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PubMed1987

Effect of interferon alpha, interferon beta, and interferon gamma on the in vitro growth of human renal adenocarcinoma cells.

Interferon-alpha, interferon-beta, and interferon-gamma differ in their antiproliferative effects for several cell lines. Interferons were thus assessed for their activity in inhibiting proliferation of three renal cell carcinoma cell lines. The malignant epithelial phenotype of each of these cell lines was confirmed by electron microscopy, histology, karyotype and tumorigenicity. When compared on an anti-viral unit basis, naturally produced interferon-beta was more effective than natural interferon-alpha for all cell lines and clones. Proliferation of each of the cell lines was inhibited by interferon-gamma. In all cases, removal of interferons from culture media resulted in resumption of the rate of cell growth after a variable delay of 6-10 days. If the antiproliferative effects of interferons predominate in mediating tumor regression, clinical response may depend upon the type of interferon to which the tumor is exposed.

Adenocarcinoma↗

PubMed2002

Daily or three times per week interferon alpha-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C not responding to previous interferon alone.

BACKGROUND/AIMS: We compared the efficacy and safety of the combined therapy of daily interferon alpha-2b and ribavirin with those of interferon alpha-2b three times per week alone or in combination with ribavirin in non-responder patients with hepatitis C virus (HCV) infection. METHODS: A total of 376 patients were randomly assigned to receive interferon alpha-2b (6 MU three times per week for 24 weeks followed by 3 MU three times per week for 24 weeks) alone (group A) or in combination with ribavirin for 48 weeks (group B), or daily interferon alpha-2b (3 MU per day for 24 weeks followed by 3 MU three times per week for 24 weeks) and ribavirin (group C). RESULTS: After 24 weeks of therapy, HCV RNA was undetectable in 11.7, 24.0, and 37.8% for groups A, B, and C, respectively. Sustained virological response was more frequent in patients who received combination therapy with three times weekly interferon (20.9%) or daily interferon (26.0%) than in patients who received interferon alone (5.8%) (P<0.001). The predictive HCV parameters for sustained response were a low viral load on day 7 and a negative HCV RNA on week 12. CONCLUSIONS: In conclusion, in non-responder patients with chronic hepatitis C, virological response with daily interferon and ribavirin, compared to interferon monotherapy, was significantly improved during treatment, although sustained virological response was similar for both combination therapies with ribavirin and three times a week or daily interferon.

Adult↗

PubMed1994

A disturbance of interferon synthesis with the hyperproduction of unusual kinds of interferon can trigger autoimmune disease and play a pathogenetic role in AIDS: the removal of these interferons can be therapeutic.

Disturbances of interferon synthesis with the hyperproduction of unusual kinds of interferons may be the initial step which triggers autoimmune disease through a chain of pathological reactions including the disturbances of several immunological and cytokine cascades. Prolonged circulation of this interferon may be a predictive marker of an autoimmune condition; the administration of interferons to animals or humans with autoimmune disease or an underlying or latent autoimmune condition can exacerbate or trigger the disease. Healthy people do not have interferon in their blood. This fundamental disturbance of interferon synthesis can result either from a genetic predisposition or from the influence of certain viruses (or viral particles) or both factors together. AIDS has many features similar to autoimmune disease, including the hyperproduction of aberrant interferon, a type with restricted anti-HIV activity, protectively induced by HIV to allow its continued replication and survival. This interferon stimulates the production of certain cytokines and autoantibodies which help unleash the potentially self-destructive powers of the immune system, bringing immunological chaos. In other words, while usual viruses induce normal interferon, which protects the cells against viral infection, HIV induces an abnormal, defective kind of interferon which ensures virus survival. Since there is no known effective method of destroying HIV directly, removing links in this chain of reactions could indirectly destroy HIV and possibly help restore immune functioning.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗

PubMed1980

Regulation of the stability of poly(I)xpoly(C)-induced human fibroblast interferon mRNA: selective inactivation of interferon mRNA and lack of involvement of 2',5'-oligo(A) synthetase activation during the shutoff of interferon production.

