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PubMed2005

Fc gamma RII-dependent sensitisation of natural interferon-producing cells for viral infection and interferon-alpha responses.

Natural interferon-producing cells (NIPC), also called plasmacytoid dendritic cells, are the most potent producers of IFN-alpha in response to viral and bacterial components, serving an important function in innate immune defences. The present work demonstrates that NIPC responsiveness can be primed by immunisation, increasing their capacity to produce IFN-alpha after viral infection. NIPC isolated from pigs immunised against classical swine fever virus (CSFV), a member of the Flaviviridae, were more receptive to viral infection and produced higher levels of IFN-alpha than NIPC from immunologically naive animals. This sensitisation of NIPC was maintained for at least 8 months after immunisation. IFN-alpha production was dependent on live virus and required replication, and the "immune" NIPC responded to lower infectious doses of virus. Co-localisation of the virus with Fc(gamma)RII (CD32) in polarised structures was observed with "immune" NIPC only. This Fc(gamma)RII-dependent virus capture and sensitisation of NIPC, evidently mediated through cytophilic CSFV-specific antibodies, was inhibited by non-specifically aggregated immunoglobulin as well as by pre-formed virus-antibody complexes. In conclusion, these results demonstrate that NIPC not only represent a major player in innate immunity but are also functionally linked to the immunological memory of the adaptive immune system.

Animals↗
PubMed1986

Interferon-activated tumor inhibition in vivo. Small amounts of interferon-gamma inhibit tumor growth by eliciting host systemic immunoreactivity.

Ten international units (IU) of recombinant (r) or natural (n) murine interferon (MuIFN)-gamma were used for the in vivo immunotherapy of a chemically induced fibrosarcoma (CE-2) of BALB/c mice. In vitro, doses of r-IFN-gamma below 100 units have a marginal antiproliferative effect on CE-2 cells and do not induce expression of H-2d class-II antigens, whereas they do increase that of class-I antigens. In vivo, 10 daily injections of 10 IU of r- or n-MuIFN-gamma at the challenge site provide significant protection against increasing doses of CE-2 tumor cells. This protection was enhanced when non-reactive T-lymphocytes from CE-2 tumor-bearing mice were admixed at a 10:1 ratio with the CE-2 tumor cells. Combined lymphocyte and r-MuIFN-gamma treatment also inhibited the growth of already established tumors when it was started before these reached a mean diameter of 5 mm. Tumor inhibition depends upon activation of the host immune system. The antitumor activity of r-MuIFN-gamma and T-lymphocytes was null when mice were first irradiated with 450 rads. Moreover, host leukocytes massively infiltrated the area of tumor growth and the small r-MuIFN-gamma doses injected daily activated various host immunoreactivity mechanisms.

Animals↗
PubMed1987

Expression of gamma-interferon receptor in murine bone marrow-derived macrophages associated with macrophage differentiation: evidence of gamma-interferon receptors in the regulation of macrophage proliferation.

The effect of purified, recombinant murine gamma interferon (IFN-gamma) on the regulation of macrophage proliferation induced by colony-stimulating factor 1 (CSF-1) was investigated. Although both hemopoietic stem cells (GM-CFC) and tissue-derived peritoneal exudate macrophages (PEM) proliferated in response to CSF-1, the more mature PEM were much more sensitive to an antiproliferative effect of IFN-gamma. The role of IFN-gamma receptor expression and its relationship to growth inhibition was examined. Bone marrow cells as a whole did not exhibit an appreciable amount of IFN-gamma receptor binding activity. Likewise, nonadherent (NA) cells derived from CSF-1-stimulated bone marrow cultures displayed low levels of IFN-gamma receptor binding activity. On the contrary, more mature adherent (AD) cells (monocytes/macrophages) from the same culture exhibited high levels of IFN-gamma receptor binding activity, which continued to increase with culture time. The elevated IFN-gamma binding activity is due to an increase in total receptor number rather than the binding affinity as judged by Scatchard analysis. Similar to the relationship between PEM and GM-CFC, more mature AD cells were also more susceptible to the inhibitory effect of IFN-gamma on CSF-1-induced proliferation than their less mature NA counterparts. The fact that the sensitivity to IFN-gamma correlated well with the expression of existing IFN-gamma receptors strongly suggests that the inhibitory effect is mediated through IFN-gamma receptors. This study shows that the expression of IFN-gamma receptors in mononuclear phagocytes may not only represent one of the phenotypic parameters acquired by the growing macrophages during the process of differentiation, but may play some role in controlling proliferation.

