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PubMed1991

Cloning and structural analysis of two distinct families of ovine interferon-alpha genes encoding functional class II and trophoblast (oTP) alpha-interferons.

Ovine trophoblast protein (oTP) is a polypeptide secreted by ovine trophectoderm from day 11 to 21, which plays a key role in maternal recognition of pregnancy. Structural analyses established that oTP shares extensive homology with class II alpha-interferon (IFN-alpha II) subfamily. Previous screening of an ovine genomic DNA library probed with an oTP cDNA incidently resulted in the isolation of a functional IFN-alpha II gene and two relevant pseudogenes, as shown by sequence analysis and study of expression in eukaryotic COS cells. The expected oTP gene together with a cognate pseudogene was successfully isolated from the series of clones selected from another genomic library probed with the oTP cDNA, using two specific oligonucleotides, each one complementary to a region of oTP cDNA with little homology with the IFN-alpha II gene and related pseudogenes. Southern blotting of ovine genomic DNA indicated the existence of at least five trophoblast IFN-alpha genes or pseudogenes. Nucleotide sequence comparisons showed that the oTP gene exhibits a higher homology (90%) with bovine trophoblast IFN gene (Stewart et al. (1990) J. Mol. Endocrinol. 4, 275-282) than with oIFN-alpha II gene (70%), thus providing evidence that embryonic IFNs constitute a distinct subfamily of IFN-alpha s.

Amino Acid Sequence↗
PubMed1992

Abnormalities in serum concentrations of interleukin-2, interferon-alpha and interferon-gamma in schizophrenia not detected.

The hypothesis of an immunological defect in schizophrenia has been supported by reports on abnormal production of interleukin-2 (IL-2) and interferons (IFNs) in schizophrenic patients. In the present study we determined the serum concentrations of IL-2, IFN-alpha and IFN-gamma in 10 first onset, neuroleptic-naive schizophrenics, in 6 pretreated patients who were drug free (1 week to 2 years) at the time of the investigation and in 15 matched healthy controls. No IFN-alpha was detected in schizophrenics' and in control sera. No differences were found in IL-2 and IFN-gamma levels between schizophrenics and controls. Thus the present study failed to support the hypothesis of an immunological abnormality in schizophrenia on the basis of the determination of IL-2 and IFNs serum levels.

Adult↗
PubMed1990

Effects of interferon-alpha in patients with AIDS-associated Kaposi's sarcoma are related to blood interferon levels and dose.

Definition of improved therapeutic regimens of interferon-alpha (IFN-alpha) for the treatment of Kaposi's sarcoma (KS) would be useful since currently recommended doses are sometimes associated with unacceptable toxicity. IFN concentrations were measured in serum samples from men with AIDS-associated KS who were enrolled in a trial of IFN-alpha alone (16 patients) or a trial of IFN-alpha combined with zidovudine (25 patients). Analyses were done to examine the relationship between the dose of IFN-alpha, blood level of IFN, and the patient's clinical response to treatment. There was no correlation between dose of zidovudine given and response. As expected, there was a high correlation between dose of IFN-alpha and blood level in both studies (p less than 0.001). Furthermore, we found relationships between clinical response and both dose of IFN-alpha and blood level achieved. In the two studies combined, among men with greater than 200 CD4+ cells/mm3 of blood at baseline on average daily doses of greater than or equal to 10 million international units (MIU) of IFN-alpha, 13/19 (68%) responded compared to 6/17 (35%) on less than MIU (p = 0.05). Similarly, of men with IFN blood levels greater than or equal to 100 IU/mL 12/16 (75%) responded compared to 7/20 (35%) of those with blood levels less than 100 IU/mL (p = 0.02). The dose and blood levels of IFN achieved and maintained may be important factors in determining responses of KS. Additional clinical trials of IFN-alpha treatment of KS at doses about 10 MIU/day appear warranted.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Antiviral activity of CHO-SS cell-derived human omega interferon and other human interferons against HCV RNA replicons and related viruses.

