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At least 991 records · Page 55Linked to original sources
PubMed1998

Interferon-gamma-inducing factor elicits antitumor immunity in association with interferon-gamma production.

Interferon-gamma-inducing factor (IGIF) is a novel cytokine that stimulates T-cell proliferation, augments natural killer (NK) cell lytic activity, and induces interferon-gamma (IFN-gamma) production in established type 1 T-helper (Th1) cells in the presence of anti-CD3 antibody. The in vitro induction of IFN-gamma by recombinant murine IGIF in these cells was more potent than that induced by murine interleukin-12 (IL-12) and occurred apparently independent of murine IL-12. Here we report that subcutaneous injection into mice of tumor cells transfected with murine IGIF complementary DNA (cDNA) resulted in > or = 10-fold increase of mitogen-stimulated IFN-gamma production in cultured splenocytes. In addition, IGIF-transfected Renca and K1735 tumor cells can be rejected in vivo. The IGIF antitumor effect was abrogated in mice that were sublethally irradiated or depleted of both CD4+ and CD8+ T cells but not in mice depleted of either subpopulation alone. The antitumor effect mediated by IGIF appears to be dependent on IFN-gamma production, because in vivo neutralization of IFN-gamma was accompanied by growth of IGIF-transfected tumors in 100% of the animals. Taken together, our results show that murine IGIF can elicit T-cell-dependent antitumor immunity associated with IFN-gamma induction.

Animals↗
PubMed2004

Surveillance of acute rejection in baboon renal transplantation by elevation of interferon-gamma inducible protein-10 and monokine induced by interferon-gamma in urine.

BACKGROUND: CXCR3 binding chemokines play a key role in recruitment of inflammatory cells into an organ transplant. This study addresses the question of whether urinary excretion of these chemokines correlates with acute rejection in a baboon kidney transplantation model. METHODS: Seven outbred baboons underwent renal allotransplantation from major histocompatibility complex (MHC)-mismatched donors. The treatment of baboons consisted of anti-CD4 monoclonal antibody (mAb), anti-CD8 mAb, rapamycin, and mycophenolate mofetil (MMF). Urinary levels of interferon-gamma inducible protein-10 (IP-10) and monokine induced by interferon-gamma (Mig) were determined by ELISA. Renal biopsies were examined by immunohistochemical staining for CXCR3 and Mig. RESULTS: Urinary levels of IP-10 and Mig increased significantly in all of the five baboons at the time of acute rejection of renal transplant. The IP-10 and Mig levels did not rise in two nonrejecting baboons. In two baboons, urinary levels of IP-10 and Mig rose before the elevation of the serum creatinine. In renal biopsies, expression of Mig was detected in glomeruli, tubules, and infiltrating cells, and the expression was significantly elevated in biopsies with acute rejection (P<0.01). CXCR3 was constitutively expressed in tubular cells in biopsies derived from both normal grafts and grafts with acute rejection. Whereas the infiltrating cells were increased in the biopsies with acute rejection, the expression of CXCR3 was also significantly higher (P<0.01) in these infiltrating cells compared with those in the normal controls. CONCLUSIONS: This study shows an important correlation between urinary excretion of IP-10 and Mig and acute rejection in baboon kidney transplantation.

Acute Disease↗
PubMed1980

SDS-polyacrylamide gel electrophoresis of purified human leucocyte interferon and the antiviral and anticellular activities of the different interferon species.

Human leucocyte interferon (HuLeIF) was purified by a series of techniques involving precipitation, gel filtration, Cu-chelate-, blue dextran- and antibody-affinity chromatography. The two major species of HuLeIF were identified in SDS-PAGE as two clearly separable and stainable proteins representing 85% of the biological activity. Three more species of HuLeIF representing 15% of the biological activity were also demonstrated. The specific activity of pure interferon proteins was approx. 10(9) IFU/mg protein. Recovery was about 50% and the purification factor exceeded 350000. All five species of HuLeIF had definite anticellular activities when tested with Daudi cells (inhibition of thymidine uptake).