The inactivation of interferon mRNA during the shutoff phase of interferon production in poly(I)xpoly(C)-induced human fibroblast cultures is selective. We have determined that the shutoff of interferon production, which takes place from 3 to 8 hr after the beginning of induction, is not associated with an appreciable declined in the rate of bulk cellular protein synthesis or of cellular protein secretion. While the amount of translatable interferon mRNA declined markedly during the shutoff phase, the level of translatable bulk cellular mRNA and the stability of [3H]uridine-labeled mRNA were unaffected. Superinduction with actinomycin D selectively stabilized interferon mRNA with no apparent effect on the stability of bulk cellular mRNA. Furthermore, an activation of the 2',5'-oligo(A) synthetase/endonuclease system does not appear to be involved in the shutoff phenomenon. Uninduced FS-4 cells contained a low basal level of 2'5'-oligo(A) synthetase activity, which was unchanged in poly(I)xpoly(C)-induced cells during the shutoff phase. Treatment of FS-4 cells with interferon for 16-18 hr prior to induction increased the enzyme activity by approximately 200-fold. However, this did not inhibit interferon production after induction with poly(I)xpoly(C) alone or after superinduction with cycloheximide or actinomycin D or both. Furthermore, the rates of decay of interferon production were comparable in cells with either a basal or an increased level of 2',5'-oligo(A) synthetase. Thus a 200-fold increase in 2',5'-oligo(A) synthetase level did not affect either the stability of interferon mRNA or the efficacy of interferon superinduction by metabolic inhibitors.

2',5'-Oligoadenylate Synthetase↗

PubMed2001

Combination of "low-dose" ribavirin and interferon alfa-2a therapy followed by interferon alfa-2a monotherapy in chronic HCV-infected non-responders and relapsers after interferon alfa-2a monotherapy.

AIM: To report on the efficacy, safety and tolerability of interferon alfa-2a combined with a low dose of ribavirin for relapsers and non-responders to alpha interferon monotherapy. METHODS: Thirty four chronic hepatitis C virus-infected non responders to interferon alfa-2a monotherapy (a course of at least 3 months treatment) and 13 relapsers to interferon alfa-2a monotherapy (a dose of 3 to 6 million units three times per week for at least 20 weeks but not more than 18 months) were treated with the same dose of interferon alfa-2a used before (3 to 6 million units three times per week) and ribavirin (10mg/kg daily) for 6 months. In complete responders, interferon alfa-2a was administered for further 6 months at the same dose used before as monotherapy. RESULTS: Seven (20.6%) of 34 non responders stopped the combined therapy due to adverse events, including two patients with histological and clinical Child A cirrhosis. In 17/27 (63%) non responders, the combined therapy was stopped after three months because of non response. Ten of the 27 non responders completed the 12 month treatment course. At a mean follow up of 28 months (16-37 months) after the treatment, 4/10 (15%) previous non responders still remained complete responders. All 13 previous relapsers completed the 12-month treatment course. At a mean follow up of 22 months (9-36 months) after treatment, 6/13 (46%) the previous relapsers were still sustained complete responders. CONCLUSION: Our treatment schedule of the combined therapy for 6 months of interferon Alfa-2a with a low dose of ribavirin (10mg/kg/day) followed by 6 months of interferon Alfa-2a monotherapy is able to induce a sustained complete response rate in 15% of non responders and 46% of relapsers with chronic hepatitis C virus related liver diseases comparable to those obtained with the standard doses of ribavirin 1000-1200 mg/day. Randomized prospective controlled trials using lower total amounts of ribavirin in combination with interferon should be performed.

Antiviral Agents↗

PubMed1982

Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. II. Role of host mechanisms.

We have attempted to determine what host mechanisms are responsible for inducing a rapid decrease in the number of Friend leukemia cells (FLC) in the peritoneal cavity of interferon-treated mice. By injecting radiolabelled FLC, we showed that there was a greater loss of radioactivity from individual interferon-treated mice than from control mice. Thus, it was likely that fewer cells were recovered from the peritoneal cavity of interferon-treated mice because of cell destruction. Treatment of mice with interferon limited to the period preceding tumor-cell inoculation conferred some degree of antitumor activity, although this regimen was far less effective than when interferon treatment was initiated and continued daily after tumor-cell inoculation. We have been unable to transfer any antitumor activity with peritoneal washings containing macrophages and lymphocytes from interferon-treated donor mice to tumor-inoculated recipient mice. Inoculation of silica particles i.p., which destroys macrophage function and may affect NK cell activity, did not abrogate interferon's antitumor activity. We suggest that interferon induces a host-mediated antitumor effect by mechanisms which are not mediated by easily recoverable soluble factors or by cytotoxic cells. The nature of this potent interferon-induced host mechanism remains unknown.