The fully glycosylated human omega interferon produced from CHO-SS cells (glycosylated IFN-omega) has been shown to be well-tolerated in man and to induce a sustained virologic response in patients infected with hepatitis C virus (HCV). We examined the antiviral activity of glycosylated IFN-omega and various human IFNs (IFN-alpha, -beta, -gamma and non-glycosylated bacterial (Escherichia coli) recombinant IFN-omega (non-glycosylated IFN-omega)) against HCV RNA replicons and several viruses related to HCV. Since none of the IFNs displayed cytotoxicity we compared their activities based on the effective concentration of the IFN that inhibited virus growth by 50% (EC50). Glycosylated IFN-omega was found to be the most potent antiviral agent of all the IFNs tested against bovine viral diarrhea virus (BVDV), yellow fever virus and West Nile virus. With HCV RNA replicons, non-glycosylated IFN-omega was comparable in activity to IFN-alpha while glycosylated IFN-omega was markedly more potent, indicating that glycosylation has an important effect on its activity. Drug combination analysis of glycosylated IFN-omega+ribavirin (RBV) in BVDV showed a synergy of antiviral effects similar to IFN-alpha+RBV, as well as a unique antagonism of RBV cytotoxic effects by glycosylated IFN-omega. Transcription factor (TF) profiling indicated that IFN-alpha or glycosylated IFN-omega treatment upregulated the same 17 TFs. IFN-alpha and glycosylated IFN-omega also upregulated 9 and 40 additional unique TFs, respectively. The differences in the expression of these TFs were modest, but statistically significantly different for eight of the TFs that were upregulated exclusively by glycosylated IFN-omega. The activation of these additional TFs by glycosylated IFN-omega might contribute to its high potency.

Animals↗
PubMed2005

Susceptibility to exogenously added interferon-beta protein depends on intracellular interferon-beta mRNA level in human glioma cells.

Exogenously added human interferon-beta (HuIFN-beta) protein possesses a remarkable antiproliferative activity in human glioma and melanoma. Endogenous HuIFN-beta protein, which is produced by its gene transfer using cationic liposomes, has much more effective antiproliferative activity against these tumors, even in cells resistant to exogenously added HuIFN-beta protein. As the first step to elucidate the possible difference in antiproliferative mechanisms between exogenous and endogenous HuIFN-beta protein, we here investigated the relationship between the intracellular level of its mRNA and susceptibility to exogenously added HuIFN-beta protein. In this study, we used seven human glioma cell lines (SK-MG-1, SK-MG-4, SK-AO2, U87MG, U251SP, U251MG and T98) and one human melanoma cell line (MMAN). At first, we examined the relationship between spontaneous expression of HuIFN-beta mRNA and susceptibility to exogenously added HuIFN-beta protein (50 IU/ml) in human glioma cells and then confirmed a significant correlation between them. Next, we confirmed that administration of 0-100 IU/ml exogenously added HuIFN-beta protein upregulated the HuIFN-beta mRNA in a dose-dependent manner using the RT-PCR technique and that the HuIFN-beta mRNA was suppressed by siRNA for HuIFN-beta in SK-MG-1 and MMAN cells. Furthermore, we confirmed that the siRNA for HuIFN-beta significantly suppressed the antiproliferative effect of SK-MG-1 cells treated with 10-100 IU/ml HuIFN-beta protein and MMAN cells with 25 and 50 IU/ml HuIFN-beta protein. We found this phenomenon in another human glioma cell line, U87MG cells, as well. This finding would suggest that susceptibility to exogenously added HuIFN-beta protein is related to the amount of intracellular HuIFN-beta mRNA in human glioma and melanoma cells.

Cell Line, Tumor↗
PubMed2005

Biological standardization of human interferon beta: establishment of a replacement world health organization international biological standard for human glycosylated interferon beta.