Animals↗
PubMed1992

Enhanced wound healing in animal models by interferon and an interferon inducer.

Healing of wounds is a significant biological process that involves the interactions of different cell types, growth factors, cytokines, and extracellular matrix molecules. Mice and rats were treated in vivo with interferon (IFN) alpha/beta or polyinosinic-polycytidylic acid (Poly I:C), a ds-RNA, a potent inducer of IFN. We observed faster and enhanced closure of wounds as compared to untreated controls on day 7 (wound area measured on Macintosh II CX using NIH image 1.30u program), increased migration of dermal fibroblasts in the wound bed, complete re-epithelialization evidenced by routine histology and scanning electron microscopic procedures, and increased collagen synthesis, which correlates to greater tensile strength. In addition, classical immunofluorescence procedures using frozen sections showed that dermal fibroblasts synthesized much more laminin following Poly I:C treatment, whereas no effect was observed on fibronectin synthesis. These results suggest that Poly I:C and IFN treatment result in a faster restoration of tissue integrity in both full skin punch biopsy and skin incision models.

Animals↗
PubMed2001

Multicenter randomized study comparing initial daily induction with high dose lymphoblastoid interferon vs. standard interferon treatment for chronic hepatitis C.

One hundred fifty-five chronic hepatitis C patients were assigned at random to receive natural lymphoblastoid interferon (IFN)alpha-n1, s.c., for 13 months in one of three treatment regimens: initial daily induction with 10 million units (MU) followed (group 1, n = 50) or not (group 2, n = 52) by 1 month of rest and then three times weekly 10 MU (2 months), 5 MU (2 months), and 3 MU (8 months); group 3 (n = 53) received tiw 5 MU (2 months) followed by 3 MU (11 months). By intention-to-treat analysis, ALT normalization at completion of treatment was greater in patients who received continuous IFNalpha-n1 therapy with initial daily induction (group 2: 24/52, 46%) compared with those given intermittent therapy with initial daily induction (group 1: 17/50, 34%) and those who received standard IFNalpha-n1 therapy (group 3, 18/53, 34%; P not significant). The sustained ALT response was 26%, 27% and 21% and the sustained virological response was 20%, 27%, and 19%, in groups 1, 2, and 3, respectively. A trend was observed towards a higher biochemical and virological end-of-treatment response in patients given induction therapy (17%) compared with standard therapy (6%, P = 0.053). Sustained biochemical and virological responses were 20%, 27%, and 17% in groups 1, 2, and 3, respectively. Platelet and leukocyte counts decreased following daily high-dose treatment and remained low until therapy cessation (P < 0.001). The data suggest that daily s.c. induction with 10 MU IFNalpha-n1 followed by intermittent or continuous maintenance therapy for 1 year does not improve the results achieved with the standard 1-year IFNalpha course in the treatment of chronic hepatitis C patients.

Adolescent↗
PubMed1996

Interferon-gamma-dependent expression of inducible nitric oxide synthase, interleukin-12, and interferon-gamma-inducing factor in macrophages elicited by allografted tumor cells.

