.5 x 10(9)/L) were treated with recombinant granulocyte colony-stimulating factor (G-CSF) at doses of 3.6 and 7.2 micrograms/kg by daily subcutaneous injection, until normalization of neutrophil counts occurred. Patients then received either recombinant interferon-alpha-2b (r-IFN-alpha-2b) or a unique IFN, recombinant consensus IFN (rIFN-con-1), each given at doses of 10 micrograms/m2 subcutaneously three times a week, coupled with continued daily G-CSF therapy, for 3 months. After 3 months the G-CSF was discontinued; patients continued to take IFN for 1 year. All 10 patients responded to G-CSF with normalization of neutrophil counts within 2 weeks; the increase in neutrophil counts was greater in previously splenectomized patients. Four patients were treated with r-IFN-alpha-2b, and six were treated with rIFN-con-1. No patients developed recurrent neutropenia with the initiation of IFN therapy. Nine patients are evaluable for response to IFN. Five of six patients demonstrated hematologic improvement with rIFN-con-1, with two patients obtaining complete responses. All three patients receiving r-IFN-alpha-2b demonstrated hematologic improvement; one complete response was observed. Toxicities of both IFNs included influenza-like symptoms. We conclude that G-CSF can abrogate the myelosuppressive effects of IFN, and may be a useful adjunct to this therapy in neutropenic patients. We conclude that rIFN-con-1, the product of a synthetic gene, has activity in the treatment of hairy cell leukemia, and merits clinical investigation in other settings.

Drug Evaluation↗
PubMed1997

Xenograft rejection of porcine islet-like cell clusters in normal, interferon-gamma, and interferon-gamma receptor deficient mice.

BACKGROUND: The aim of the present study was to evaluate the role of the T-cell cytokine interferon (IFN)-gamma in mediating macrophage activation in xenograft rejection. METHODS: For this purpose, fetal porcine islet-like cell cluster (ICC) transplants were placed under the renal capsule of normal mice and mice with a homozygous targeted disruption of the IFN-gamma or the IFN-gamma receptor gene. Some of the mice were continuously infused with cyclosporine (CsA, 12.4 mg/kg body weight/day) or CsA vehicle by subcutaneously implanted osmotic pumps. Histological evaluation of the xenografts was performed 6 or 12 days after transplantation. RESULTS: All animals, irrespective of recipient group, readily rejected the ICC xenograft, although the rejection process was slightly delayed in mice deficient in IFN-gamma. Analysis of the infiltrating cells within the xenograft in knockout mice revealed a pattern similar to that found in control animals. Six days after transplantation, there was an abundant infiltration of macrophages (Mac-1, F4/80, and major histocompatibility complex II markers) in the ICC grafts. Quite in contrast, there was only a low to moderate number of T cells (CD3 marker) present in the ICC grafts. Treatment with CsA had no effect on the rejection process. In grafts removed from mice with a disruption of the IFN-gamma gene, occasional surviving endocrine cells, and in some cases also a few intact ICC, were found within the otherwise obliterated xenograft. Few or no surviving endocrine cells were found in the grafts obtained from the other groups of mice. CONCLUSIONS: Thus, the present study demonstrates that macrophage activation, and subsequent destruction of an ICC xenograft, can operate in the absence of IFN-gamma in the pig-to-mouse model.

Animals↗
PubMed1994

Hepatitis delta virus replication in vitro is not affected by interferon-alpha or -gamma despite intact cellular responses to interferon and dsRNA.

The hepatitis delta virus (HDV) genome consists of circular ssRNA which has extensive intramolecular complementarity and can form a dsRNA rod-like structure. If such RNA species were to exist in an unmasked form in cells, they would be expected to induce interferon (IFN) expression and activate two IFN-inducible dsRNA-dependent enzymes with anti-viral activity, namely the dsRNA-dependent protein kinase (PKR) and 2',5' oligoadenylate (2',5' A) synthetase. Since the virus replicates to high copy number for prolonged periods in infected cells it is apparently able to evade these antiviral mechanisms. The RNA genome may be masked and fail to induce or activate the antiviral response, or the virus may inhibit such a response. Treatment of a hepatoma cell line, Huh7, and a fibrosarcoma cell line, HT1080, stably transfected with a trimeric HDV cDNA construct, with IFN-alpha or IFN-gamma for up to seven days failed to influence the level of expression of genomic or antigenomic HDV RNA, or delta antigen (Ag). This is consistent with either failure of activation or inhibition of the IFN response. However the induction of several IFN-responsive genes, including PKR, 2',5' A synthetase and class I MHC is normal and cotransfection of a construct expressing delta Ag did not affect expression from an IFN-inducible chloramphenicol acetyltransferase construct. In addition, the activation of PKR is not inhibited in HDV-expressing cells and antiviral assays suggest that the ability of these cells to mount an antiviral response to at least two cytopathic viruses is unaffected. IFN-beta is inducible normally by dsRNA in cells transfected with the delta cDNA trimer. We conclude that HDV replication is not inhibited by IFN-alpha or IFN-gamma, even though the responses of cells expressing HDV RNA and antigen to IFN and dsRNA are intact.

