Search

Background: Impaired antiviral interferon expression may be involved in asthma exacerbations commonly caused by rhinovirus infections. Allergy is a known risk factor for viral-induced asthma exacerbation, but little is known whether allergens may affect interferon responses., Objective: Our hypothesis is that house dust mite (HDM) impairs viral stimulus-induced antiviral signalling., Methods: Experimental asthma exacerbations were produced in vitro in human bronchial epithelial cells (HBECs) and in mice using sequential challenges with HDM and a viral infection mimic, Poly(I:C). We examined rhinovirus pattern recognition receptors (PRRs) signalling pathways and potential mechanisms of impaired interferon response., Results: HBECs and mice exposed to HDM prior to Poly(I:C) exhibited a reduced antiviral response compared to Poly(I:C) alone, including reduced IFN-β, IFN-λ, TLR3, RIG-I, MDA5, IRF-3 and IRF-7. Heat inactivation of HDM partially restored the TLR3-induced interferon response in vitro and in vivo. Our HBEC-data further showed that HDM directly affects TLR3 signalling by targeting the receptor glycosylation level., Conclusions: Direct effects of allergens such as HDM on PRRs can present as potential mechanism for defective antiviral airway responses. Accordingly, therapeutic measures targeting inhibitory effects of allergens on antiviral PRRs may find use as a strategy to boost antiviral response and ameliorate exacerbations in asthmatic patients., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Rhinoviruses (RVs) are associated with exacerbations of cystic fibrosis (CF), asthma and COPD. There is growing evidence suggesting the involvement of the interferon (IFN) pathway in RV-associated morbidity in asthma and COPD. The mechanisms of RV-triggered exacerbations in CF are poorly understood. In a pilot study, we assessed the antiviral response of CF and healthy bronchial epithelial cells (BECs) to RV infection, we measured the levels of IFNs, pattern recognition receptors (PRRs) and IFN-stimulated genes (ISGs) upon infection with major and minor group RVs and poly(IC) stimulation. Major group RV infection of CF BECs resulted in a trend towards a diminished IFN response at the level of IFNs, PRRs and ISGs in comparison to healthy BECs. Contrary to major group RV, the IFN pathway induction upon minor group RV infection was significantly increased at the level of IFNs and PRRs in CF BECs compared to healthy BECs., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The role of interferon in influenza and herpes infections, general patterns of the interferon system in these diseases, the identification of interferon deficiency, the possibility of their correction with the immune active drugs, including interferon inducers combining antiviral immunomodulatory interferon effects with etiopathogenic corrective mode of action, are discussed. Clinical values of faster recovery confirm the suitability of their application in the immunocompromised patients.

Interferon (IFN) signaling is initiated by the recognition of viral components by host pattern recognition receptors. Dengue virus (DEN) triggers IFN-beta induction through a molecular mechanism involving the cellular RIG-I/MAVS signaling pathway. Here we report that the MAVS protein level is reduced in DEN-infected cells and that caspase-1 and caspase-3 cleave MAVS at residue D429. In addition to its well-known function in IFN induction, MAVS is also a proapoptotic molecule that triggers disruption of the mitochondrial membrane potential and activation of caspases. Although different domains are required for the induction of cytotoxicity and IFN, caspase cleavage at residue 429 abolished both functions of MAVS. The apoptotic role of MAVS in viral infection and double-stranded RNA (dsRNA) stimulation was demonstrated in cells with reduced endogenous MAVS expression induced by RNA interference. Even though IFN-beta promoter activation was largely suppressed, DEN production was not affected greatly in MAVS knockdown cells. Instead, DEN- and dsRNA-induced cell death and caspase activation were delayed and attenuated in the cells with reduced levels of MAVS. These results reveal a new role of MAVS in the regulation of cell death beyond its well-known function of IFN induction in antiviral innate immunity.

