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PubMed2001

Interferon-alpha plus amantadine in chronic hepatitis C resistant to interferon alone: a pilot randomized study.

The optimal therapy for patients with chronic hepatitis C who have not responded to interferon (IFN) is still an unsolved issue. The aim of this study was to evaluate the efficacy and tolerability of a high dose of IFN-alpha2a plus amantadine for chronic hepatitis C patients who were non-responders to a previous course of IFN. Forty consecutive patients with chronic hepatitis C, genotype 1b, who had not responded to IFN-alpha, were randomized to receive: (i) IFN 4.5 MU daily plus amantadine 200 mg/day for 4 weeks and then IFN 6 MU thrice weekly plus amantadine 200 mg/day for an additional 5 months (group A) or (ii) IFN alone at the same dosage and duration (group B). After 1 month of therapy, normal alanine aminotransferase (ALT) values were observed in three of 21 (14.3%) patients in group A and in three of 19 (15.8%) in group B; serum hepatitis C virus (HCV)-RNA clearance was observed in one patient (4.8%) in group A and in six (31.6%) in group B. At the end of treatment, six patients (28.6%) in group A and three (15.8%) in group B had normal ALT levels; however, HCV-RNA in serum was detectable in all of them at levels comparable to the basal values; an ALT relapse occurred within 3 months of stopping therapy. The combination of daily IFN plus amantadine was ineffective in this setting.

Amantadine↗
PubMed2001

Biochemical response to interferon therapy correlates with interferon sensitivity-determining region in hepatitis C virus genotype 1b infection.

Biochemical responders maintain normal alanine aminotransferase levels after interferon (IFN) therapy despite persistent presence of hepatitis C virus (HCV) RNA in their sera. There have been few reports on predictive factors for biochemical response. A region associated with sensitivity to IFN was identified in the nonstructural protein 5 A of genotype 1b [aa 2209-2248; IFN sensitivity-determining region (ISDR)]. The substitutions in ISDR correlate with sustained response to IFN. In this report, we assessed the association of ISDR with biochemical response. The sequences of ISDR were determined in 62 patients with HCV genotype 1b treated by IFN in two randomized controlled trials. 30 patients had wild ISDR (identical to HCV-J), 20 intermediate ISDR (1-3 amino acid substitutions compared with HCV-J), and 12 mutant ISDR (four or more amino acid substitutions). All 12 patients with mutant ISDR had a sustained response, while only one of those with wild or intermediate ISDR had a sustained response (P < 0.0001). In the 49 patients other than sustained responders, the patients with intermediate ISDR obtained biochemical response significantly more frequently (52.6%, 10/19) than those with wild-type ISDR (20.0%, 6/30) (P < 0.05). Multivariate analysis indicated the number of substitutions in ISDR as the most important predictor for biochemical response (discriminant coefficient=1.08, P < 0.05) and sustained response (discriminant coefficient=6.13, P < 0.0001). In phylogenetic analysis, clustering of sustained responders and biochemical responders was observed. These results demonstrate that the substitutions in ISDR are the most important predictor for biochemical response to IFN in patients infected with genotype 1b as well as for sustained response.

Adult↗
PubMed2003

Withdrawal of interferon-alpha results in prompt resolution of thrombocytopenia and hemolysis but not renal failure in hemolytic uremic syndrome caused by interferon-alpha.

This case report describes 2 patients with chronic myeloid leukemia in whom hemolytic uremic syndrome developed while being treated with interferon-alpha and hydroxycarbamide. Hemolytic uremic syndrome was recognized by progressive renal dysfunction, thrombocytopenia, microangiopathic hemolytic anemia, and histologic features of thrombotic microangiopathy in the kidney. Although renal dysfunction progressed to dialysis-dependent renal failure in one patient despite treatment with prednisolone and plasmapheresis but not in other, withdrawal of the treatment resulted in a prompt resolution of thrombocytopenia and microangiopathic hemolytic anemia in both patients.

Adult↗
PubMed2001

Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy: a meta-analysis of controlled and uncontrolled trials.