Cell Division↗
PubMed1982

Control of interferon mRNA levels and interferon yields in butyrate and 5'-bromodeoxyuridine-treated Namalwa cells.

Treatment of Namalwa cells with butyrate or 5'-bromodeoxyuridine (BrdUrd) before induction with Sendai virus caused an increase in the production of both interferon (IFN) and interferon mRNA (IFN mRNA). However, the increase in IFN mRNA did not completely account for the increase in IFN yield. The treatments did not affect the time course of IFN mRNA transcription and translation, or the association of IFN mRNA with polysomes. Likewise, the treatments did not alter the post-translational fate of the IFN produced. We conclude that butyrate and BrdUrd affect IFN production at the level of transcription or processing of IFN mRNA and suggest that increased efficiency of translation provides an additional level of control.

Bromodeoxyuridine↗
PubMed1983

Circulating interferon in rabbits and monkeys after administration of human gamma interferon by different routes.

Rabbits and rhesus monkeys were injected with 3 X 10(5) units of human gamma interferon (IFN) prepared in human leukocyte suspensions. Circulating IFN was detected up to 4 h after intravenous administration. Intramuscular injection maintained a relatively stable serum IFN level of about 50 units/ml for 7 to 9 h. The results in both species were similar. Little or no circulating IFN was detected after subcutaneous injection of 3 X 10(5) units, but 1.5 X 10(6) units maintained about 50 units per ml of serum for 30 h. Pharmacokinetically, human gamma IFN resembled human alpha interferons rather than human beta IFN.

Animals↗
PubMed1997

In vivo induction of interferon-alpha in pig by non-infectious coronavirus: tissue localization and in situ phenotypic characterization of interferon-alpha-producing cells.

A low frequency peripheral blood mononuclear cell (PBMC) subpopulation, referred to as natural interferon-producing (NIP) cells, is described as producing interferon-alpha (IFN-alpha) following contact with non-infectious viral structures, namely viral glycoproteins. These cells are characterized in vitro as non-T, non-B, MHC class II+ and CD4+ cells. In this study, NIP cells were analysed in vivo after an intravenous injection of UV-inactivated transmissible gastroenteritis virus in newborn piglets, which resulted in strong serum IFN-alpha production. Splenocytes, but not PBMC, were the IFN-alpha producers in vivo. Using double immunohistochemical labelling for both IFN-alpha and leukocyte markers, we established that splenic NIP cells were not T or B cells. The majority were MHC class II+ and only a minority expressed a macrophage marker. NIP cells were localized in contact with MHC class II-expressing cells and T cells, which suggested that NIP cells might modulate the antiviral immune response.

Animals↗
PubMed1995

Re-treatment of interferon-resistant patients with chronic hepatitis C with interferon-alpha.

Non-responders to 6-months treatment with recombinant interferon (rIFN)-alpha, 3 MU thrice weekly (primary non-responders) were treated for 6 further months with the same therapy or with a double dose of rIFN-alpha or with a different type of IFN (L-IFN). 112 primary non-responders were randomly enrolled into four groups of 28 patients each over a period of 4 years and were followed up for 6 months: group A continued the same dose of rIFN-alpha, group B was treated with the same rIFN-alpha but received a double dose (6 MU thrice weekly), group C received L-IFN, 3 MU thrice weekly, and group D stopped IFN therapy and did not receive any treatment. Patients were examined at monthly intervals and response was defined as a complete normalization of alanine amino transferase (ALT). The four groups were homogeneous as to age, sex, duration of the disease, probable source of infection, histological diagnosis. ALT and gamma glutamyl transferase (gamma GT) levels. No patient discontinued therapy for side-effects. Further treatment with rIFN-alpha 3 MU thrice weekly (group A) induced normalization of ALT levels in four patients (14%); treatment with double-dosed rIFN-alpha (group B) induced normalization of liver enzymes in six cases (21%); a different type of interferon (L-IFN) (group C) achieved normalization of serum ALT in five patients (18%). None of 28 primary non-responders who did not receive any treatment (group D) showed normalization of ALT levels. None of the patients was anti-HCV negative at the end of the study and no statistically significant difference was noted between responders and non-responders to the second course of IFN therapy as to age, sex, duration of the disease. ALT and gamma GT levels at the end of the trial. Overall at the end of the study the primary non-responders with normal levels of ALT were 15/112 (13%), with a therapeutic advantage of 7%. No statistically significant difference in the response rate was found among patients who continued IFN therapy, but prolongation of rIFN-alpha treatment at double dosage seems to be the best therapeutic regimen.