Human interferon beta (IFN-beta) has been developed as a major biotherapeutic agent for the treatment of multiple sclerosis. Since World Health Organization (WHO) international standards (IS) for IFN-beta were established several years prior to the development of clinical grade IFN-beta products, a number of scientific issues with regard to the biological standardisation of natural and recombinant IFN-beta products have emerged. In order to address these issues, an international collaborative study to evaluate WHO IS and candidate international standards (CIS) of IFN-beta was instigated by the National Institute for Biological Standards and Control (NIBSC) in 2000 and was carried out in the succeeding year. Sixteen expert laboratories from 8 countries worldwide participated in the study. They performed titrations on 8 different IFN-beta preparations, including IS and new CIS, in a variety of mainly antiviral- but also including some antiproliferative- and reporter gene-assays, and contributed raw data from these assays to NIBSC for statistical analysis and calculation of potencies. While both intra- and inter-laboratory variation of potency estimates was evident, overall validity of the study as a whole was clearly shown by comparison of two pairs of internal coded duplicates, which gave the expected relative potency of 1 and the lowest inter-laboratory variability of potency estimates in all assay types. The CIS containing Chinese hamster ovary (CHO) cell- or human fibroblast-derived, glycosylated, IFN-beta gave similar low inter-laboratory variation in potency estimates one to another as the coded duplicates, which was significantly less than to the 2nd WHO IS of IFN-beta, human fibroblast-derived, Gb23-902-531. One of these CIS, designated 00/572, containing CHO cell-derived IFN-beta and formulated with both bovine casein and human serum albumin, could be assigned a potency, consistent for all assay types, of 40,000 international units (IU) per ampoule relative to the IU of the 2nd IS of IFN-beta, Gb23-902-531. Other CIS containing glycosylated IFN-beta, either CHO cell- or human-fibroblast-derived, could also be assigned potency values that were continuous with the IU of Gb23-902-531 and 00/572. However, greater inter-laboratory variations in estimates were evident from comparisons of Gb23-902-531 or 00/572 with either the 1st IS for E. coli-derived, non-glycosylated, IFN-beta with serine substitution at position 17 (IFN-beta Ser 17 mutein), Gxb02-901-535, or with a CIS (00/574) containing IFN-beta Ser 17 mutein. Indeed, variations in potency estimates for preparations containing IFN-beta Ser 17 mutein were sufficiently large to indicate that assays could distinguish preparations of IFN-beta Ser 17 mutein from preparations of glycosylated IFN-beta. Thus, neither the 2nd IS of IFN-beta, Gb23-902-531, containing fibroblast-derived IFN-beta, nor CIS, 00/572, containing CHO cell-derived IFN-beta, was appropriate for standardisation of preparations of IFN-beta Ser 17 mutein. Conversely, neither the IS of IFN-beta Ser 17 mutein, Gxb02-901-535, or a CIS of IFN-beta Ser 17 mutein, 00/574, was appropriate for the standardisation of preparations of glycosylated IFN-beta. CIS 00/572, containing CHO cell-derived, glycosylated IFN-beta, was clearly shown to be suitable to serve as a primary standard for glycosylated forms of IFN-beta, especially clinical grade IFN-beta-1a products. It was further shown to exhibit high thermal and long-term stability. Since the CHO cell-derived IFN-beta used for preparation of 00/572 was of a greater purity than the IFN-beta used for the 2nd IS of IFN-beta, Gb23-902-531, it was recommended by the WHO Informal Consultation on the Standardisation of Cytokines, Growth Factors and Other Endocrinological Substances, which met in October 2003, that 00/572 should replace Gb23-902-531 as the IS for glycosylated IFN-beta. This recommendation was accepted by the WHO Expert Committee on Biological Standardization (ECBS) at its annual meeting in November 2003 and 00/572 was established as the 3rd IS for human glycosylated IFN-beta with an assigned potency of 40,000 IU. As this study identified no advantage to replacing the existing 1st IS for IFN-beta Ser 17 mutein, Gxb02-901-535, WHO ECBS accepted that this should continue to serve as the IS for this material.

Animals↗
PubMed2005

Interferon-gamma and interferon-beta affect endogenous catecholamines in human peripheral blood mononuclear cells: implications for multiple sclerosis.

