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PubMed2000

Interferon-gamma- and lipopolysaccharide-induced tumor necrosis factor-alpha is required for nitric oxide production: tumor necrosis factor-alpha and nitric oxide are independently involved in the killing of Mycobacterium microti in interferon-gamma- and lipopolysaccharide-treated J774A.1 cells.

A comparative study was done using J774A.1 and J774A.1-derived transfected cells (J774A.1 C.1) containing antisense tumor necrosis factor alpha (TNF-alpha) plasmid to determine the role of endogenous TNF-alpha on nitric oxide production as well as on the growth of Mycobacterium microti in interferon gamma (IFN-gamma)- and lipopolysaccharide (LPS)-treated cells. On stimulation with IFN-gamma and LPS a higher level of NO was observed in J774A.1 cells compared to J774A.1 C.1 which indicated that endogenous TNF-alpha is required for the production of NO. Comparing the effect of IFN-gamma and LPS on the intracellular growth of M. microti, the growth-reducing activity was higher in J774A.1 cells than in J774A.1 C.1 cells and was not completely abrogated in the presence of the nitric oxide inhibitor NG-methyl-L-arginine (L-NMA). J774A.1 C.1 cells infected with M. microti produced a significant amount of NO when exogenous TNF-alpha was added along with IFN-gamma and LPS and the concentration of intracellular bacteria decreased almost to that in IFN-gamma and LPS treated parental J774A.1 cells. Addition of exogenous TNF-alpha even in the presence of L-NMA in J774A.1 C.1 cells could also partially restore intracellular growth inhibition of M. microti caused by IFN-gamma and LPS. TNF-alpha is probably required for the production of NO in J774A.1 cells by IFN-gamma and LPS but TNF-alpha and NO are independently involved in the killing of intracellular M. microti with IFN-gamma and LPS.

Animals↗
PubMed1987

Influence of interferon on the growth of primary ovarian carcinoma cells in a semi-solid agar system: comparison with clinical effects of interferon therapy.

The sensitivity of primary human ovarian cancer cells to interferon (IFN) was studied in vitro by the use of a tumor cloning system in semi-solid agar. Tumor colonies were found in 37% (34/93) of the experiments with tumor cells from ascites and in 35% (6/17) of the experiments with solid tumors. The relative colony-forming ability could not be correlated to prior treatment. In 15 out of 18 patients the ascitic tumor cells were sensitive to IFN-alpha. Sensitivity was found in one test out of three with solid tumors. The sensitivity was dependent on the dose of IFN but could vary for the natural IFNs alpha and gamma. In seven patients the relation between in vitro and in vivo sensitivity of the tumor cells to IFN could be studied. Any correlation between in vitro and in vivo sensitivity could not be revealed in this small group of patients.

Adult↗
PubMed2004

Striking complete remission after interferon-alpha for secondary recurrent non-Hodgkin's lymphoma but rare interferon-induced side effects.

Interferon (IFN) treatment is a therapeutic option in the treatment of non-Hodgkin's lymphoma (NHL). Although randomized trials have failed to show significant differences in progression-free and overall survival (OS) with IFN compared to placebo after peripheral blood stem cell transplantation (PBSCT) as well as standard therapy for NHL, anecdotal case reports have documented impressive results in selected patients. With this case report, we demonstrate an astounding success of IFN therapy given in the treatment of a young man with second relapse after two consecutive autologous PBSCTs and abdominal irradiation. With occurrence of multiple lymph node enlargements despite this intensive treatment, he received IFN and obtained a well-documented complete remission (CR). Yet, treatment with IFN always has to be considered in the context of its significant side effect profile, which can have considerable impact on the patient's quality of life as illustrated in this case report.

Drug Evaluation↗
PubMed2004

Efficacy of interferon retreatment after relapse for chronic hepatitis C patients with biochemical response after first interferon therapy.