Aim: To study in vivo efficacy of combined administration of cancer vaccine (CV), interferon (IFN) and inducer of endogenous IFN - amixin., Materials and Methods: Sarcoma-37 cells were transplanted to female Balb/c mice. For the treatment, CV prepared from sarcoma-37 cells with the use of cytotoxic lectines from B. subtilis B-7025, murine IFN and amixin or their combinations were used. IFN production, content of circulating immune complexes and level of specific IgG antibodies in blood serum were determined by standard immunologic methods., Results: Using solid form of sarcoma-37 it has been shown that introduction of IFN and amixin significantly elevated efficacy of vaccine therapy, in particular index of tumor growth inhibition reach 89.2% and 81.7%. Upon combined use of CV and IFN or CV and amixin (25 mg/kg) respectively. Significant prolongation of average life span of the animals treated with CV and IFN or CV and amixin (25 mg/kg) has been registered (up to 92.7 -/+ 10.4 and 95.0 -/+ 6.2 days respectively, vs 46.8 -/+ 1.5 days for control animals)., Conclusion: Obtained results have shown expediency of the development of schemes for combined introduction of CV with exogenous IFN, and with inducer of endogenous IFN (amixin) for elevation of efficacy of vaccine therapy.

Chicken embryonic cells (CEC) are nonpermissive hosts for the replication of human adenoviruses, yet they respond to infection by producing interferon (IFN). The nature of the IFN inducer moiety in these viruses has been elusive since its initial study by Ilona Béládi and colleagues some 40 years ago. We tested the hypothesis that viral dsRNA was the IFN inducer molecule--for two reasons: (i) dsRNA has been identified as a potent inducer of IFN, and (ii) developmentally mature CEC cells as cultured in vitro can develop a hyper-responsive state to dsRNA such that a single molecule of dsRNA per cell constitutes the threshold of detection. Furthermore, the number of particles in a virus population capable of inducing-IFN, irrespective of their replication capacity, can be quantified through the analysis of dose (multiplicity)-response (IFN yield) curves, thus allowing a determination of the number particles in virus populations that possess the capacity to induce IFN. This study demonstrates that type 5 wild type adenovirus (Ad5) and mutants dl312, dl334, and ts19 induce from 8,000 to 80,000 IFN U per 10(7) CEC. UV irradiation showed that transcription of about 20-50% of the Ad5 genome was required to produce the IFN inducer moiety. The ratio of IFN-inducing particles to plaque-forming particles (IFP : PFP) was as low as 1:6, indicating that only a small fraction of the total particles in a virus population ever function as IFP. We conclude that adenovirus dsRNA produced during symmetric transcription of some regions of the viral genome, coupled with fine-tuning of the IFN-induction pathway, account for the IFN-inducing capacity of adenoviruses in the non-permissive chicken cell.

Spirulina platensis is a cyanobacterial species that is surmised to potentiate the immune system leading to suppression of cancer development and viral infection. Here, we identified the molecular mechanism of the human immune potentiating capacity of Spirulina by analyzing blood cells of volunteers with pre and post oral administration of hot water extract of Spirulina. NK functions represented by IFN gamma production and cytolysis were enhanced after administration of Spirulina in >50% subjects. IFN gamma was produced in an IL-12/IL-18-dependent fashion. In vitro stimulation of blood cells with BCG cell wall skeleton (CWS) allowed more potent IL-12 p40 production in cells from volunteers given Spirulina than in cells without pre-exposure to Spirulina. As BCG-CWS serves as a ligand for Toll-like receptor (TLR) 2 and 4 to raise the maturation stage of monocytes/macrophages, Spirulina may be involved in the signaling responses through Toll in blood cells even when orally administered. These observations indicated that in humans Spirulina acts directly on myeloid lineages and either directly or indirectly on NK cells. The presence of co-operative IL-12 and IL-18 is critically important for NK-mediated IFN gamma production.

We studied in vitro production of interferon-alpha and interferon-gamma by peripheral blood leukocytes from 15 patients with multiple sclerosis. The priming effects of interferon preparations weakly correlated with interferon-alpha production by leukocytes from patients with multiple sclerosis, but negatively correlated with interferon-gamma production. The effects of interferon inducers in most cases positively correlated with its spontaneous production. We found a weak positive correlation between the priming effect of natural interferon-alpha and the effect of recombinant interferons. There were positive or strong positive correlations between the effects of recombinant interferons on leukocytes from patients with multiple sclerosis. The relationship between the effects of medicinal interferon inducers and interferon preparation varied from negative to strong positive correlations. These data suggest that correlation analysis can be used for dynamic control and elaboration of methods for combined immunotherapy of multiple sclerosis with various interferon preparations or interferon and its inducers.