We have examined the mechanisms of activation of macrophages (Møs) induced by i.p. allografted Meth A tumor cells (Meth A-Møs) during the rejection of the cells by C57BL/6 mice. Inducible nitric oxide (NO) synthase (iNOS), interleukin-12 (IL-12), and interferon-gamma (IFN-gamma)-inducing factor (IGIF) were transiently expressed in Meth A-Møs during the rejection. The expression was impaired in mice in which the gene encoding IFN-gamma had been disrupted (IFN-gamma-/-). In vitro studies showed that Meth A-Møs from IFN-gamma +/+ mice induced an apoptotic type of cell death in P815 cells, without cell-to-cell contact, in an NO-dependent manner, whereas Meth A-Møs from IFN-gamma-/- mice could not lyse these cells. The iNOS, IL-12, and IGIF expression was also impaired in bacteria-activated Møs from IFN-gamma-/-mice, indicating that IFN-gamma, but not IGIF, would be the initial signal that leads to the activation of Møs in vivo.

Animals↗
PubMed1993

Regulation of human B cell responsiveness by interferon-alpha: interferon-alpha-mediated suppression of B cell function is reversed through direct interactions between monocytes and B cells.

Previous studies have revealed that interferon-alpha (IFN-alpha) suppresses the B cell responses stimulated with Staphylococcus aureus (SA) + IL-2 in the complete absence of monocytes but enhances the responses of B cells contaminated with monocytes. The current studies therefore examined in detail the combined effects of IFN-alpha and monocytes on the B cell responses induced by SA + IL-2. Monocytes overcome the suppressive effects of IFN-alpha on the IgM production induced by SA + IL-2. Thus, in the presence of monocytes, IFN-alpha enhanced the IgM production by B cells stimulated with SA + IL-2. IFN-alpha still enhanced the IgM production induced by SA + IL-2 in the presence of monocytes and indomethacin. The IFN-alpha-mediated suppression of B cell responsiveness was not overcome by addition of factors generated from SA-activated monocytes, or any of IL-1 beta, IL-6, and TNF-alpha. Of note, the IFN-alpha-mediated suppression of B cell responsiveness was overcome only when B cells and monocytes were allowed to contact with each other. This reversal of the IFN-alpha-mediated suppression of B cell function was not blocked by any of the mAb to CD11a, CD18, CD54, or monomorphic determinants of HLA-DR. These results indicate that IFN-alpha enhances the B cell responses induced by SA + IL-2 through direct interactions between monocytes and B cells that do not involve lymphocyte-function-associated-1 molecules, intercellular adhesion molecule-1, or HLA-DR antigens. Thus, the data demonstrate the presence of unique direct interactions between B cells and monocytes that regulate human B cell responsiveness.

Adult↗
PubMed1993

Selective alteration of the turnover of interferon beta mRNA in peritoneal macrophages from LPS-hyporesponsive mice and its role in the defective expression of spontaneous interferon.

Basal levels of interferon (IFN)-beta mRNA transcription were detected in both freshly explanted LPS-responsive (Lpsn) and LPS-hyporesponsive (Lpsd) peritoneal macrophages (PM). In vitro cultivation of PM resulted in a time-dependent reduction in the level of IFN-beta mRNA, which was far more rapid in Lpsd than in Lpsn PM. Treatment of Lpsn PM with cycloheximide (CHX) resulted in a marked accumulation of IFN-beta mRNA, which was not associated with an increase in IFN-beta gene transcription. However, treatment of Lpsd PM with CHX did not induce accumulation of IFN-beta mRNA. CHX induced the accumulation of IFN-alpha-4 mRNA in both Lpsn and Lpsd PM, CHX enhanced the accumulation of two cytoplasmic factors interacting with AU-rich sequences within the 3' untranslated region of IFN-beta mRNA. We conclude that Lpsd PM exhibit an impaired capacity to stabilize IFN-beta mRNA that may account for their low expression of IFN-beta.

Animals↗
PubMed1994

Mechanism of interferon action motif I of the interferon-induced, RNA-dependent protein kinase (PKR) is sufficient to mediate RNA-binding activity.