Interferon (IFN)-gamma plays a pivotal role in the pathogenesis of multiple sclerosis (MS), while IFN-beta may be able to modify the clinical course of the disease, eventually also by counterbalancing IFN-gamma-mediated effects. Catecholamines (CA) exert important effects on the immune response, both as transmitters between the nervous and the immune system, as well as autocrine/paracrine mediators in immune cells, and several lines of evidence support their involvement in MS. In particular, dysregulated production of CA seems to occur in peripheral blood mononuclear cells (PBMCs) of MS patients. We assessed the effects of IFN-beta and IFN-gamma on endogenous CA in PBMCs. In cultured PBMCs stimulated with phytohaemagglutinin (PHA), IFN-beta increased CA production and induced CA release in the culture medium, while IFN-gamma decreased both CA production and the expression of mRNA for the CA-synthesizing enzyme tyrosine hydroxylase. Coincubation with both IFNs prevented the inhibitory effect of IFN-gamma, as well as the stimulatory effect of IFN-beta. IFNs are the first physiological compounds shown to affect endogenous CA in PBMCs: in view of the role of CA-dependent mechanisms in the immune response, these findings may help to better understand the mechanisms of action of IFN-beta as an immunomodulatory drug in MS.

Blotting, Northern↗
PubMed2005

West Nile virus replication interferes with both poly(I:C)-induced interferon gene transcription and response to interferon treatment.

West Nile virus (WNV), the leading cause of viral encephalitis in the United States, is an arthropod-transmitted member of the family Flaviviridae. We have explored the interaction of this positive-strand RNA virus with signaling pathways involved in induction of the host's innate immune response. Phosphorylation of STAT-1 in response to interferon (IFN) treatment and the ability of IFN to establish an antiviral state were reduced in WNV replicon-bearing cell lines. Similarly, the activation of IRF3 and stimulation of IFN-beta transcription in response to the double-stranded RNA (dsRNA) mimetic poly(I:C) were inhibited in replicon-bearing and WNV-infected HeLa cells. In contrast, WNV replicons did not affect IRF3 activation by Sendai virus infection, suggesting that not all IRF3 activating pathways are inhibited by WNV. Taken together, these findings demonstrate that WNV replication in cultured cells interferes with both the response to IFN and synthesis of IFN-beta in response to dsRNA.

Active Transport, Cell Nucleus↗
PubMed2003

Inhibition of interferon-gamma-activated nuclear factor-kappa B by cyclosporin A: A possible mechanism for synergistic induction of apoptosis by interferon-gamma and cyclosporin A in gastric carcinoma cells.

We previously reported synergistic induction of apoptosis by IFN-gamma plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-gamma plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-gamma induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-gamma alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-gamma pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-gamma-induced anti-apoptotic pathway and we evaluated the effect of IFN-gamma and CsA on calcium-sensitive nuclear factor-kappa B (NF-kappa B) activation. IFN-gamma increased intracellular calcium ion concentration ([Ca(2+)](i)) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-kappa B occurred in response to IFN-gamma, and which was markedly inhibited by either CsA or FK506. NF-kappa B decoy also enhanced the cytotoxic effect of IFN-gamma. These results suggest that IFN-gamma may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-kappa B and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway.

Antineoplastic Agents↗
PubMed1997

Interferon gamma and interleukin 1, but not interferon alfa, inhibit rotavirus entry into human intestinal cell lines.

BACKGROUND & AIMS: Rotavirus, an important agent of gastroenteritis in children, causes diarrhea by infecting differentiated villus enterocytes in the small intestine. The aim of this study was to determine whether cytokines that can be expressed by mucosal cells have an effect on the rotavirus susceptibility of cultured human enterocytes. METHODS: Caco-2 and HT-29 cells were pretreated with various cytokines before challenge with rotavirus. RESULTS: Interleukin (IL)-1, interferon (IFN)-alpha, and IFN-gamma pretreatment led to a dose-dependent resistance to rotavirus infection. Maximum effects occurred after 72 hours of pretreatment, whereas no detectable inhibition occurred with <12 hours of pretreatment. Liposomal transfection of single-shelled and double-shelled rotavirus particles bypassed the block to rotavirus replication in IFN-gamma- and IL-1-treated but not IFN-alpha-treated cells. Binding studies with purified, metabolically labeled rotavirus showed no significant difference among IFN-gamma- and IFN-alpha-treated and control Caco-2 cells. Viral entry into Caco-2 cells was significantly inhibited by IFN-gamma and IL-1 but not IFN-alpha. CONCLUSIONS: IFN-alpha and IFN-gamma induce rotavirus resistance by different mechanisms, suggesting that cytokines play a role in host defense against viral agents by changing the phenotype of intestinal epithelial cells.