2',5'-Oligoadenylate Synthetase↗
PubMed2005

Beta interferon and gamma interferon synergize to block viral DNA and virion synthesis in herpes simplex virus-infected cells.

The capacity of herpes simplex virus type 1 (HSV-1) to replicate in vitro decreases tremendously when animal cell cultures are exposed to ligands of both the alpha/beta interferon (IFN-alpha/beta) receptor and IFN-gamma receptor prior to inoculation with low m.o.i.s of HSV-1. However, the available evidence provides no insight into the possible mechanisms by which co-activation of the IFN-alpha/beta- and IFN-gamma-signalling pathways produces this effect. Therefore, it has not been possible to differentiate between whether these observations represent an important in vitro model of host immunological suppression of HSV-1 infection or an irrelevant laboratory phenomenon. Therefore, the current study was initiated to determine whether co-activation of the host cell's IFN-alpha/beta and IFN-gamma pathways either (i) induced death of HSV-1-infected cells such that virus replication was unable to occur; or (ii) disrupted one or more steps in the process of HSV-1 replication. To this end, multiple steps in HSV-1 infection were compared in populations of Vero cells infected with HSV-1 strain KOS (m.o.i. of 2.5) and exposed to ligands of the IFN-alpha/beta receptor, the IFN-gamma receptor or both. The results demonstrated that IFN-beta and IFN-gamma interact in a synergistic manner to block the efficient synthesis of viral DNA and nucleocapsid formation in HSV-1-infected cells and do so without compromising host-cell viability. It was inferred that IFN-mediated suppression of HSV-1 replication may be a central mechanism by which the host immune system limits the spread of HSV-1 infection in vivo.

Animals↗
PubMed1991

Treatment of anti-recombinant interferon-alpha 2 antibody positive CML patients with natural interferon-alpha.

Of 38 patients with a Philadelphia-chromosome positive chronic myeloid leukaemia treated with recombinant interferon alpha (rIFN-alpha) 2a or 2b and monitored for emergence of IFN-antibodies in their sera 11 patients developed rIFN-alpha 2 binding and 10 rIFN-alpha 2 neutralizing antibodies. rIFN-alpha neutralizing antibody positive patients experienced significantly (P less than 0.025) more clinical relapses (6/10) than IFN-antibody negative patients (6/28) during continuous IFN-therapy. Furthermore, IFN-antibody-positive patients with titre above 400 INU/ml were more likely to relapse under rIFN-alpha-therapy than IFN-antibody-negative patients with titre below 400 INU/ml (P less than 0.05). Seven rIFN-antibody-positive patients experiencing a clinical relapse or a primary non-responsiveness were treated with two- to three-fold increased doses of rIFN-alpha 2. Only one of these seven patients developed a partial haematological remission upon intensification of the rIFN-alpha 2 therapy. Consecutively, the six patients failing high dose rIFN-alpha treatment were switched to a natural IFN-alpha preparation (3 x 9 x 10(6) I.U. weekly s.c.). Under such treatment two of the six patients achieved a long-lasting complete, one a partial haematological remission. In high-titred IFN-antibody positive patients significantly altered serum-IFN-titre and minimal IFN-inducible Mx-homologue concentrations were measured; in contrast, nIFN-alpha induced normal IFN-titre and dose-equivalent Mx-homologue amounts in these patients. The data prove that high-titred rIFN-alpha neutralizing antibodies abrogate the biological action of rIFN-alpha, but not of nIFN-alpha in vivo and explains why nIFN-alpha can be effective in the anti rIFN-alpha 2 positive patients.

Antibodies, Neoplasm↗
PubMed1992

Combination therapy with interferon alpha-2b plus low-dose interferon gamma in pretreated patients with Ph-positive chronic myelogenous leukaemia.