The interferon-induced P1/eIF-2 alpha protein kinase cDNA, designated PKR, was expressed both in Escherichia coli and in transfected monkey COS cells. TrpE-PKR fusion proteins and PKR nonfusion proteins were examined for their RNA-binding activity by Northwestern blot analysis. PKR is a RNA-binding protein that possesses two copies of a highly conserved motif, RI and RII, within the N-terminal region of the protein. Amino acid residues between 11 and 243 of PKR, which includes both copies of the R motif, displayed RNA-binding activity comparable to that of the full-length 551-amino-acid PKR protein. Analysis of substitution and deletion mutant PKR proteins revealed that motif RI was both necessary and sufficient for RNA-binding activity, whereas motif RII was not. Substitution of the highly conserved lysine at position 64 within the RI motif abolished RNA-binding activity, both of full-length PKR and the N-terminal 243-amino-acid truncated PKR. Finally, PKR substitution and deletion mutant cDNAs deficient for kinase function were expressed to much higher levels in transfected monkey cells than was the full-length wild-type PKR cDNA.

Animals↗
PubMed2002

Regulation of the interferon-inducible PKR kinase gene: the KCS element is a constitutive promoter element that functions in concert with the interferon-stimulated response element.

The RNA-dependent protein kinase PKR plays important roles in the antiviral and antiproliferative actions of IFN. The IFN-inducible promoter of the human PKR gene contains a 15-bp DNA element designated KCS. The KCS element is located 4 bp upstream of the interferon-stimulated response element (ISRE) and is required for both basal and IFN-inducible transcription. We have examined the effect of insertion mutations between the KCS and the ISRE elements, as well as altered orientation of the KCS element relative to the ISRE element, to assess a possible functional interaction between them. Large insertions (>or=93 bp) between the KCS and ISRE elements significantly reduced both basal and IFN-inducible promoter activity. The function of the KCS element was dependent on the orientation of KCS relative to the ISRE element. Multimerization of the KCS element increased both basal and IFN-inducible transcription. Electrophoretic mobility shift analyses (EMSA) identified IFN-inducible protein complex formation that required both the KCS and the ISRE DNA element sequences. The novel IFN-inducible protein complexes contained the transcription factor STAT1, as shown by supershift analyses and by their presence in extracts prepared from STAT1 wild-type but not from STAT1-/- null cells. These results, taken together, strongly suggest that the KCS and ISRE elements of the human PKR promoter represent a functional unit.

Animals↗
PubMed1987

Studies on in vitro interferon induction capacity and interferon sensitivity of simian foamy viruses.

We demonstrate that Simian Foamy viruses (SFV) types 1, 2, 4 and 10 do not induce Interferon (IFN) production in mouse and primate (simian and human) cell lines, but that their cytopathogenic effect is blocked by this viral inhibitor. The mechanisms of action of IFN seems to be different from that of other Retroviridae. No trapping of virions appears in treated cells examined by ectron microscopy. Moreover, neither precursor nor mature virus particles were observed in infected cultures submitted to IFN treatment.

Animals↗
PubMed1986

Interferon production in L929 cells under impaired translational conditions: comparison of rates of interferon, actin, Newcastle disease and encephalomyocarditis viruses mRNAs initiation of protein synthesis.

The pattern of Interferon (IFN) production in virus-infected cells has been compared with the rate of bulk cellular protein synthesis, on one hand, and with the synthesis of representative cell and virus proteins such as actin, the gamma and the NP proteins of encephalomyocarditis (EMC) and Newcastle Disease (NDV) viruses, on the other hand. This was investigated under conditions of impaired protein synthesis such as i) high osmolarity media, ii) a virus-induced shut-off, and iii) in cells exposed to relatively low doses of cycloheximide (CXM), which slow elongation of protein chain and thus favour the translation of low-affinity messenger RNAs (mRNAs). In each instance IFN production was compared with 35S-methionine incorporation into TCA-precipitable materials and into SDS-polyacrylamide gel-analysed proteins. Data obtained from each of the experimental approaches all indicate that IFN production and cellular protein synthesis are modified in a closely related fashion suggesting that their mRNAs share a similar degree of affinity for ribosomes. Conversely, two mRNAs coding for representative EMC and NDV virus proteins exhibit, respectively, the highest and the lowest affinity for ribosomes as compared to actin mRNA.