Adult↗
PubMed1983

Expression of interferon-alpha and interferon-beta genes in human lymphoblastoid (Namalwa) cells.

Treatment of human lymphoblastoid (Namalwa) cells with Sendai virus induced the coordinate synthesis of both IFN-alpha and IFN-beta interferon mRNAs. One sub-line of Namalwa cells (WRL) produced no IFN-beta activity, although IFN-beta mRNA was induced and was associated with polysomes. The IFN-alpha mRNA was heterogeneous, ranging in size over 1.20-1.35 X 10(3) bases, probably because of variation in the size of the transcribale DNA in the alpha-gene family. The IFN-beta mRNA was monodisperse with a size of 1.05 X 10(3) bases. The kinetics of accumulation and decay of both IFN-alpha and IFN-beta mRNAs, as assessed by hybridization with cDNA probes, were very similar to those of translatable interferon mRNA, as assessed by translation in Xenopus oocytes. Treatment of the cells with butyrate or 5'-bromodeoxyuridine increased the amount of hybridizable IFN-alpha and IFN-beta mRNA about 15-fold and 4-fold respectively, again demonstrating coordinate control of IFN-alpha and IFN-beta production.

Base Composition↗
PubMed1994

Functional differences in the promoters of the interferon-inducible (2'-5')A oligoadenylate synthetase and 6-16 genes in interferon-resistant Daudi cells.

A clone of interferon-alpha-resistant (IFNr) Daudi cells retained much greater transcriptional inducibility of the (2'-5') oligoadenylate synthetase than the 6-16 gene despite the fact that the response of both genes is mediated by highly similar interferon-stimulable DNA response elements (ISRE). The primary IFN-alpha activatable transcription factor E (ISGF3) and the additional IFN-alpha-inducible ISRE-binding complex M were greatly reduced in the IFNr cells. The defect in E was in the E alpha subunit. In electrophoretic mobility-shift assays the 6-16 and (2'-5') oligoadenylate synthetase ISRE competed approximately equivalently for E and M. Moreover although active in wild-type cells the (2'-5') oligoadenylate synthetase ISRE was no more capable of conferring inducibility on a reporter gene in the IFNr cells than was the 6-16 ISRE. The contrasting response of the endogenous (2'-5') oligoadenylate synthetase and 6-16 genes in the IFNr cells is, therefore, unlikely simply to reflect the slight difference in the sequence of their ISRE. Consistent with this, in addition to the ISRE, sequences 5' to the ISRE in the (2'-5') oligoadenylate synthetase promoter appeared necessary for good induction by IFN alpha in the IFNr cells. Subtle quantitative changes in the phenotype of the IFNr cells have, however, precluded a more precise definition of the DNA element(s) involved.

2',5'-Oligoadenylate Synthetase↗
PubMed2005

Non-interferon-based therapy: an option for amelioration of necro-inflammation in hepatitis C patients who cannot afford interferon therapy.