Animals↗

PubMed2000

Interferon and ribavirin versus interferon and amantadine in interferon nonresponders with chronic hepatitis C.

OBJECTIVE: The aim of this study was to compare the potential efficacy and safety of a combination of interferon and ribavirin with that of interferon and amantadine in patients who had previously failed to respond to interferon monotherapy. METHODS: A total of 29 patients were randomized to 3 million units of alpha-interferon three times weekly with 1000 mg of ribavirin daily (group A, n = 14) or an identical dose of alpha-interferon and amantadine hydrochloride given in a dose of 200 mg daily (group B, n = 15). Patients were treated for 24 wk and observed for 24 wk posttreatment. RESULTS: The treatment groups were evenly matched with respect to gender, frequency of genotype 1, presence of fibrosis, as well as baseline alanine aminotransferase (ALT) and HCV RNA levels. At the end of therapy, five of 14 or 36% of patients in group A versus 0 of 15 in group B had both normal serum ALT and nondetectable HCV RNA by polymerase chain reaction (p = 0.017). A complete response was sustained, however, in only two of 13 patients (15%) in group A who completed 24 wk of observation posttreatment. CONCLUSIONS: A substantial proportion of interferon nonresponders have an end-of-treatment biochemical and virological response to a combination of interferon and ribavirin, and sustained responses are possible. The addition of amantadine to interferon, in contrast, does not seem to enhance the antiviral effectiveness of interferon in patients who have previously failed to respond.

Adult↗

PubMed1999

Interferon alpha plus ketoprofen or interferon alpha plus ribavirin in chronic hepatitis C non-responder to interferon alpha alone: results of a pilot study.

BACKGROUND: Recently, in vitro and in vivo studies demonstrated that non-steroidal anti-inflammatory drugs are able to enhance the activity of interferon alpha. AIM: To evaluate the efficacy and tolerability of ketoprofen (a non-steroidal anti-inflammatory drug) plus interferon alpha (group B) compared to interferon alpha plus ribavirin (group C) and interferon alpha alone (group A) in chronic hepatitis C non-responders after a 5-month course with interferon alpha. PATIENTS AND METHODS: Without stopping interferon alpha, 49 patients were randomized to receive one of the three treatment regimens for 4 months. RESULTS: Three patients discontinued the therapy. One out of 16 patients in group A, 6/16 in group B and 5/14 in group C, alanine aminotransferase returned to normal at the end of the therapies (B vs A: p=0.04); serum hepatitis C virus-RNA became negative in 1 patient in group A and in 4 patients in both group B and group C. Six months after treatment, normal alanine transferase and negative hepatitis C virus-RNA were observed in 3 patients in group B and 2 in group C. In these patients, liver histology significantly improved. CONCLUSIONS: These results indicate that a certain number of non-responder patients to interferon alpha can benefit from a combination therapy of interferon alpha plus ketoprofen that is at least as effective as the combination interferon alpha plus ribavirin.

Adolescent↗

PubMed1986

31P-nuclear magnetic resonance analysis of interferon-induced alterations of phospholipid metabolites in interferon-sensitive and interferon-resistant Friend leukemia cell tumors in mice.

Adult DBA/2 mice were given injections s.c. with either interferon-sensitive (745) or -resistant (3Cl-8) Friend erythroleukemia cells (FLC). After tumor nodules had developed, mouse interferon-alpha/beta was injected daily into the tumor. 31P-Nuclear magnetic resonance (NMR) spectroscopy examinations were undertaken on freshly dissected tumors at different days of treatment with either interferon or control preparations. Analysis of 745 FLC tumors in untreated mice at different days of tumor growth (day 8 to 13 after tumor implantation) showed marked increases in the levels of phosphorylcholine (PCho), glycerophosphorylethanolamine (GroPEtn) and glycerophosphorylcholine (GroPCho). In contrast high levels of PCho, GroPEtn and GroPCho were already detectable in the 3Cl-8 FLC tumors on day 8, and no significant changes were observed during subsequent tumor growth. The intracellular pH value remained practically constant in both FLC tumors. Daily intratumoral administration of either partially purified (10(7) IU/mg of protein) or highly purified (10(9) IU/mg of protein) mouse interferon-alpha/beta to both cell tumors resulted in decreases in the levels of PCho, GroPEtn and GroPCho and in increases in the intracellular pH with respect to tumors treated with control preparations or left untreated. Two days of daily treatment of mice with interferon sufficed to induce these metabolic changes which preceded the appearance of necrosis in the tumors. Treatment of FLC tumors with X-rays on day 12 of tumor growth did not result in any comparable metabolic changes 2 days after irradiation. Changes in the levels of phospholipid metabolites were not observed when 745 or 3Cl-8 cells were cultivated in the presence of interferon. As interferon induced these changes in both interferon-sensitive and -resistant tumors we conclude that interferon treatment results in host-mediated effects on the biosynthesis and/or catabolism of tumor cell phospholipids.