Antiviral Agents↗
PubMed1998

Interferons and interferon-induced antiviral proteins in the testis.

Despite the dramatic development of sexually transmissible diseases, the antiviral capabilities of testicular cells have not yet been explored. Interferons (IFNs) are proteins playing a key role in the antiviral defense system, their activity being mediated by several IFN-induced proteins. In the present study, we have investigated both the expression of IFN and of the three main IFN-induced proteins by isolated testicular cells. The highest responders to a viral stimulation in terms of IFN production are the Leydig and the Sertoli cells, followed by peritubular cells and testicular macrophages, while germ cells are devoid or virtually devoid of IFN and IFN-induced protein expression. Sertoli cells constitutively expressed the three IFN-induced proteins tested, and their levels were greatly increased after exposure to Sendai virus. Peritubular cells were also able to markedly express these three proteins after viral exposure. In conclusion, we hypothesize that, for a virus coming from the blood, the first testicular line of defence is ensured by Leydig cells and testicular macrophages, the second line being ensured by the myoid cells, lining the seminiferous tubules, and by Sertoli cells. These two barriers are probably fundamental in protecting both androgen production and spermatogenesis.

Animals↗
PubMed2000

Interferon-beta treatment in multiple sclerosis patients decreases the number of circulating T cells producing interferon-gamma and interleukin-4.

Systemic administration of interferon (IFN)-beta has been recently approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The immunological mechanism by which IFN-beta ameliorates MS is still partially unknown. We measured the number of blood circulating CD4(+), CD4(-), CD8(+), and CD8(-) T cells secreting IFN-gamma and IL-4 in 26 RRMS patients followed for up to 9 months of an alternate day s.c. treatment with 8x16 IU of IFN-beta1b. Compared to pre-treatment values, a significant (P<0.05) reduction of CD4(+), CD4(-), CD8(+) and CD8(-) cells producing IFN-gamma and of CD4(+) and CD4(-) cells producing IL-4 was observed in MS patients. The IFN-beta-associated effect was evident soon after the beginning of the treatment and persisted for the entire follow-up period. We did not observe any effect of IFN-beta treatment on the percentage of IL-4-producing CD8(+) and CD8(-) cells nor in that of natural killer (NK) cells producing IFN-gamma. Our results show that IFN-beta treatment in MS patients induces a profound and persistent down-regulation of the number of circulating T cells secreting IFN-gamma and IL-4 thus suggesting a broader rather than a specific immunomodulatory effect of IFN-beta in MS.

Adjuvants, Immunologic↗
PubMed2001

Topical application of the cornea post-infection with plasmid DNA encoding interferon-alpha1 but not recombinant interferon-alphaA reduces herpes simplex virus type 1-induced mortality in mice.

A study was undertaken to compare the efficacy of recombinant interferon (rIFN)-alphaA to plasmid DNA encoding IFN-alpha1 against ocular herpes simplex virus type 1 (HSV-1) infection. The topical application of rIFN-alphaA (100-300 units/eye) onto the cornea of mice subsequently infected 24 h later with HSV-1 antagonized viral-induced mortality. The enhancement in cumulative survival in the rIFN-alphaA-treated mice correlated with a reduction of viral titers recovered in the eye and trigeminal ganglion (TG) at 3 and 6 days post-infection. The protective effect was site-specific such that when rIFN-alphaA was administered orally or intranasally, no efficacy against HSV-1 was observed. However, the protective effect was time-dependent. Specifically, when the rIFN-alphaA (100-1000 units/eye) was administered at 24 h post-infection, no protective effect was observed against HSV-1 compared to the vehicle-treated group. In contrast, plasmid DNA (100 microg/eye) containing the IFN-alpha1 transgene showed significant protection when topically applied 24 h post-infection. Although the transgene was found to traffic distal from the site of application (eye), including the trigeminal ganglion and the spleen where CD11b(+) and CD11c(+) cells express the transgene, the migration of the transgene did not correlate with efficacy. Collectively, the results suggest that naked DNA encoding type I IFN applied post-infection provides a greater degree of protection against ocular HSV-1 infection in comparison with recombinant protein effectively antagonizing viral replication and spread.