The efficacy of interferon (IFN) combined with ribavirin for the treatment of patients with hepatitis C who failed to respond to initial IFN therapy is not well established. The primary goal of this study was to perform a systematic review of the literature evaluating the efficacy of combination therapy in nonresponders. Studies were retrieved from MEDLINE, abstracts of scientific meetings, and review of the bibliographies of retrieved studies. Controlled trials were included in the primary analysis whereas uncontrolled trials and trials reported as abstracts were included for sensitivity analysis. The primary endpoints were biochemical and virologic response. A combined estimate of the odds ratio (OR) for each endpoint was obtained by using the random effects model. The number needed to treat (NNT) was calculated by taking the inverse of the pooled risk difference. Nine controlled trials (789 patients) were identified. Six months after treatment, the overall sustained biochemical and virologic responses to 24 weeks of combination therapy were 15.2% and 13.2% with a common OR of 3.8 (95% confidence interval [CI] 2.2-6.7) and 4.9 (95% CI 2.1-11.2) compared with patients treated with IFN monotherapy. The pooled risk difference for the sustained virologic response (SVR) to combination therapy was 7% (95% CI 2-13). The NNT was 14 (95% CI 8-50), suggesting that approximately 14 patients would need to be treated with 6 months of combination therapy for 1 patient to have a SVR. A number of variables were associated with a high response rate in individual studies. Sensitivity analysis of preliminary trials suggest a higher response rate with longer duration of therapy and non-type 1 genotypes.

Adult↗
PubMed2001

Combination of interferon and ribavirin in chronic hepatitis C: re-treatment of nonresponders to interferon.

Chronic infection with hepatitis C virus (HCV) may result in cirrhosis, liver failure, and hepatocellular carcinoma. A minority of patients have a sustained response to antiviral therapy, and nonresponders remain at risk of developing progressive liver disease. We conducted a randomized, controlled trial of therapy with the combination of interferon (IFN) and ribavirin in patients with chronic hepatitis C who had not responded to an initial course of therapy with IFN alone. A total of 124 patients were randomized to receive the combination of IFN and ribavirin for either 24 or 48 weeks and followed for an additional 24 weeks after stopping therapy. Thirty-eight treated patients (30.6%) achieved a sustained virologic response (undetectable HCV RNA at the 24-week follow-up point). This was associated with significant improvement in necroinflammatory activity noted on liver biopsy. Interestingly, there was not a statistically significant difference in response rates based on the duration of treatment; HCV genotype was the strongest predictor of a sustained response. Sustained responses were noted even in patients with poor predictive factors, including those with advanced hepatic fibrosis or cirrhosis, high levels of HCV RNA in serum, and those infected with HCV genotype 1. The study included 24 patients with normal serum alanine transaminase (ALT) values before therapy who had similar responses to those with initially elevated transaminase values. This study suggests that the combination of IFN and ribavirin is a useful modality of therapy in patients with chronic hepatitis C who did not respond to IFN alone.

Adult↗
PubMed2001

Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone: results of a pilot study.

Sustained viral suppression using monotherapy with interferon alfa (IFN-alpha) or lamivudine can only be achieved in a small percentage of patients with chronic hepatitis B. The concomitant administration of lamivudine and IFN-alpha does not enhance efficacy. We postulated that the optimal timing of therapy might be sequential treatment with lamivudine and IFN-alpha. The aim of this study was therefore to assess the efficacy of sequential treatment in patients resistant to IFN-alpha alone. Fourteen male patients, with a median age of 40 years, nonresponders to IFN-alpha with hepatitis B virus (HBV) DNA > 100 pg/mL (branched DNA [bDNA] Chiron) and positive hepatitis B e antigen (HBeAg) in 11 of 14 patients, were treated with lamivudine 100 mg/d alone for 20 weeks, then with both IFN-alpha2b 5 MU 3 times per week and lamivudine for 4 weeks, and lastly with IFN-alpha alone for 24 weeks. At the end of lamivudine therapy, all patients had undetectable serum HBV DNA, and none exhibited an emergence of HBV polymerase mutant or breakthrough. Sustained serum HBV-DNA clearance 6 months after the end of sequential treatment was achieved in 8 of 14 patients, HBeAg-to-anti-HBe seroconversion in 5 of 11 patients, and HBeAg and hepatitis B surface antigen (HBsAg) seroconversions in 3 of 14 patients (anti-HBs > 100 IU/mL). All sustained responders had normalized their alanine transaminase (ALT) values and exhibited histologic improvements. In conclusion, the results of this pilot study suggest that sequential treatment with lamivudine and IFN-alpha can induce a sustained virologic response, including HBs seroconversion, in patients with chronic hepatitis B not responding to IFN-alpha alone, without the selection of drug-resistant mutants. This therapeutic schedule warrants further evaluation in clinical trials.