Animals↗

PubMed2001

A randomized, double-blind controlled trial of interferon alpha-2b and ribavirin vs. interferon alpha-2b and amantadine for treatment of chronic hepatitis C non-responder to interferon monotherapy.

BACKGROUND/AIMS: Interferon-based regimens (alone or with ribavairin) are standard therapies for chronic hepatitis C. The aim of this study was to compare a 24-week regimen of interferon alpha-2b + ribavirin (IFN + RIBA) to interferon alpha-2b + amantadine (IFN + AMANT) in non-responders to previous interferon monotherapy. METHODS: In a multi-center, double-blind clinical trial, 118 patients (non-responders to previous interferon monotherapy) were equally randomized into the two arms: interferon alpha-2b (3 MU thrice weekly) and ribavirin (800 mg daily) vs. interferon alpha-2b (3 MU thrice weekly) and amantadine (200 mg daily). RESULTS: After 24 weeks of therapy, HCV RNA became undetectable in 34.8% (95% CI: 23.7-49.2) of IFN + RIBA and 19.6% (95% CI: 10.6-34.7) of IFN + AMANT (P = 0.10). This response was sustained in 3.9% (95% CI: 1.0-14.9) of IFN + RIBA and 0% of IFN + AMANT (P = 0.16). Ten patients from IFN + AMANT (17%) and 12 patients (20%) from IFN + RIBA were discontinued before completion of therapy. Of these, 7% in IFN + AMANT and 12% in IFN + RIBA were discontinued due to adverse effects. CONCLUSIONS: Re-treatment of interferon non-responders with a 24-week course of IFN + AMANT was not associated with any sustained viral eradication. Although IFN + RIBA in this group was associated with a reasonable end of treatment response, relapses were common and sustained responses were low.

Adult↗

PubMed1999

Interferon versus ribavirin plus interferon in chronic hepatitis C previously resistant to interferon: a randomized trial.

BACKGROUND: More than 70% of patients with chronic hepatitis C are resistant to interferon therapy. Ribavirin, in association with interferon, has been demonstrated as effective, at a dose of 800-1200 mg/day, but the efficacy of a lower dose has not been established. METHODS: We assessed the effectiveness of the combination of 600 mg/day of ribavirin plus 3 MU of interferon over a period of 6 months, in a group of patients previously resistant to interferon. Sixty-two patients with chronic hepatitis C with serum and hepatic HCV RNA relapsers or non-responders to interferon, were randomly divided into two groups: group A received 3 MU of interferon alpha-2b, three times a week for 6 months; group B was given the same dose plus 600 mg per day of ribavirin for 6 months. Two patients from each group dropped from therapy. One patient from group A and two from group B withdrew from treatment because of adverse effects. RESULTS: Mean alanine aminotransferase levels were similar in both groups throughout the study. A sustained response was observed in 7% and 7.4% of groups A and B with short-term response in 39% and 59%, and no response in 54% and 34% from both groups respectively (non-significant). At 12 months, 4 and 7 patients from groups A and B respectively, cleared serum HCV RNA however, only one sustained responder from each group cleared HCV RNA from peripheral blood mononuclear cells. At 18 months, 3 patients remained serum HCV RNA negative. Adverse effects were similar. Only haemoglobin values were lower in group B in the first month of therapy (p<0.05). CONCLUSION: In conclusion, the combination of 3 MU of interferon plus 600 mg of ribavirin is not effective in chronic hepatitis C resistant to interferon.

Adult↗

PubMed1983

Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. III. Inhibition of growth and necrosis of tumors implanted subcutaneously.