Administration, Topical↗
PubMed1999

Interferon (IFN)-beta treatment enhances CD95 and interleukin 10 expression but reduces interferon-gamma producing T cells in MS patients.

Interferon (IFN)-beta has been shown to favorably alter the disease course of relapsing-remitting multiple sclerosis (RRMS) patients. Although its mode of action is still unclear, there is ample evidence from in vitro studies that IFN-beta directly modulates the function of immune cells. We analyzed here the effects of IFN-beta treatment on immune functions in vivo in a group of 25 RRMS patients who received IFN-beta (8 MIU) on alternate days. At baseline and at 1, 3 and 6 months from the start of the treatment, parameters for differentiation and activation states of both monocytes and T lymphocytes were assessed. A transient increase was seen in plasma (p) interleukin (IL)-10 level whereas pIL-12 (p40) was not affected. A similar change was found in the ability of monocytes to secrete these cytokines in vitro. Notably, patients who in vitro readily responded to IFN-beta with enhanced IL-10 production had the highest pIL-10 levels. Concerning T-cell differentiation, flow cytometric analysis of cytokine production showed that treatment with IFN-beta moderately decreased the mean percentages of CD8pos T cells producing IL-2 and IFN-gamma and CD8neg T cells producing IL-4 (p<0.05 for all cytokines), whereas a more significant decline was seen in the mean percentage of CD8neg T cells producing IFN-gamma (p<0.01). This resulted in a significant lower ratio T(HELPER(H))1 vs. T(HELPER(H))2 type cells in the CD8pos T-cell subset (p<0.05), but not in the CD8neg T-cell subset. Finally, IFN-beta treatment resulted in an initial rise in the mean percentage of CD95pos T cells and in a gradual increase in the mean level of soluble CD95 (sCD95) in plasma (p<0.01). Additional in vitro studies showed that IFN-beta indeed rapidly (within 24 h) upregulates CD95 expression on both primed and unprimed T cells and augments the release of sCD95 in culture supernatants. Thus, we confirm here that IFN-beta treatment leads to similar changes in cytokine production of T cells and monocytes as previously described in vitro. Enhanced IL-10 secretion may downmodulate cytokine secretion by activated T cells and in this way dampen newly-induced and/or ongoing immune responses. In addition, we identified a novel effect of IFN-beta treatment, i.e., induction of CD95 expression. The augmentation of CD95 expression may directly interfere with T-cell selection, notably of autoaggressive T cells. Future studies are needed to show whether this increased CD95 expression indeed leads to increased apoptosis of immune cells.

Adjuvants, Immunologic↗
PubMed2003

Expression of the sodium channel transcripts Na(v)1.8 and Na(v)1.9 in injured dorsal root ganglion neurons of interferon-gamma or interferon-gamma receptor deficient mice.

Changes in the dorsal root ganglion (DRG) expression of the sodium channels Na(v)1.8 and Na(v)1.9 may contribute to injury-induced hyperexcitability and pain. Interferon (IFN)-gamma receptor -/- mice display a reduced pain-related behavior after nerve injury as compared to wild-type mice (NeuroReport 8 (1997) 1311). To elucidate a possible role for IFN-gamma in the regulation of sodium channels, we have studied the DRG mRNA expression of Na(v)1.8/Na(v)1.9 in IFN-gamma- or IFN-gamma receptor-deficient mice. In both types of mice, nerve damage induced a downregulation of Na(v)1.8 as well as Na(v)1.9. The magnitude of this reduction was similar to that observed in wild-type animals. These results indicate that the downregulation of Na(v)1.8/Na(v)1.9 in damaged DRG neurons is not influenced by IFN-gamma. Thus, the reduced pain-related behavior of nerve-injured IFN-gamma receptor null mice is not due to differential changes in the regulation of Na(v)1.8/Na(v)1.9 mRNA.