Adult↗
PubMed2002

Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients: A pilot study.

Interferon alfa (IFN-alpha) therapy remains a mainstay of treatment in active hepatitis B. However, sustained remission rates remain relatively low, and the search for factors important for response to therapy continues. Our study aimed to identify the host single nucleotide polymorphisms (SNPs) that predict IFN response in hepatitis B patients. We selected genes in the IFN pathway involved in antiviral and signaling activities and sequenced 22 SNPs for each of our 82 patients. Our results identified 2 SNPs in the antiviral pathway that may influence IFN response. One SNP in the regulatory region of the eIF-2alpha gene revealed A/G alleles. The rate of A/G heterozygotes is 22% in nonresponders (NR) and 2% in sustained responders (R), with an odds ratio (OR) of 12.82 (95% CI: 1.52-107.85, P =.009). After adjustment for age, sex, and HBV DNA level, the OR reaches 14.94 (95% CI: 1.45-153.71, P =.023). This marker revealed greater significance than HBV DNA levels (OR: 5, 95% CI: 1.01-2.43, P =.033) as a marker for IFN response, suggesting its potential advantage over conventional predictors. In addition, borderline significance for the SNP in MxA gene promoter at nt -88 revealed G/T alleles, with the G/T heterozygote rate being 19% in nonresponders and 43% in sustained R (P =.061), concurring with a previous study involving hepatitis C patients. In conclusion, this pilot identified SNPs as potential markers that could predict hepatitis B patient response. These observations may help guide future large-scale studies in examining host SNPs for their clinical utility in predicting IFN response.

Adult↗
PubMed2001

Recurrent hepatitis C after liver transplantation: a nonrandomized trial of interferon alfa alone versus interferon alfa and ribavirin.

Liver transplant recipients with recurrent hepatitis C virus (HCV) infection often have histological hepatitis, and in some patients, graft failure develops. The aim of this nonrandomized study is to determine the efficacy and tolerability of interferon alfa (IFN alfa) alone and IFN alfa and ribavirin combination therapy in such patients. Forty transplant recipients with recurrent hepatitis were initiated on therapy with IFN alfa-2b at 3 million units (MU) three times weekly for 1 month followed by 5 MU three times weekly for 5 months. Twenty patients were administered IFN alfa-2b, 3 MU three times weekly for 1 month followed by 5 MU three times weekly for 11 months, and ribavirin, 600 mg, twice daily orally for 12 months concurrently. The primary end point was sustained clearance of serum HCV RNA, and secondary end points were serum alanine aminotransferase (ALT) level normalization and histological improvement. Thirty patients completed 6 months of IFN-alfa monotherapy and 15 patients completed 12 months of IFN alfa and ribavirin combination therapy. End-of-treatment biochemical responses were similar in the two groups (IFN alfa, 20% v combination therapy, 25%); however, viral clearance was greater in the combination-therapy group (40% v 15%; P = .04). Six months after the completion of therapy, only 1 patient (2.5%) in the IFN-alfa group and 4 patients (20%) in the combination-therapy group were HCV RNA negative (P = .03). Serum ALT and HCV RNA levels declined significantly in both groups during therapy. There was no improvement in inflammatory grade, and fibrosis score was worse in both groups. Ten patients (25%) in the IFN-alfa group and 5 patients (20%) in the combination-therapy group withdrew because of adverse effects. We conclude that in liver allograft recipients with recurrent hepatitis C, combination therapy with IFN alfa and ribavirin is more efficacious than treatment with IFN alfa alone. However, the efficacy is limited by tolerability.

Administration, Oral↗
PubMed1985

Close linkage of alpha and beta interferons and infrequent duplication of beta interferon in humans.

Five restriction fragment length polymorphisms in the human alpha/beta interferon (IFN-alpha/beta) gene region were identified, three with an IFN-alpha probe and two with an IFN-beta probe. Heterozygosities are 74% for IFN-alpha, 57% for IFN-beta, and 87% jointly, making IFN-alpha/beta genes excellent markers for the short arm of chromosome 9. The pedigrees of about 25 families of Caucasian background were studied. Segregation analysis disclosed the occurrence of 12 of 32 possible haplotypes. No recombinant was found between IFN-alpha and -beta genetic markers; linkage disequilibrium within the IFN-alpha markers is of a similar order of magnitude as that between the IFN-alpha and -beta markers. The IFN-alpha and -beta genes might cluster within several hundred kilobases. In two parents, the IFN-beta gene is duplicated; the duplications segregate regularly. They are of independent, probably recent, origin. Therefore, some degree of multiplicity might even be found for IFN-beta, at least in some individuals.