Actins↗
PubMed1986

Effects of antibodies and interferon on mumps virus persistently infected L929 cells. Generation of variant viruses in the cells during incubation with monoclonal antibodies and interferon.

We studied the effect of antibodies and interferon (IFN) on L929 cells persistently infected with mumps virus (MuV). The persistent infection was maintained by horizontal transmission of the virus within the culture but was regulated by endogenously produced IFN (8). The maintenance of the persistently infected cells in the continuous presence of anti-MuV serum suppressed the production of infectious virus. No virus antigen-positive cells were detected beyond 14 passages. Once antiserum was removed from the seemingly "cured cultures", however, a small number of antigen-positive cells appeared and the release of infectious virus into the culture fluid resumed. Even after 67 passages (200 days) of culture in the presence of anti-serum, the virus reappeared in the culture. At least 0.01 per cent of L929 cells in cultures maintained under antiserum harbored the virus without expression of virus antigen. The virus recovered from such cells was temperature sensitive. The infection of fresh L929 cells with the variant led to noncytocidal persistent infection which was maintained by propagation of virus-infected cells. MuV carrier cultures could be cured by serial cultivation in medium containing the mixture of antiserum and IFN. When L-MuV cells were subcultured with medium containing neutralizing monoclonal antibodies (MoAbs), antibody-resistant variant viruses were rapidly generated and selected. In the presence of IFN variant viruses resistant to IFN were generated. In view of the small amount of virus produced from persistently infected cells, variant viruses appeared to be generated in an unusually high frequency in carrier cultures. Thus, this experimental system may offer a useful in vitro model for studying antigenic variation and generation of various variant viruses.

Animals↗
PubMed1977

Interferon production and response to exogenous interferon in two cell lines of mouse brain origin persistently infected with Sendai virus.

Two persistently infected cell lines established from C3H mouse brain cells infected in vivo with Sendai virus were shown to differ with respect to interferon (IF) production and response to exogenous IF. MB/Sen carrier cells contained 1-5 per cent antigen positive cells when examined by immunofluorescence, and virus was occasionally recovered from the culture medium. MB/SenAS carrier cells were maintained with 0.16 per cent Sendai antiserum in the supernatant medium. All MB/SenAS cells contained viral antigen and infectious virus was present in the culture medium. MB/Sen released IF spontaneously into the culture medium. Further IF production could be stimulated in MB/Sen by superinfection with Newcastle disease virus (NDV) or vesicular stomatitis virus (VSV). Exogenous IF provided good protection against VSV challenge. In contrast, MB/SenAS produced no IF spontaneously but could be stimulated by NDV and VSV to produce IF. Exogenous IF failed to reduce the amount of VSV released into the supernatant fluid. Replication of VSV was restricted in MB/SenAS as shown by a 2.3 log10 lower virus yield compared to MB/Sen.

Animals↗
PubMed1994

Neutralizing interferon beta antibodies in melanoma patients treated with recombinant and natural interferon beta.

The incidence and clinical significance of therapy-induced neutralizing interferon beta (IFN beta) antibodies was studied in a group of 21 melanoma patients treated with natural IFN beta and 7 patients treated with recombinant IFN beta. They were treated subcutaneously with 3 x 10(6) IU three times per week in an adjuvant open trial for 24 weeks after surgical removal of all detectable metastases. Of the 21 patients treated with natural IFN beta, 95% developed significant levels of neutralizing antibodies after 24 weeks. In comparison, 28% of the 7 patients treated with recombinant IFN beta developed neutralizing IFN beta antibodies. Cross-reactivity of the antibodies could be demonstrated. Persistence of antibody titers was seen in 80% of the patients 24 weeks after cessation of treatment with natural IFN beta. No correlation between the maximum antibody titers and the antibody persistence after cessation of therapy could be established. We detected a clear correlation between the formation of neutralizing antibodies and the decrease in beta 2-microglobulin and 2',5'-oligoadenylate synthetase and therefore the drop in biological activity. In this adjuvant trial there was no difference in relapse rate and time until relapse between antibody-positive and antibody-negative patients. No difference in clinical outcome could be established between the patients treated with natural IFN beta and recombinant IFN beta.