BACKGROUND: With respect to interferon (IFN) treatment for chronic hepatitis C, normalization of alanine aminotransferase (ALT) as well as clearance of hepatitis C virus (HCV)-RNA after IFN therapy is important. It has been shown that the incidence of hepatocellular carcinoma (HCC) in patients with normal ALT is significantly lower than that in those with elevated ALT after IFN therapy. We assessed the efficacy of IFN retreatment for chronic hepatitis C patients who had a biochemical response (BR) after the first IFN therapy and reelevated ALT during follow up, by a case control study. METHODS: Fifteen patients (case group; group 1) enrolled in this study showed a BR after the first IFN therapy and reelevated ALT during follow up. Next, we retrospectively selected 30 patients (control group; group 2) with no response (NR) after the first IFN therapy. Group 2 patients were matched 1 : 2 with group 1 patients for sex and age. All patients were given intramuscular injections of human lymphoblastoid IFN alpha daily (6 MU) for 8 weeks and then three times a week for 16 weeks. We compared the clinical and biological differences between group 1 patients and group 2 patients. Virological response (VR) was defined when serum HCV-RNA showed negativity more than 6 months after the completion of IFN therapy. BR was defined when ALT values remained normal during more than 6 months in spite of positive serum HCV-RNA, by reverse-transcription nested polymerase chain reaction, 3 and 6 months after the completion of IFN therapy. NR was defined as any response except for VR or BR. RESULTS: The rate of patients showing VR in this study was 6.7% (1/15) in group 1 and 13.3% (4/30) in group 2. There was no significant difference between the groups with respect to VR. BR occurred in 73.3% (11/15) of patients in group 1, but in only 3.3% (1/30) of patients in group 2 (P = 0.0002). CONCLUSIONS: We conclude that IFN retreatment is one of the effective strategies with which to achieve BR again in HCV-positive patients who had a BR after their first IFN therapy and reelevation of ALT during follow up.

Adult↗
PubMed1984

Mechanism of interferon action. Inhibition of vesicular stomatitis virus in human amnion U cells by cloned human leukocyte interferon.

The effects of a subsaturating, long treatment (24 h) dose of a highly purified cloned subspecies of human leukocyte interferon (IFN-alpha A) on vesicular stomatitis virus (VSV) primary macromolecular synthesis in tsG41-infected human amnion U cells were examined. IFN-alpha A, under these conditions, was found to inhibit primary VSV protein synthesis ten-fold while producing no detectable effect on the amount or integrity of primary viral message transcripts. There was no selective reduction by IFN-alpha A of the VSV G or M proteins.

Amnion↗
PubMed1985

Calmodulin in interferon preparations: effect of interferon on calmodulin bioactivity.

Heat-stable calmodulin immunoreactivity and bioactivity were detected in crude preparations of various types of human, murine and chicken interferons (IFNs). Calmodulin containing HuIFN-alpha was retained on a trifluorophenothiazine-Sepharose column. The two activities were separated by serial elutions with 50 microM Ca2+ (HuIFN-alpha) followed by 2 mM EGTA (calmodulin). While maintaining its full antiviral activity, calmodulin free HuIFN-alpha inhibited enhancement of Ca2+-ATPase activity in vitro by authentic purified eukaryote calmodulin. These results indicate that IFNs are calmodulin-binding proteins and that the secretion of both IFNs and calmodulin occurs from IFN-induced cells.

Animals↗
PubMed1985

Mechanism of interferon action. Production and characterization of monoclonal and polyclonal antibodies to the interferon-induced phosphoprotein P1.

Monoclonal and polyclonal antibodies to the interferon-induced phosphoprotein P1 were prepared using protein P1 purified from human amnion U cells as the immunogen. Rabbit antiserum to protein P1 recognized with comparable efficiency P1 both from human U cells and from mouse L929 cells. Immunoprecipitates that contained protein P1 also possessed a protein kinase activity that catalyzed the phosphorylation of protein P1 and the alpha subunit of initiation factor eIF-2. Three BALB/C mouse monoclonal antibodies efficiently recognized human protein P1, but either did not recognize or recognized very poorly P1 from mouse cells. A fourth monoclonal antibody against human P1 recognized mouse P1 with nearly equal efficiency. Immunoprecipitation of human P1 with different sequential combinations of the monoclonal antibodies suggest that two antigenic classes of protein P1 may exist.

Animals↗
PubMed1990

Existence and unique N-terminal sequence of alpha II (omega) interferon in natural leukocyte interferon preparation.

Human alpha interferon produced in Sendai virus-stimulated leukocytes was purified by immunosorbent affinity chromatography and subjected to subtype analysis. All subtypes in leukocyte culture supernatant were confirmed in purified preparation. One of these subtypes was reactive in Western blotting with antibody specific to alpha II (omega). N-terminal amino acid sequence analysis of this particular subtype showed addition of two amino acids to the N-terminus of alpha II predicted through cDNA studies. The apparent cleavage site for leader sequence of alpha II was different from the site common to all other alpha subtypes. This is the first report on the isolation of natural alpha II and its unique N-terminal amino acid sequence.