Adult↗
PubMed1988

Interferon-induced transcription of a major histocompatibility class I gene accompanies binding of inducible nuclear factors to the interferon consensus sequence.

Interferon (IFN) induces transcription of major histocompatibility class I genes by way of the conserved cis-acting regulatory element, termed the IFN consensus sequence (ICS). Binding of nuclear factors to the ICS was studied in gel mobility shift assays with the 5' upstream region of the murine H-2Ld gene. We found that the ICS binds a constitutive nuclear factor present in lymphocytes and fibroblasts regardless of IFN treatment. Within 1 hr after IFN treatment, new ICS binding activity was induced, which consisted of at least two binding activities distinguished by their requirement for de novo protein synthesis. Methylation interference and competition experiments showed that both constitutive and induced factors bind to the same approximately equal to 10-base-pair binding site within the ICS. Site-directed mutagenesis of H-2Ld-chloramphenicol acetyltransferase fusion genes showed that mutations in the binding site, but not in other regions of the ICS, abolish transcriptional activation of class I genes by IFN, providing evidence that specific binding of nuclear factors to the ICS is an essential requirement for transcriptional induction. Finally, we show that IFN-inducible genes of various species share a sequence motif that is capable of competing for the nuclear factors identified here. We propose that specific protein binding to the conserved motif represents a basic mechanism of IFN-mediated transcriptional induction of a number of genes.

Amino Acid Sequence↗
PubMed1988

Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes.

Nuclear proteins induced by interferon (IFN) treatment of human cells are capable of forming two specific complexes with DNA fragments containing the IFN-stimulated response element (ISRE). These two complexes, designated B2 and B3, are distinguished by differential migration in gel retardation assays. The factor that forms the B3 complex, termed IFN-stimulated gene factor 3 (ISGF-3), preexists in cells, is activated upon IFN treatment, and appears with kinetics paralleling those for transcriptional activation of IFN-stimulated genes. The factor that forms the B2 complex (ISGF-2) appears following a time lag after IFN treatment during which protein synthesis must occur. By extensive point mutagenesis of the ISREs from two IFN-stimulated promoters (ISG54 and ISG15), we demonstrate that the B2 and B3 complexes are formed by factors binding to the same DNA sequence. Mutations at this site decrease or eliminate transcriptional activation and impair binding of both ISGF-2 and ISGF-3. This analysis has shown that the ISGF-3 binding site is slightly broader than the ISGF-2 binding site, which is completely contained within the sequence necessary both for ISGF-3 binding and for transcriptional activation. The evidence strongly implicates ISGF-3 as the positive transcriptional regulator of IFN-stimulated genes.

Amino Acid Sequence↗
PubMed1992

The c-rel protooncogene product c-Rel but not NF-kappa B binds to the intronic region of the human interferon-gamma gene at a site related to an interferon-stimulable response element.

Interferon-gamma (IFN-gamma) is an important immunoregulatory protein that is expressed usually only in large granular lymphocytes and T cells. The gene encoding IFN-gamma was previously found to contain an intronic enhancer element that was not tissue-specific in its activity, despite the restricted expression of the intact IFN-gamma-encoding gene. Using nuclear extracts from the human T-cell line Jurkat, we have now identified two protein-binding regions in this intronic enhancer element. One of the protected regions has strong partial identify to the NF-kappa B site present in the promoter region of the human interleukin 2-encoding gene. Based on this observation and recent reports of the interaction of the c-rel protooncogene product (c-Rel) with NF-kappa B sites, we determined whether c-Rel could interact with the intronic enhancer element in the human IFN-gamma genomic DNA. Most surprisingly, gel-shift analysis, using c-Rel expressed in Escherichia coli established that c-Rel binds specifically to the IFN-gamma intronic DNA but not to the interleukin 2-like NF-kappa B site. Additional studies with antibodies prepared against c-Rel peptides verified specificity of the interaction of c-Rel with this binding site. In addition, using an affinity-purified p50 subunit of the NF-kappa B complex, we observed that the p50 protein did not bind to this additional c-Rel-binding site. Furthermore, nucleotide sequence analysis of this DNA region revealed a strong similarity of the additional c-Rel-binding site to a previously identified IFN-stimulable response element. These data show that c-Rel can interact with DNA regions distinct from that recognized by NF-kappa B and may, in fact, be involved in transcriptional regulation of the IFN-stimulable genes via the IFN-stimulable response element.