2',5'-Oligoadenylate Synthetase↗
PubMed1994

Human atherosclerotic abdominal aortic aneurysms produce interleukin (IL)-6 and interferon-gamma but not IL-2 and IL-4: the possible role for IL-6 and interferon-gamma in vascular inflammation.

Immunological mechanisms play an important role in the pathogenesis of atherosclerosis and atherosclerotic abdominal aortic aneurysms (AAA). Inflammatory leukocytes invade the vessel wall and produce cytokines which perpetuate the immune events underlying these diseases. Interleukin (IL)-1 beta, IL-8, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1, among others, may play a role in the generation by AAA. The aim of this study was to investigate the possible pathogenetic role of other proinflammatory cytokines, namely IL-2, IL-4, IL-6, and interferon (IFN)-gamma. Enzyme-linked immunosorbent assay of human explant culture supernatants revealed a significant increase in IFN-gamma production by AAA compared to occlusive (atherosclerotic) or normal (NL) aortic explants. IL-6 production was also increased in AAA compared to NL aortic explant supernatants. Neither AAA nor NL aortic tissues produced IL-2 or IL-4 in the same culture system. These results suggest that IL-6, a cytokine involved in T and B lymphocyte activation during inflammation, and IFN-gamma, which stimulates T and B lymphocytes, macrophages, endothelial cells and fibroblasts, may play a role in the pathogenesis of various vascular inflammatory diseases such as AAA.

Aorta, Abdominal↗
PubMed1997

Interferon antibodies in patients with infectious diseases. Anti-interferon antibodies.

Interferons (IFNs) are generally recognized as the most important therapeutic agent in some infectious diseases such as chronic hepatitis B and C. Since the early clinical trials it was documented that the therapeutic use of IFNs could be complicated by the development of antibodies able to neutralize or to bind to the IFN molecule. After several years of research it is now widely accepted that the presence of circulating anti-IFN antibodies may affect the response to IFN. Here we summarize what is currently know on the clinical significance of antibodies to IFN in IFN-treated viral diseases patients.

Antibodies↗
PubMed1989

Decreased interferon binding capacity of peripheral blood mononuclear cells during interferon treatment of chronic hepatitis B with special reference to (2'-5') oligoadenylate synthetase activity.

The levels of (2'-5') oligoadenylate synthetase (2-5 AS) activity and interferon (IFN) binding capacity were measured in peripheral blood mononuclear cells (PBMC) obtained from 9 patients with chronic hepatitis B (CHB) during IFN treatment. Six of the patients received human lymphoblastoid IFN (HLBI) or IFN-beta daily for 4 weeks at doses of 6 million units (MU); of the remaining three, 2 were treated on alternate days at doses of 3 MU for 5 weeks, and the other given daily IFN doses of 3 MU for 4 weeks. IFN binding was measured using HLBI (2 X 10(8) IU/mg protein) and completely purified 125I-labeled HLBI (290 Ci/mmol specific activity). The levels of 2-5 AS activity in PBMC were measured using radioimmunoassay. Before IFN treatment, the levels of IFN binding capacity were similar to those of normal subjects. During treatment, however, IFN binding capacity decreased significantly from 40 to 60% of initial levels 1 to 2 weeks after the start of treatment in the 7 patients receiving daily IFN, while in the remaining 2 patients given IFN on alternate days, IFN binding capacity did not decrease during treatment. On the other hand, 2-5 AS activity in PBMC increased during IFN treatment in all patients. Even after IFN binding capacity decreased in the 7 patients, the levels of 2-5 AS activity remained high during the remainder of treatment. These finding suggest that some mechanism other than IFN binding capacity may be responsible for the determination of 2-5 AS levels.

2',5'-Oligoadenylate Synthetase↗