OBJECTIVES: Interferon (IFN) therapy is not affordable by the majority of Egyptian patients. Our aim was to tailor an effective and inexpensive regimen that ameliorates hepatic necro-inflammatory activity among chronic hepatitis C (CHC) patients. METHODS: One hundred and seventy naïve CHC patients with elevated alanine aminotransferase (ALT) (>1.5-fold) and detectable hepatitis C virus (HCV)-RNA by polymerase chain reaction, who cannot afford IFN-based therapy were randomly allocated either to non-interferon-based therapy (N-IFN-BT) (group I) or silymarin therapy (group II). Group I comprised 87 patients (biopsy proved chronic hepatitis in 62 patients) who were administered a daily combination of ribavirin (600-800 mg) plus amantadine (200 mg) and ursodeoxycholic acid (UDCA) (500 mg) for 24 weeks. Group II comprised 83 patients who were administered Silymarin 450 mg/day for 24 weeks. RESULTS: Statistical evaluation was conducted on 82 patients from group I and 72 from group II because of the withdrawal of five and 11 patients from Groups I and II, respectively. Age, sex, social status and biochemical parameters were comparable in both groups. Normalization of ALT at the end of treatment was achieved in 58.5% and 15.3% (P<0.001), whereas end of treatment virologic response (ETVR) was achieved in 2.4% and 0% of Groups I and II, respectively. Twenty-four weeks after cessation of therapy, sustained biochemical response (SBR) was achieved in 28% and 2.8% (P<0.001), while sustained virologic response (SVR) was maintained in 2.4% and 0% of the patients in Groups I and II, respectively. In Group I, histopathological examination revealed a decreased activity index by an average score of 1.5 points among 38/62 of the rebiopsied patients. CONCLUSION: Twenty-four weeks N-IFN-BT achieved a fourfold-higher ETBR and a tenfold-higher SBR compared with silymarin therapy, which reflects an improvement of necroinflammatory activity as proven by repeat histopathology.

Alanine Transaminase↗
PubMed1989

PHA-induced interferon in multiple sclerosis: association between gamma interferon and clinical and genetical variables.

Gamma interferon (INF-gamma) production, after PHA stimulation of peripheral blood mononuclear cells, from multiple sclerosis (MS) patients with the acute remitting and chronic progressive forms, in attack and remission phases, and from normal controls, was studied by immunoradiometric assay. MS patients in all these 4 clinical states of disease produced less INF-gamma (log value range from 2.55 to 2.65). MNC from the total MS patients produced significantly low levels of INF-gamma compared to the control group (log values 2.60 vs. 2.82; P = 0.001). No association between the interferon production and antigens at any HLA locus (A, B, C, Dw and Bf) was found. There was no correlation between IFN-gamma production and age, sex, duration of disease, or disability index. However there was a slight tendency to negative correlation with the progression index of the disease. The results suggest that this lower IFN-gamma production in MS may be secondary to the disease, and the primary defect may be a severe reduction of the essential lymphocyte populations required for an effective lymphokine cascade to produce the normal immune response against infection.

Adult↗
PubMed1987

The antichlamydial, antiviral, and antiproliferative activities of human gamma interferon are dependent on the integrity of the C terminus of the interferon molecule.

The effects of recombinant human gamma interferon (rHuIFN-gamma; two identical monomers of 140 residues in length) and of two re-engineered C-terminal variants, rHuIFN-gamma Tetra-Ser (residues 129 to 132 replaced by serine) and rHuIFN-gamma 125 (two identical monomers of 125 residues each with the last 14 residues plus an additional alanine from the C terminus deleted), were compared in terms of several in vitro biological activities. By using three different human cell lines (HeLa 229, HEp-2, and A549), the interferons were tested for their ability to inhibit: (i) growth of Chlamydia trachomatis; (ii) replication of encephalomyocarditis virus; and (iii) cell growth. rHuIFN-gamma restricted the growth of chlamydiae to 50% of the non-IFN-treated control at concentrations ranging from 0.01 to 0.05 ng/ml, depending on the cell type assayed. One of the modified proteins, rHuIFN-gamma Tetra-Ser, also decreased the growth of chlamydiae, but it required a concentration of approximately 0.5 ng/ml to produce 50% inhibition. rHuIFN-gamma 125 had the lowest antichlamydial activity of the three IFN-gamma variants tested; concentrations of 1 to 20 ng/ml were needed to reduce the growth of C. trachomatis to 50% of that of the control. The relative antiviral and antiproliferative activities of the three IFN-gamma preparations paralleled their antichlamydial activities in these three cell lines. The antiencephalomyocarditis virus activities of rHuIFN-gamma Tetra-Ser and rHuIFN-gamma 125 were reduced by approximately 10-fold and 10(2)- to 10(3)-fold, respectively, compared with the antiviral activity of rHuIFN-gamma. Proliferation of the three cell lines was restricted to approximately 50% of the control with 0.5 to 10 ng of rHuIFN-gamma per ml. Inhibition of cell growth by rHuIFN-gamma Tetra-Ser was significant only at concentrations equal to or greater than 30 ng/ml, and the rHuIFN-gamma 125 variant did not significantly decrease the growth of any of the three cell lines at the concentrations tested. These results suggest that the C-terminal portion of rHuIFN-gamma is critical for maintaining the conformation necessary for inducing the antichlamydial, antiviral, and antiproliferative activities of the molecule.