Base Sequence↗
PubMed1998

STAT3 complements defects in an interferon-resistant cell line: evidence for an essential role for STAT3 in interferon signaling and biological activities.

STAT proteins play critical roles in the signal transduction pathways for various cytokines. The type I interferons (IFNalpha/beta) promote the DNA-binding activity of the transcription factors STAT1, STAT2, and STAT3. Although the requirement for STAT1 and STAT2 in IFNalpha/beta signaling and action is well documented, the biological importance of STAT3 to IFN action has not yet been addressed. We found that STAT3 plays a critical role in signal transduction by IFNalpha/beta. A human cell line that is resistant to the antiviral and antiproliferative activities of IFN but is still IFN-responsive by virtue of STAT1 and STAT2 activation was found to be defective in STAT3 activation and in induction of NF-kappaB DNA-binding activity. Expression of STAT3 in these resistant cells complemented these signaling defects and also markedly increased cellular sensitivity to the antiviral and antiproliferative effects of IFN. Because STAT3 is involved in the induction of NF-kappaB DNA-binding activity and in the induction of antiviral and antiproliferative activity, our results place STAT3 as an important upstream element in type I IFN signal transduction and in the induction of biological activities. Therefore, our results indicate that STAT1 and STAT2 are not the only STATs required for the expression of the key biological activities of IFNalpha/beta.

Antiviral Agents↗
PubMed1998

Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages.

Hallmarks of chronic inflammation and tissue fibrosis are increased influx of activated inflammatory cells, mediator release, and increased turnover and production of the extracellular matrix (ECM). Recent evidence has suggested that fragments of the ECM component hyaluronan play a role in chronic inflammation by inducing macrophage expression of chemokines. Interferon-gamma (IFN-gamma), an important regulator of macrophage functions, has been shown to induce the C-X-C chemokines Mig and IP-10. These chemokines affect T-cell recruitment and inhibit angiogenesis. The purpose of this investigation was to determine the effect of hyaluronan (HA) on IFN-gamma-induced Mig and IP-10 expression in mouse macrophages. We found a marked synergy between HA and IFN-gamma on Mig and IP-10 mRNA and protein expression in mouse macrophages. This was most significant with Mig, which was not induced by HA alone. The synergy was specific for HA, was not dependent on new protein synthesis, was not mediated by tumor necrosis factor-alpha, was selective for Mig and IP-10, and occurred at the level of gene transcription. These data suggest that the ECM component HA may influence chronic inflammatory states by working in concert with IFN-gamma to alter macrophage chemokine expression.

Animals↗
PubMed2002

A novel mechanism by which interferon-gamma can regulate interleukin (IL)-13 responses. Evidence for intracellular stores of IL-13 receptor alpha -2 and their rapid mobilization by interferon-gamma.

Interleukin (IL)-13 mediates its activities via a complex receptor system. Interleukin-13 receptor alpha-1 chain (IL-13Ralpha1) binds IL-13 with low affinity, but does not signal. However, when IL-13Ralpha1 combines with IL-4 receptor alpha (IL-4Ralpha), a signaling high affinity receptor complex for IL-13 is generated. In contrast, IL-13Ralpha2 alone binds IL-13 with high affinity, but does not signal and has been postulated to be a decoy receptor. Herein, we investigated the cellular localization of IL-13Ralpha2 and the regulation of its expression by confocal microscopy and flow cytometry in primary and cultured cells. Our results demonstrate that IL-13Ralpha2 is largely an intracellular molecule, which is rapidly mobilized from intracellular stores following treatment with interferon (IFN)-gamma. Up-regulation of IL-13Ralpha2 surface expression in response to IFN-gamma was rapid, did not require protein synthesis, and resulted in diminished IL-13 signaling. These results provide the first evidence that the IL-13Ralpha2 is predominantly an intracellular molecule and demonstrate a novel mechanism by which IFN-gamma can regulate IL-13 responses.

Amino Acid Motifs↗
PubMed2003

Interferon-gamma induces p11 gene and protein expression in human epithelial cells through interferon-gamma-activated sequences in the p11 promoter.