Between March 1988 and July 1990, 28 adults with chronic myelogenous leukaemia (CML) were treated with a combination of recombinant human interferon (IFN) alpha-2b s.c. (initial dose 4 x 10(6) U/m2) and recombinant human IFN gamma s.c. (50 micrograms totally) daily. All patients were in chronic phase disease and had been treated previously with chemotherapy or bone marrow transplantation. A complete haematologic remission was achieved in three patients (11%), a haematologic remission in 12 patients (43%), and a partial haematologic remission in seven patients (25%). Six patients did not respond to this schedule. Acute side-effects were flu-like symptoms, fever and chills. During long-term treatment six patients developed polyarthralgia. Haematotoxicity WHO grade III occurred in three patients, and WHO grade IV in two patients. One patient developed psychosis, and in another patient an exacerbation of a pre-existing sarcoidosis was observed. We conclude that this combination is tolerable and effective in inducing haematological remissions in pretreated CML patients.

Adolescent↗
PubMed2004

Polymorphisms in the genes encoding interferon-gamma and interferon-gamma receptors in multiple sclerosis.

Genome screens suggest that several genes, each contributing to a small extent, are involved in multiple sclerosis (MS) susceptibility. Simultaneous analysis of related genes may improve the power to detect such small effects. Interferon-gamma (IFN-gamma), mediating its effects through the IFN-gamma receptor, is a pleiotropic, pro-inflammatory cytokine for which a detrimental effect on the course of MS has been reported. The role of IFN-gamma receptor 1 (IFNGR1) and IFN-gamma receptor 2 (IFNGR2) gene polymorphisms has not been studied in MS, and, for the IFNG gene polymorphism there is only one previous study, which incorporates clinical, but not imaging, data. The aim of this study was to investigate whether polymorphisms in the IFNG and IFNGR1 and IFNGR2 genes are associated with susceptibility to MS, or disease characteristics, as defined by clinical and imaging criteria. Genotypes for IFNG, IFNGR1 and IFNGR2 were determined in 509 patients with MS and in 193 healthy controls. Patient files were reviewed for disease course, age at onset of disease, and rate of progression. Serial magnetic resonance imaging (MRI) data were available for 107 patients. No significant differences in the distribution of IFNG, IFNGR1 and IFNGR2 genotype and allele frequencies were found between patients and controls. A progressive, as opposed to a relapsing, onset was significantly more frequent in carriers of the IFNGR2 allele Arg64 (P = 0.028). Moreover, IFNGR2 allele Arg64 carriers had a lower black hole ratio than non-carriers (P = 0.016). No other associations with clinical parameters, such as age at onset or rate of progression, or with imaging parameters, were observed. The IFNG intron 1 gene polymorphism studied is unlikely to play a major role in MS susceptibility or disease course. The IFNGR1 and IFNGR2 gene polymorphisms studied do not exert an important influence on MS susceptibility, but allele IFNGR2*Arg64 may be associated with a progressive disease onset.

Adult↗
PubMed1995

Clinical efficacy of intramuscular human interferon-beta vs interferon-alpha 2b for the treatment of chronic hepatitis C.

We have conducted a randomized study to compare the efficacy and tolerance of human interferon (IFN) beta vs recombinant IFN-alpha 2b in patients with chronic active hepatitis C. Forty patients were included: 21 received IFN-alpha (group A) and 19 IFN-beta (group B). IFN was administered intramuscularly at a dose of 6 MU three times a week (tiw) for 2 months (induction phase), followed by 3 MU tiw for 4 months. Clinical, epidemiological and pathological features were similar in the two groups. Normal alanine aminotransferase (ALT) values at the end of treatment was regarded as a response to therapy and the response rate was 57% (12/21) in group A and 5.2% (1/19) in group B (P < 0.01). Both types of IFN induced a significant decrease in mean ALT values by the end of the induction phase (P < 0.01). When the dose was reduced to 3 MU, a marked, but not significant increase in ALT, was seen in group B, whereas no increase was seen in group A. IFN-beta was better tolerated and haematological adverse effects (platelet and leucocyte decrease) were less pronounced with IFN-beta. Hence, human IFN-beta was less effective than IFN-alpha in treating chronic hepatitis C virus (HCV). Doses of IFN-beta of 3 MU intramuscular (IM) tiw were clearly insufficient and it remains to be established whether higher doses of intramuscularly IFN-beta can be useful.

Chronic Disease↗
PubMed1999

Biochemical and viral response to consensus interferon (CIFN) therapy in chronic hepatitis C patients: effect of baseline viral concentration. Consensus Interferon Study Group.