Amino Acid Sequence↗
PubMed1984

Role of the E receptor in interferon-gamma expression: sheep erythrocytes augment interferon-gamma production by human lymphocytes.

The E receptor is found on virtually all human T cells and is defined by its ability to bind to sheep erythrocytes (SRBCs). It was recently shown that a monoclonal antibody (MoAb) binding to the E receptor regulates interferon-gamma (IFN-gamma) production and lymphocyte activation. Here the effects of SRBCs on IFN production is examined since these bind to the E receptor. IFN-gamma production induced by phytohemagglutinin (PHA) in both fresh peripheral blood mononuclear leukocytes ( PBML ) and T-lymphocyte lines was augmented by 5- to 10-fold when cultured with SRBCs. The SRBCs increased IFN by interacting with the E receptor since its augmenting effect was blocked by the E-receptor MoAb 9.6. The augmenting effect of SRBCs was independent of blastogenic events since DNA synthesis was not similarly augmented by SRBCs and because IFN-gamma production was only increased after blastogenesis had occurred (in already differentiated lymphoblasts or in PBML 2-3 days after induction). Since it was found that only a short pulse of SRBCs was required for their action, this suggests that the studies employing SRBC rosetting as a fractionation technique for investigating the cell source of IFN-gamma should be viewed with caution.

Animals↗
PubMed1987

Macrophage activation by interferon alpha + beta is associated with a loss of proliferative capacity: role of interferon alpha + beta in the regulation of macrophage proliferation and function.

Murine peritoneal exudate macrophages (PEM) can be induced by colony-stimulating factor (CSF-1) to undergo extensive proliferation and colony formation in vitro. In the presence of interferon alpha + beta (IFN alpha + beta) the proliferative capacity of PEM was greatly suppressed in a dose-dependent manner. The antiproliferative activity of IFN alpha + beta appears to be noncytocidal and reversible at low concentrations. At higher concentrations, exposure to IFN alpha + beta was sufficient to cause growth inhibition in PEM. Tissue-derived PEM were at least 25-fold more sensitive than bone marrow GM-CFC to the antiproliferative activity of IFN alpha + beta. The fact that bone marrow-derived adherent cells also exhibited a higher degree of sensitivity than the less differentiated nonadherent counterparts suggests that the primary targets of IFN alpha + beta are cells derived from a later stage of development. Concomitantly with the loss of proliferative activity, both the tumoricidal and Fc receptor-mediated phagocytic activities in IFN alpha + beta treated PEM were greatly enhanced. These effects could be completely neutralized by the addition of anti-IFN alpha + beta immunoglobulin, indicating that they are mediated by the same molecule. This remarkable dichotomy in the actions of IFN alpha + beta (stimulates functional activities but suppresses proliferative capacity) suggests that IFN alpha + beta may play a role in the regulation of macrophage production and function.

Animals↗
PubMed1994

A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C.

BACKGROUND/AIMS: In chronic hepatitis C, interferon alfa (IFN-alpha) therapy fails to achieve a sustained response in approximately 75% of patients. Similarly, ribavirin induces only a transient response. The aim of this study was to evaluate whether ribavirin and IFN-alpha in combination could be effective in IFN-alpha-resistant chronic hepatitis C. METHODS: Twenty patients with chronic hepatitis C resistant to a previous course of IFN-alpha were randomly assigned to receive either ribavirin combined with IFN-alpha or IFN-alpha alone for 6 months. RESULTS: Serum alanine aminotransferase levels decreased significantly during therapy in both treatment groups, but after therapy, the levels remained significantly decreased only in the combination therapy group. Nine months after treatment, sustained normalization of aminotransferase levels, associated with sustained loss of serum hepatitis C virus RNA, was observed in 40% of the patients in the combination therapy group but in none of the patients treated with IFN-alpha alone (P < 0.05). The sustained response was accompanied by reduced hepatic necroinflammatory activity on biopsy. CONCLUSIONS: These findings suggest that ribavirin plus IFN-alpha combination therapy is able to induce a sustained biochemical and virological response in a significant proportion of patients with IFN-alpha-resistant chronic hepatitis C.

Adult↗
PubMed1984

Resistance of vaccinia virus to interferon is related to an interference phenomenon between the virus and the interferon system.