Administration of highly purified interferon to DBA/2 mice inhibited the growth of interferon-sensitive or interferon-resistant Friend erythroleukemia cells implanted subcutaneously. Injection of interferon at the site of tumor inoculation was more effective than injection of interferon intraperitoneally. Histologic examination of tumors in interferon-treated mice showed extensive areas of tumor-cell necrosis in the absence of an obvious host-cell infiltrate. Interferon inhibited the growth of established subcutaneous tumors and induced complete tumor regression in some mice. Interferon treatment also resulted in an inhibition of tumor metastases in the liver and spleen.

Animals↗

PubMed1993

A disturbance of interferon synthesis with the hyperproduction of unusual kinds of interferon can trigger autoimmune disease and play a pathogenetic role in AIDS: the removal of these interferons can be therapeutic.

Disturbances of interferon synthesis with the hyperproduction of unusual kinds of interferons may be the initial step which triggers autoimmune disease through a concatenation of pathological reactions including the disturbance of several immunological and interferon cascades. This fundamental disturbance can result either from a genetic predisposition or from the influence of certain viruses (or viral particles) or both factors together. The administration of interferons to individuals with an underlying or latent autoimmune condition can exacerbate or trigger the disease. AIDS has many features similar to autoimmune disease, including the hyperproduction of aberrant interferon, a type with little or no anti-HIV activity, protectively induced by HIV to allow its continued replication and survival. In other words, while most viruses induce normal IFN which protects the cells against viral infection, HIV induces an abnormal, defective kind of IFN which insures viral survival. The neutralization of hyperproduced interferons by polyclonal or monoclonal antibody produced in mouse, or preferably, human hybridoma, removal via extracorporeal means, or the use of antagonists which diminish the production or biological activity of these interferons can be a therapeutic approach to the management of these chronic diseases. In addition, the extracorporeal removal of different kinds of interferons, autoantibodies, autoantigens and other substances from the organism in certain pathological conditions may be an effective and safe method of treatment for autoimmune diseases and AIDS.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Effect of mouse interferon alpha/beta on the expression of H-2 (class I) antigens and on the levels of 2'-5' oligoadenylate synthetase activity in interferon-sensitive and interferon-resistant Friend leukemia cell tumors in mice.

DBA/2 mice were injected intraperitoneally (i.p.) with interferon-sensitive 745 or interferon-resistant 3C1-8 Friend erythroleukemia cells (FLC) and then injected i.p. with mouse interferon alpha/beta. Interferon enhanced the expression of histocompatibility (H-2) antigens on individual 745 FLC within the peritoneum, but did not alter the expression of H-2 antigens on individual 3C1-8 FLC. Likewise, interferon treatment resulted in an increase in the level of 2'-5' oligo-adenylate (2-5A) synthetase activity in 745 FLC, but did not affect the level of activity in 3C1-8 FLC. These results provide evidence that the phenotype of interferon sensitivity or resistance of FLC does not change within the peritoneum. An incidental finding was that the basal level of 2-5A synthetase activity of in vivo passaged 745 cells was greater than that of 3C1-8 FLC. The finding that injection of mice bearing 745 FLC with antibody to mouse interferon alpha/beta reduced the level of 2-5A synthetase activity in these cells, but did not alter the level of 2-5A activity in 3C1-8 FLC, suggests that endogenous interferon in the peritoneum may have been the responsible factor.

2',5'-Oligoadenylate Synthetase↗

PubMed2000

Loss of interferon alpha and interferon tau-induced antiviral protection in interferon regulatory factor-2 DNA-binding domain dominant negative mutants.

The role of the interferon regulatory factory (IRF) family of transcription factors in regulation of interferon alpha and interferon tau antiviral activity was investigated using a dominant negative mutant of IRF-2. The IRF-2 DNA binding domain (DBD), without the C-terminal regulatory region, was stably transfected into myeloid U937 cells. Expression of the IRF-2 DBD resulted in an increase in constitutive 2'5' oligoadenylate synthetase (OAS) levels, indicative of an active repressive mechanism, but was not sufficient to protect cells from challenge with vesicular stomatitis virus. Treatment of the DBD clones with interferons alpha A and tau failed to upregulate 2'5' OAS expression and did not elicit an antiviral response. While interferon alpha A was more sensitive than interferon tau to the inhibitory effects of the IRF-2 DBD, IRF-mediated gene induction is involved in successful interferon alpha and tau-induced anti-VSV activity.