OBJECTIVE: The effect of baseline viral concentration on response was assessed as part of a multicenter phase 3 trial evaluating the safety and efficacy of CIFN therapy for chronic HCV infection. METHODS: Patients (n = 472) received either CIFN 9 microg or IFN alpha-2b 3 MU subcutaneously t.i.w. for 24 wk, followed by 24 wk of observation. RESULTS: Efficacy was assessed by the percentage of patients who achieved normal ALT values or undetectable HCV RNA values (using RT-PCR with a sensitivity of 100 copies/ml). There was a clear relationship between baseline viral concentration and either ALT or HCV RNA response; patients with lower titer HCV RNA had better response rates. End-of-treatment HCV RNA responses were better for patients with low viral concentrations treated with CIFN (51%) than for patients treated with IFN a-2b (31%) (p = 0.03). ALT responses in patients with low viral concentrations were 60% for CIFN-treated patients and 27% for IFN alpha-2b-treated patients (p < 0.01) at the end of treatment. Patients with high titer HCV RNA were more likely to have a sustained HCV RNA response after treatment with CIFN 9 microg, compared with those treated with IFN alpha-2b (7% vs 0%, p = 0.03). CONCLUSIONS: Both genotype and baseline viral concentration were independent factors that affected response to interferon.

Adult↗
PubMed1983

Characterization of interferons induced by bacteria and interferon-producing leukocytes in human peripheral blood.

All of 23 different preparations of formaldehyde-fixed and heat-killed bacteria induced the appearance of high levels of interferon (IFN) in cultures of human peripheral blood mononuclear leukocytes. Some bacteria induced peak IFN titers after 24 h of culture, whereas other bacteria showed maximal titers on culture days 2 to 3. The IFN displayed various properties. One type, which appeared early during the cultures, had characteristics of IFN-alpha, being resistant to pH 2 treatment but neutralized by antibodies to IFN-alpha. A second type, which appeared later, on culture days 2 to 3, resembled IFN-gamma in being sensitive to pH 2 treatment but resistant to anti-IFN-alpha antibodies. A third type, which appeared to be sensitive to both pH 2 and antibody treatment, was interpreted as atypical IFN-alpha. The application of cell fractionation procedures indicated that nonadherent, predominantly Fc receptor-bearing, non-T, non-B cells were producers of IFN-alpha as defined by its antigenic properties. They copurified approximately with cells carrying natural killer activity toward human erythroid leukemia K562 cells. Some bacteria apparently also stimulated T lymphocytes to produce material with properties of IFN-gamma.

Antibodies, Viral↗
PubMed2005

Identification of the rabies virus alpha/beta interferon antagonist: phosphoprotein P interferes with phosphorylation of interferon regulatory factor 3.

Rabies virus (RV) of the Rhabdoviridae family grows in alpha/beta interferon (IFN)-competent cells, suggesting the existence of viral mechanisms preventing IFN gene expression. We here identify the viral phosphoprotein P as the responsible IFN antagonist. The critical involvement of P was first suggested by the observation that an RV expressing an enhanced green fluorescent protein (eGFP)-P fusion protein (SAD eGFP-P) (S. Finke, K. Brzozka, and K. K. Conzelmann, J. Virol. 78:12333-12343, 2004) was eliminated in IFN-competent HEp-2 cell cultures, in contrast to wild-type (wt) RV or an RV replicon lacking the genes for matrix protein and glycoprotein. SAD eGFP-P induced transcription of the IFN-beta gene and expression of the IFN-responsive MxA and STAT-1 genes. Similarly, an RV expressing low levels of P, which was generated by moving the P gene to a promoter-distal gene position (SAD DeltaPLP), lost the ability to prevent IFN induction. The analysis of RV mutants lacking expression of truncated P proteins P2, P3, or P4, which are expressed from internal AUG codons of the wt RV P open reading frame, further showed that full-length P is competent in suppressing IFN-beta gene expression. In contrast to wt RV, the IFN-inducing SAD DeltaPLP caused S386 phosphorylation, dimerization, and transcriptional activity of IFN regulatory factor 3 (IRF-3). Phosphorylation of IRF-3 by TANK-binding kinase-1 expressed from transfected plasmids was abolished in wt RV-infected cells or by cotransfection of P-encoding plasmids. Thus, RV P is necessary and sufficient to prevent a critical IFN response in virus-infected cells by targeting activation of IRF-3 by an upstream kinase.

Animals↗
PubMed2005

Early alpha/beta interferon production by myeloid dendritic cells in response to UV-inactivated virus requires viral entry and interferon regulatory factor 3 but not MyD88.