In this investigation the sensitivity of vaccinia virus to interferon (IFN) has been examined in cultured cells. In a variety of mouse and human cells of different origins vaccinia virus functions (RNA, protein, and virus yields) were found to be relatively resistant to IFN. In these systems, the levels of the IFN-mediated enzyme activities (2-5A synthetase and protein kinase) were severely impaired by the virus. This virus-mediated inhibitory effect developed with time after infection and was dependent on viral protein synthesis. Mixed infections between vaccinia virus and viruses (VSV or polio) which are sensitive to IFN showed that both protein synthesis and virus yields were not inhibited. These findings show that vaccinia virus can overcome the antiviral action of IFN and that viral gene functions appear to be involved in this interference phenomenon.

2',5'-Oligoadenylate Synthetase↗
PubMed1989

Interferon induction by viruses. XIX. Vesicular stomatitis virus--New Jersey: high multiplicity passages generate interferon-inducing, defective-interfering particles.

The infectious particles of plaque-derived, low multiplicity passaged wild-type VSV of New Jersey origin consistently induce about 1800 units of interferon (IFN)/10(7) aged chick embryo cells. This inducing capacity is sensitive to both uv radiation and heat (50 degrees). Virus obtained after two successive high multiplicity passages in GMK-Vero cells consistently induced over 25,000 units of IFN/10(7) cells. The IFN induction dose-response curve showed that one IFN-inducing particle (IFP) per cell sufficed to produce a quantum yield of IFN, but infection with two or more IFPs led initially to a marked suppression in the yield of IFN. IFN induction was attributed to two distinct defective particles that differed in size, both containing snap-back RNA, i.e., covalently linked, self-complementary [+/-]RNA. The IFN-inducing capacity of these defective-interfering particles was not inactivated by uv or heat. However heat did eliminate the IFN suppressing activity observed at higher multiplicities, implicating a heat-sensitive component in the virion as a regulator of IFN yield, and involving possibly the virion transcriptase and 3'-leader RNA product.

Animals↗
PubMed1991

Are the acid-labile interferon alpha and interferon omega-1 identical?

The interferon (IFN) activity found in human leukocyte IFN alpha preparations, autoimmune and AIDS sera, and others was reported to have distinct antigenic and deviating biological properties. This led to its vague designation as acid-labile and thermolabile IFN alpha. However, using specific monoclonal antibodies, the acid-labile component of IFN alpha (not exposed to pH 2) and recombinant IFN omega 1 showed significant relatedness. Monoclonal antibody T19, generated with virus-induced leukocyte IFN alpha that had not been exposed to pH 2, neutralized both the antiviral and antiproliferative activities of IFN omega-1, and vice versa; monoclonal antibody OMG 5, specific for recombinant IFN omega-1, cross-neutralized the antiviral and antiproliferative effects of the acid-labile component of leukocyte IFN alpha. When these two IFN preparations were incubated at pH 2 for 72 hr, their biological activity significantly decreased.

Animals↗
PubMed1992

Mechanism of interferon action: cDNA structure, expression, and regulation of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from human cells.

A molecular cDNA clone (P1 KIN) was isolated that encodes the human RNA-dependent P1/eIF-2 alpha protein kinase. The complete cDNA sequence of the P1 KIN cDNA was determined; the longest open reading frame (ORF) encoded a 551 amino acid protein with a deduced molecular weight of 62055 Da. Transcripts prepared from the P1 KIN cDNA by transcription in vitro with T7 RNA polymerase programmed the cell-free synthesis of a protein indistinguishable by immunoprecipitation and immunoblot gel analyses from the authentic 67-kDa P1 protein synthesized in human U cells treated with interferon (IFN). Furthermore, by use of a sensitive primer extension assay with T7 DNA polymerase, the major site of translation initiation within the deduced ORF of the P1 KIN cDNA was directly identified. Northern RNA gel-blot analysis revealed that the P1 KIN cDNA strongly hybridized to two IFN-induced mRNAs present in both human amnion U cells and HeLa cells; their sizes were 2.5 and 6 kb. Both transcripts were efficiently induced by IFN-alpha, but poorly by IFN-gamma. Polyclonal antibody was prepared against the product of the P1 KIN cDNA expressed in Escherichia coli. In Western blot analysis the antibody recognized a 67-kDa protein induced in human cells by IFN-alpha and, in addition, a 90-kDa protein whose level was not greatly altered by IFN treatment. The IFN-induced 67-kDa protein was found associated with the ribosomal salt-wash fraction of IFN-treated human cells, whereas the 90-kDa protein was predominantly in the S100 soluble fraction. The time course for the induction by IFN-alpha of RNA-dependent protein P1 kinase activity measured by immunoprecipitation was comparable to the time course for protein P1 induction measured by Western immunoblot analysis. The amino acid sequence of P1/eIF-2 alpha protein kinase deduced from the cDNA was 62% identical with the 518-residue murine TIK kinase and contained, within the carboxy-terminal half of the protein, the motifs commonly conserved among protein-serine/threonine kinases. The amino-terminal half of the P1 protein did not possess conserved kinase motifs, but did show extensive homology with vaccinia virus-predicted protein E3L.