The effect of interferon (IFN)-gamma on p11 expression was studied in two human epithelial cell lines (BEAS-2B and HeLa). Treatment with IFN-gamma resulted in increased steady-state levels of p11 mRNA and protein expression, with a time-dependent and dose-dependent effect. Transient transfection experiments of a reporter gene construct containing 1498 bp of the 5'-flanking region of the p11 promoter demonstrated that IFN-gamma induced p11 gene expression at the transcriptional level. These effects were inhibited at the promoter and protein levels by a specific JAK-2 kinase inhibitor, AG-490. Functional analysis of the p11 promoter indicates that two gamma-activated sequence elements (GAS) located at positions 1219 and 1090 are important for the induction of the p11 promoter by IFN-gamma. Transfection of mutated reporter constructs demonstrated that the mutation at the GAS-2 site (1090) inhibited the p11 promoter activity, with a reduction of about approximately 73% and mutation at the GAS-3 site (1219) eliminated about 26% of the p11 promoter activity. A STAT1 dominant negative mutant vector at Tyr-701 (JAK kinase phosphorylation site) blocked the effect of IFN-gamma on the p11 promoter activity. IFN-gamma induced a rapid tyrosine phosphorylation and nuclear translocation of STAT1 protein, which is involved in the binding to the GAS-2 site in the p11 promoter by EMSA analysis. These data suggest that IFN-gamma-induced p11 expression is mediated through the binding of STAT1 to GAS sites in the p11 promoter. Inhibition of p11 expression by inhibitory antisense RNAs (iRNA) treatment resulted in enhanced IFN-gamma and calcium ionophore-stimulated arachidonic acid release suggesting that at least in part IFN-gamma-stimulated p11 expression may serve a counterregulatory role.

Annexin A2↗
PubMed2003

Interferon-gamma stimulates the expression of the inducible cAMP early repressor in macrophages through the activation of casein kinase 2. A potentially novel pathway for interferon-gamma-mediated inhibition of gene transcription.

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that modulates the immune function, cell proliferation, apoptosis, macrophage activation, and numerous other cellular responses. These biological actions of IFN-gamma are characterized by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanisms through which the cytokine suppresses gene transcription remain largely unclear. We show here for the first time that exposure of macrophages to IFN-gamma leads to a dramatic induction in the expression of the inducible cAMP early repressor (ICER), a potent inhibitor of gene transcription. In addition, a synergistic action of IFN-gamma and calcium in the activation of ICER expression was identified. The IFN-gamma-mediated activation of ICER expression was not blocked by H89, bisindoylmaleimide, SB202190, PD98059, W7, and AG490, which inhibit protein kinase A, protein kinase C, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, calcium-calmodulin-dependent protein kinase, and Janus kinase-2, respectively. In contrast, apigenin, a selective casein kinase 2 (CK2) inhibitor, was found to inhibit response. Consistent with this finding, IFN-gamma stimulated CK2 activity and the level of phosphorylated cAMP response element-binding protein, which is known to induce ICER gene transcription, and this response was inhibited in the presence of apigenin. These studies, therefore, identify a previously uncharacterized pathway, involving the IFN-gamma-mediated stimulation of CK2 activity, activation of cAMP response element-binding protein, and increased production of ICER, which may then play an important role in the inhibition of macrophage gene transcription by this cytokine.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Role of nuclear factor-kappaB in the antiviral action of interferon and interferon-regulated gene expression.

Interferons (IFNs) play critical roles in host defense by modulating the expression of various genes via tyrosine phosphorylation of STAT transcription factors. IFN-alpha/beta activates another important transcription factor, nuclear factor-kappaB (NF-kappaB), but its role in IFN-mediated activity is poorly understood. Sensitivity to the antiviral and gene-inducing effects of IFN was examined in normal fibroblasts and in NF-kappaB knockout fibroblasts from p50- and p65-null mice. Antiviral assays demonstrated that NF-kappaB knockout fibroblasts were sensitized to the antiviral action of IFN. Moreover, analysis of IFN-stimulated gene expression by real-time PCR demonstrated selective effects of NF-kappaB on gene expression. Our results demonstrate that a subset of IFN-stimulated genes is regulated through an NF-kappaB-dependent pathway and that NF-kappaB may regulate the sensitivity of cells to IFN-mediated antiviral activity.

Animals↗