Alpha/beta interferons (IFN-alpha/beta) are key mediators of innate immunity and important modulators of adaptive immunity. The mechanisms by which IFN-alpha/beta are induced are becoming increasingly well understood. Recent studies showed that Toll-like receptors 7 and 8 expressed by plasmacytoid dendritic cells (pDCs) mediate the endosomal recognition of incoming viral RNA genomes, a process which requires myeloid differentiation factor 88 (MyD88). Here we investigate the requirements for virus-induced IFN-alpha/beta production in cultures of bone marrow-derived murine myeloid DCs (mDCs). Using recombinant Semliki Forest virus blocked at different steps in the viral life cycle, we show that replication-defective virus induced IFN-alpha/beta in mDCs while fusion-defective virus did not induce IFN-alpha/beta. The response to replication-defective virus was largely intact in MyD88-/- mDC cultures but was severely reduced in mDC cultures from mice lacking IFN regulatory factor 3. Our observations suggest that mDCs respond to incoming virus via a pathway that differs from the fusion-independent, MyD88-mediated endosomal pathway described for the induction of IFN-alpha/beta in pDCs. We propose that events during or downstream of viral fusion, but prior to replication, can activate IFN-alpha/beta in mDCs. Thus, mDCs may contribute to the antiviral response activated by the immune system at early time points after infection.

Adaptor Proteins, Signal Transducing↗
PubMed1993

Recognition DNA sequences of interferon regulatory factor 1 (IRF-1) and IRF-2, regulators of cell growth and the interferon system.

Interferon (IFN) regulatory factor 1 (IRF-1) and IRF-2 were originally identified as transcription factors involved in the regulation of the IFN system. IRF-1 functions as a transcriptional activator, while IRF-2 represses IRF-1 function. More recently, evidence has been provided that IRF-1 and IRF-2 manifest antioncogenic and oncogenic properties, respectively, and that loss of one or both of the IRF-1 alleles may be critical for the development of human hematopoietic neoplasms. Both factors show a high degree of structural similarity in their N-terminal DNA-binding domains, and previous studies suggested that IRF-1 and IRF-2 bind to similar or identical cis elements within type I IFN (IFN-alpha and -beta) and IFN-inducible genes. However, the exact recognition sequences of these two factors have not yet been determined; hence, the spectrum of the IRF-responsive genes remains unclear. In this study, we determined the DNA sequences recognized by IRF-1 and IRF-2, using a polymerase chain reaction-assisted DNA-binding site selection method. We report that sequences selected by this method and the affinities for each sequence were virtually indistinguishable between IRF-1 and IRF-2. We confirm the presence of two contiguous IRF recognition sequences within the promoter region of the IFN-beta gene and of at least one such sequence in all of the IFN-inducible genes examined. Furthermore, we report the presence of potential IRF sequences in the upstream region of several genes involved in cell growth control.

Base Sequence↗
PubMed2003

High dose consensus interferon in nonresponders to interferon alpha-2b and ribavirin with chronic hepatitis C.

OBJECTIVES: Approximately 60% of patients with chronic hepatitis C treated with a combination of interferon (IFN) alpha-2b and ribavirin are nonresponders. The purpose of the present study was to evaluate the efficacy of treatment with high dose consensus IFN (CIFN) (15 microg/day) in nonresponders. METHODS: Patients were administered 15 microg CIFN/day. Treatment was stopped in those whose serum hepatitis C virus (HCV) RNA remained detectable at 12 weeks. Those with undetectable HCV RNA at 12 weeks continued on 15 microg three times per week for a further 36 weeks. RESULTS: Twenty-four patients were recruited; six (25%) withdrew before 12 weeks because of side effects. Of the 18 patients who completed 12 weeks of therapy, nine (38%) had undetectable HCV RNA. Seven of nine patients who were HCV RNA-negative at week 12 completed 48 weeks of treatment and two withdrew because of intolerable side effects. At 48 weeks, HCV RNA remained undetectable in three patients. After six months of follow-up off treatment, two patients (8%) continued with no detectable HCV RNA in their sera. CONCLUSIONS: High dose induction therapy with CIFN 15 microg/day in prior nonresponders to IFN alpha-2b and ribavirin led to loss of detectable HCV RNA in 50% of patients, but this response was only sustained in 8% of patients on completion of therapy.

Adult↗
PubMed2000

Sensitivity to interferon-alpha and interferon-stimulated gene factor 3 binding activity in human chronic myelogenous leukemia cell line KT-1.

The mechanism of responsiveness of chronic myelogenous leukemia (CML) cells to interferon (IFN)-alpha was examined by using two subclones of CML cell line KT-1 which exhibited significantly different sensitivities to the antiproliferative and apoptosis-inducing effects of IFN-alpha. IFN-stimulated gene factor 3 (ISGF3) formation by IFN-alpha was reduced in the IFN-alpha-resistant subclone compared to the IFN-alpha-sensitive subclone. We conclude that the level of ISGF3 formation is responsible for the difference in IFN-alpha responses between these subclones.

Antineoplastic Agents↗