2',5'-Oligoadenylate Synthetase↗

PubMed1998

Cytomegalovirus activates interferon immediate-early response gene expression and an interferon regulatory factor 3-containing interferon-stimulated response element-binding complex.

Interferon establishes an antiviral state in numerous cell types through the induction of a set of immediate-early response genes. Activation of these genes is mediated by phosphorylation of latent transcription factors of the STAT family. We found that infection of primary foreskin fibroblasts with human cytomegalovirus (HCMV) causes selective transcriptional activation of the alpha/beta-interferon-responsive ISG54 gene. However, no activation or nuclear translocation of STAT proteins was detected. Activation of ISG54 occurs independent of protein synthesis but is prevented by protein tyrosine kinase inhibitors. Further analysis revealed that HCMV infection induced the DNA binding of a novel complex, tentatively called cytomegalovirus-induced interferon-stimulated response element binding factor (CIF). CIF is composed, at least in part, of the recently identified interferon regulatory factor 3 (IRF3), but it does not contain the STAT1 and STAT2 proteins that participate in the formation of interferon-stimulated gene factor 3. IRF3, which has previously been shown to possess no intrinsic transcriptional activation potential, interacts with the transcriptional coactivator CREB binding protein, but not with p300, to form CIF. Activating interferon-stimulated genes without the need for prior synthesis of interferons might provide the host cell with a potential shortcut in the activation of its antiviral defense.

2-Aminopurine↗

PubMed2003

Interferons, interferon inducers, and interferon-ribavirin in treatment of flavivirus-induced encephalitis in mice.

We evaluated the prophylactic and therapeutic efficacy of interferon alpha-2b, pegylated interferon alpha-2b, poly(I. C), and Ampligen against Modoc virus encephalitis in an animal model for flavivirus infections. All compounds significantly delayed virus-induced morbidity (paralysis) and mortality (due to progressive encephalitis). Viral load (as measured on day 7 postinfection) was significantly reduced by 80 to 100% in the serum, brain, and spleen in mice that had been treated with either interferon alpha-2b, pegylated interferon alpha-2b, poly(I. C), or Ampligen. We also studied whether a combination of interferon alpha-2b and ribavirin (presently the standard therapy for the treatment of infections with hepatitis C virus) would be more effective than treatment with interferon alone. However, ribavirin did not enhance the inhibitory effect of interferon therapy in this animal model for flavivirus infections.

Animals↗

PubMed1990

Gene induction by interferons: functional complementation between trans-acting factors induced by alpha interferon and gamma interferon.

HeLaM is a variant cell line in which the transcriptional induction of many genes by alpha interferon has special characteristics (Tiwari et al., Mol. Cell. Biol. 8:4289-4294, 1988). The same characteristics were also displayed for induced transcription of a permanently transfected chimeric gene containing the interferon-stimulated response element of gene 561. For understanding the molecular basis of the special requirements of HeLaM cells, an analysis of the interferon-stimulated gene factors (ISGF) was undertaken. By using gel shift assays, it was shown that the activation of ISGF3 by alpha interferon treatment of HeLaM cells had characteristics identical to those of induced transcription: inhibition by 2-aminopurine and the need for ongoing protein synthesis which was obviated by pretreating the cells with gamma interferon. Upon mixing in vitro the cytoplasmic fraction of gamma interferon-treated HeLaM cells with that of cells treated with alpha interferon and cycloheximide, active ISGF3 was reconstituted, presumably through complementation of two components, ISGF3 gamma and ISGF3 alpha, present in the two respective fractions. Because, unlike other cells, untreated HeLaM cells did not contain detectable levels of either component, we could induce them individually and study their independent properties. Induction of ISGF3 gamma but not of ISGF3 alpha needed ongoing protein synthesis and was blocked by 2-aminopurine. Once induced, ISGF3 gamma was active for 24 h and was present in both the nuclear and cytoplasmic fractions. Activated ISGF3 alpha, on the other hand, did not translocate to the nucleus in the absence of ISGF3 gamma, and in the cytoplasm its activity decayed within 2 h of its activation. In reference to our working model, all of the above observations indicate that ISGF3 gamma is the product of signal 1 and ISGF3 alpha is the product of signal 2.

Base Sequence↗