Animals↗
PubMed2004

Prevention of lethal respiratory vaccinia infections in mice with interferon-alpha and interferon-gamma.

The antiviral efficacy of interferons (IFNs) was evaluated using a vaccinia intranasal infection model in mice in this study. We provide evidence that intranasal administration of IFN-alpha and IFN-gamma (days -1 to +3) resulted in 100 and 90% survival against a lethal respiratory vaccinia infection (8 LD50) in mice, respectively; whereas no animals in the placebo group survived through the study period (21 days). The IFN treatment consisted of a single daily dose of 5x10(3) U per mouse for 5 consecutive days. The efficacy of IFN-gamma was evident even when the IFN-gamma treatments started 1-2 days after infection and when a lower dose (2x10(3) U per mouse) was used. The treatment of IFN-alpha and IFN-gamma reduced the virus titers in the lungs of infected mice by 1000-10,000-fold, when the administration started 1 day after infection. Our data suggest that IFN-alpha and IFN-gamma are effective in protecting vaccinia-infected mice from viral replication in lungs and mortality, and may be beneficial in other human orthopoxvirus infections.

Animals↗
PubMedDate not supplied

The interferon system and interferon regulatory factor transcription factors -- studies from gene knockout mice.

Interferon regulatory factors (IRFs) were initially identified as regulators of IFN-alpha/beta genes and to date nine members have been determined in human and mouse. They share a conserved DNA-binding domain in the N-terminal portion that recognizes similar DNA sequences. Despite their similar DNA binding specificity, the IRFs show diverse functions in response to extra cellular stimuli. Although the study of IRFs was started with respect to regulation of the IFN-alpha/beta gene expression, recent studies have revealed other aspects of IRF functions. In this review, we summarize our current knowledge of the functions of IRF family members revealed by our gene targeting study in mice, focusing on the regulation of the IFN system.

Animals↗
PubMed1999

Interferon-alpha, unlike interferon-gamma, does not cause bone loss in the rat.

Interferons (IFN) are a group of related glycoproteins. IFN-gamma, in vitro, has been shown to inhibit resorption; however, an in vivo experiment showed that it had the opposite effect, resulting in bone loss that was comparable to that caused by cyclosporine A. IFN-alpha has numerous clinical applications but is used most extensively in the treatment of chronic hepatitis B and chronic hepatitis C. Research into the effects of IFN-alpha on bone mineral metabolism has been very sparse, and the majority of studies reflect in vitro models. Like IFN-gamma, there exists discordance between in vitro and in vivo studies on IFN-alpha. Both in vivo and in vitro studies demonstrate that IFN-alpha decreases bone resorption, whereas osteoblasts may or may not be affected in vivo. This study was designed to provide information on the in vivo effects of IFN-alpha in the rat model, because we feel that, given its widespread clinical use, this is an extremely important issue. Rats were given low dose IFN-alpha (1.6 x 10(6) IU/m2), intermediate dose IFN-alpha (5.35 x 10(6) IU/m2), and high dose IFN-alpha (30 x 10(6) IU/m2) three times per week for 28 days. Serum osteocalcin (bone gla protein, or BGP) and parathyroid hormone (PTH) were measured serially and, after double labeling, the bones were examined histomorphometrically. IFN-alpha did not alter any of the histomorphometric parameters measured and did not affect PTH. However, it produced a disparate BGP response. Low dose IFN-alpha resulted in a statistically significant increase in serum BGP on days 14 and 28, whereas intermediate and high doses of IFN-alpha did not. Overall, these results provide no evidence of a deleterious effect of IFN-alpha on bone metabolism and confirm the limited clinical study.

Animals↗