Amino Acid Sequence↗
PubMed2005

Interferon-inducible protein 10, but not monokine induced by gamma interferon, promotes protective type 1 immunity in murine Klebsiella pneumoniae pneumonia.

CXC chemokines that lack the ELR motif, including interferon-inducible protein 10 [IP-10 (CXCL10)] and monokine induced by gamma interferon (IFN-gamma) [MIG (CXCL9)], have been shown to mediate the generation of type 1 immune responses. In this study, we found that intrapulmonary administration of the gram-negative bacterium Klebsiella pneumoniae resulted in the local and systemic expression of IP-10, followed sequentially by MIG expression. MIG mRNA expression in the lungs of Klebsiella-infected mice required the endogenous production of IFN-gamma, whereas IP-10 was expressed in both an IFN-gamma-dependent and an IFN-gamma-independent fashion. Antibody-mediated neutralization of IP-10 resulted in reduced bacterial clearance and decreased survival, whereas bacterial clearance was unaltered in mice treated with anti-MIG antibody. Impaired bacterial clearance in anti-IP-10 antibody-treated mice was associated with significant reductions in the number and/or activational status of NK and NK-T cells, CD4+ T cells, and gammadelta T cells, as well as a reduction in the expression of IFN-gamma. Conversely, the transient transgenic expression of murine IP-10 using adenovirus-mediated gene transfer resulted in improved bacterial clearance when IP-10 adenovirus was given concomitant with intrapulmonary bacterial challenge. These results indicate that IP-10 is an important component of innate immunity against extracellular bacterial pathogens of the lung and may represent a candidate molecule for immunotherapy in the setting of severe respiratory tract infection.

Adenoviridae↗
PubMed1986

Levels of interferon in blood serum and toxicity studies of bacteria-derived bovine alpha I1 interferon in dairy calves.

This paper reports information on the levels of interferon (IFN) in the blood serum of dairy calves given 10(6) U of bacteria-derived bovine alpha I1 interferon per kg of body weight by intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.), and intranasal (i.n.) routes. Highest levels (10,000 U/ml) in the vesicular stomatitis viral assay system were obtained after i.v. administration and occurred within 30 min of a dose; levels rapidly declined thereafter to a low of 200 to 300 U/ml by 24 h. Serum inhibitory activity against vesicular stomatitis virus in this range is sometimes found in normal dairy calves. Levels after i.m. and s.c. administration were similar: a plateau of 1,000 to 2,000 U/ml between 2 and 8 h after a treatment with a decline to 200 to 300 U/ml by 24 h. Serum IFN was not detected after i.n. dosing or in the control group given physiological buffered saline by the i.m. route. A transitory moderate febrile response, but no other clinical adverse effects, was noted after the first intramuscular dose of IFN, but not after subsequent i.m. doses. No clinical signs were noted after i.v., s.c., or i.n. dosing or in the control calves given physiological buffered saline intramuscularly. After i.v., s.c., and i.m. administration of IFN, leukopenia, neutropenia, and lymphocytopenia were observed; these were most prominent within the first 24 h after the initial dose of IFN.