Amino Acid Sequence↗
PubMed1990

Prospective randomized trial of topical alpha-interferon (alpha-interferon gels) for the treatment of vulvar intraepithelial neoplasia III.

Twenty-one patients were prospectively randomized into a blinded double-armed crossover study comparing alpha-interferon (alpha-IFN, 10(6) IU in a 3.5% aqueous methylcellulose base) with and without 1% nonoxynol-9. Nine and twelve patients were randomized to arms with (+N) and without (-N) 1% nonoxynol-9, respectively. Patients applied the gel to affected areas every 8 hr and were evaluated biweekly. Including those crossed over, 14 patients were treated with -N. Six of fourteen (43%) achieved complete responses: biopsy proven with at least 1 year follow-up (CR). One patient achieved a partial response with at least a 50% reduction in the total surface area of all lesions present (PR). Similarly, 13 patients were treated with +N. Two patients in this group were found to have invasive cancer and one to have HIV and thus were eliminated from statistical analysis. Of the remaining 10 patients, 3 had CRs (30%), 5 had PRs (50%), and 2 failed to respond. There was no significant difference in responses between the two groups. Overall, 14 of 18 (67%) patients demonstrated some response to alpha-IFN applied topically. These data support the conclusion that alpha-IFN is an active agent in the treatment of vulvar intraepithelial neoplasia III.

Administration, Topical↗
PubMed1993

Mechanism of interferon-gamma down-regulation of the interleukin 4-induced CD23/Fc epsilon RII expression in human B cells: post-transcriptional modulation by interferon-gamma.

It has been reported that the interleukin 4 (IL-4) specific induction of cell surface CD23 (Fc epsilon RII) is down-regulated by interferon-gamma (IFN-gamma) in monocytes and B cells. However, the molecular level at which the inhibition occurs seems to vary depending on the cell types. In normal human B cells, IFN-gamma inhibits the IL-4 induced de novo synthesis of CD23 at the level of gene expression. Analysis of inhibition kinetics suggested a rapid signal transmission by IFN-gamma. Yet the inhibitory action of IFN-gamma on CD23 mRNA accumulation appeared as a secondary response requiring a new protein synthesis. Through nuclear run-on transcription and mRNA stability studies, we further demonstrate that the IL-4 induced CD23 gene expression is down-regulated by IFN-gamma mainly at post-transcriptional levels by decreasing mRNA stability.

B-Lymphocytes↗
PubMed1995

The sequence 130-137 of human interferon-alpha 2 is involved in the competition of interferon, prothymosin alpha and cholera toxin B subunit for common receptors on human fibroblasts.

125I-labelled recombinant human interferon alpha 2 (rHuIFN-alpha 2) capable of high-affinity binding (Kd = 2.46 +/- 0.18 x 10(-10) M) with receptors expressed on mouse thymocytes was obtained. Prothymosin alpha (proTM-alpha) but not cholera toxin was found to compete with radiolabelled IFN-alpha 2 for binding to the same receptor (Ki = 3.68 +/- 0.21 x 10(-11) M). The synthetic peptide covering the sequence 130-137 of IFN-alpha 2 (authors' definition: alpha-peptoferon) was shown to have the capacity to displace the labelled IFN-alpha 2 from the IFN-alpha 2/receptor complex (Ki = 7.19 +/- 0.12 x 10(-11) M). It was shown that receptors of this type are localized in plasmatic membrane fraction. Using [125I]-alpha-peptoferon, specific and saturable binding was detected on human fibroblasts and the data fitted a single binding site. Scatchard analysis yielded a Kd of 9.63 +/- 0.17 x 10(-8) M. The binding was competitively inhibited by IFN-alpha 2 (the Ki value in competition assays was 1.37 +/- 0.12 x 10(-8) M), proTM-alpha(Ki = 2.2 +/- 0.2 x 10(-7) M) and cholera toxin B subunit (Ki = 5.5 +/- 0.2 x 10(-7)). The present study has demonstrated that the sequence 130-137 of HuIFN-alpha 2 is involved in the competition of HuIFN-alpha 2, proTM-alpha and cholera toxin B subunit for common receptors on human fibroblasts.

Amino Acid Sequence↗