Administration, Intranasal↗
PubMed2002

Transcriptional profiling of interferon regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated genes.

Ubiquitously expressed interferon regulatory factor 3 (IRF-3) is directly activated after virus infection and functions as a key activator of the immediate-early alpha/beta interferon (IFN) genes, as well as the RANTES chemokine gene. In the present study, a tetracycline-inducible expression system expressing a constitutively active form of IRF-3 (IRF-3 5D) was combined with DNA microarray analysis to identify target genes regulated by IRF-3. Changes in mRNA expression profiles of 8,556 genes were monitored after Tet-inducible expression of IRF-3 5D. Among the genes upregulated by IRF-3 were transcripts for several known IFN-stimulated genes (ISGs). Subsequent analysis revealed that IRF-3 directly induced the expression of ISG56 in an IFN-independent manner through the IFN-stimulated responsive elements (ISREs) of the ISG56 promoter. These results demonstrate that, in addition to its role in the formation of a functional immediate-early IFN-beta enhanceosome, IRF-3 is able to discriminate among ISRE-containing genes involved in the establishment of the antiviral state as a direct response to virus infection.

DNA-Binding Proteins↗
PubMed1986

Transcriptional and posttranscriptional regulation of exogenous human beta interferon gene in simian cells defective in interferon synthesis.

We determined that the defect in beta interferon induction in Vero cells is due to the absence of the simian beta interferon (IFN-beta) gene. Nevertheless, the human IFN-beta gene or a hybrid gene, in which the human IFN-beta promoter-regulatory region directs expression of the chloramphenicol acetyltransferase gene (pIFN-CAT), could be induced in transfected Vero cells, and these cells also regulated IFN-beta mRNA (but not pIFN-CAT mRNA) posttranscriptionally. These results indicate that the instability in the human IFN-beta gene is coded for by the coding or 3'-end region of IFN-beta mRNA and that the human IFN-beta gene is regulated in Vero and human cells in an identical manner.

Animals↗
PubMed1998

Gamma-interferon activates a nuclear protein that binds to the gamma-interferon activation site of the thyroglobulin gene.

The release of interferon-gamma (IFNgamma) has been demonstrated from the infiltrating T lymphocytes of the thyroid gland from patients with autoimmune thyroid disease (AITD). We have shown previously that IFNgamma inhibited thyroglobulin (Tg) gene transcription, and that its action was mediated by an increase in intracellular calcium and inositol phosphates. In the present study, we tried to determine the specific site of action of IFNgamma on the Tg gene. A 565 bp fragment (position -530 to +34) spanning the transcriptional start site of the human Tg promoter was ligated to the luciferase plasmid and transiently transfected into human thyrocytes. Stimulation with TSH (10 mIU/l) and IFNgamma (500 IU/l) resulted in a twofold increase and a 60% reduction in the luciferase activity respectively, similar to the effect observed with the endogenous Tg gene. Deletion studies revealed that the region with the strongest suppression by IFNgamma lay between 5' -388 to -258. Mobility gel shift experiments and DNA footprinting experiments demonstrated that the action of IFNgamma was mediated through a trans-acting protein which complexed to position -282 to -262 TTGAGCCTGTTCCCTC CAAA. Position -272 to -261 TTCCCTCCAA corresponded to the gamma-interferon activation site (GAS) consensus sequence TTNC(C)T NNNA. The turnover time of the nuclear protein lasted for only 4 h although the suppressive effect of IFNgamma on Tg gene transcription lasted for 48 h. The effect of IFNgamma was lost when the thyrocytes were co-treated with genistein, a specific tyrosine kinase inhibitor. The presence of the GAS in the promoter sequence of the Tg gene confirms the specific action of IFNgamma in thyroid hormone metabolism. In conclusion, apart from its regulatory role in T cell development and perpetuation of the immune response in AITD, IFNgamma may also play a role in altering cellular function of the thyrocytes by its action on the Tg gene promoter.

Base Sequence↗