We have tentatively identified colostrinines as novel cytokines produced by the mammary gland after delivery and detectable in colostrum. The primary colostrinine, the proline-rich polypeptide, was isolated from ovine colostrum in 1974. It is generally understood that the various factors present in colostrum play a pivotal role in transmitting of passive or active immunity from mother to child. We have found previously that both ovine and human colostrinines are inducers of interferon (IFN) gamma and other cytokines. In this paper, we reported that the leukocytes isolated from human colostrum donated by healthy mothers at 1-9 days after delivery, produced IFNs and tumor necrosis factors (TFNs) spontaneously. The release of IFNs and TNFs coincided with production of a colostrinine that has been isolated from the human colostrum samples and partially characterized. Our results suggest that the maximum production of colostrinine occurs 3 days after delivery. The tolerance (hyporeactivity) of the colostral leukocytes to IFN inducers and the modulation of the TNF response may be the late effects of the colostrinine release.

The spontaneous and induced interferon (IFN) production in whole blood cultures was examined in 45 psychiatric inpatients and in 65 normal controls. Among inpatients there were 32 who were chronic schizophrenics (14 women, 18 men) and 13 who were severely depressed (11 women, 2 men). The analysis of the pooled results of assays in the heterogeneous population showed that leukocytes of the psychiatric patients produced significantly lower levels of IFN after stimulation with virus (NDV), lipopolysaccharide (LPS), and IFN spontaneously released without the inducers that control cells. In contrast, there was no difference between the psychiatric patients and controls in IFN response to phytohemagglutinin and phorbol myristate acetate (PHA + PMA). The results apparently confirmed observations made by Moises et al (1985) and Katila et al (1989). We have also tested our hypothesis that the statistics may mask the individual pattern of IFN response related to the specific psychiatric diagnosis, however. In fact, in the group of chronic schizophrenics we have found either high or low responders to all IFN inducers (NDV, PHA + PMA and LPS). Furthermore, the patients with high IFN response had dominant positive symptoms of schizophrenia (delusions, hallucinations, bizarre behavior and thought disorder). Whereas, in the patients with low IFN response the negative symptoms prevailed (asociality or withdrawal, flat affect, attention impairment, abolition or apathy). In plasma samples of schizophrenics, factors were detected that transferred a hypersensitivity to the IFN inducers to normal donor leukocytes. For instance, in leukocytes cultured in the presence of plasma from schizophrenics, there were 71% of high IFN responders after stimulation with NDV, versus 26% of high IFN responders in the presence of plasma from normal controls. We suggest that the factors may belong to the class of opioid peptides, which interact with the production of cytokines including IFNs.

Newcastle disease virus (NDV) envelope glycoproteins that are expressed at the surface of fixed NDV (Ploufragan strain)-infected chick fibroblasts induce interferon (IFN) in mouse spleen cells. HN protein appears to be involved, since an anti-HN monoclonal antibody (Mab 3115) reduces the IFN production to 6% at most. However, the precise site of the molecule responsible for IFN induction is probably not exactly superimposed on the Mab 3115-epitope, since the NDV (83309 strain)-HN protein, which exhibits a modified Mab 3115-epitope, is also able to induce IFN. These preliminary results require further investigation in order to characterize the IFN herein demonstrated, to establish whether this induction mechanism exists in chicken lymphoid cells and to more accurately define the part of the HN molecule involved.

A polyvalent bacterial lysate (IRS 19) could be shown to induce interferon (IFN) in peripheral mononuclear leukocytes isolated from human and mouse blood by density gradient centrifugation. Upon stimulation with optimal doses of the inducer, the cells of both species produced 1000 to 2000 IU IFN/ml when cultured for up to 72 hours. In both systems the interferon was released to the culture supernatants in a first wave from one to four hours after addition of the inducer and in a second beyond the 16th hour of incubation increasing up to 72 hours, this time, reaching a 10 fold higher titer.

The general function of the immune system is discussed in the present review paper. In addition to the discussion of 'specific' and 'non-specific' defence mechanisms, particular attention is paid to the important role played by macrophages in the two systems. Macrophages are found to have a specific regulatory function both in the induction and the effector phase of the immune response. The part dealing with the effector phase of the immune response is concerned with the action of sensitized T lymphocytes on the one hand and provides a review of the present state of knowledge of (sub)classes of immunoglobulins in domestic animals on the other. In the section on interferon, efforts are made to answer a number of questions concerning the properties and chemical composition of interferons as well as the induction of interferons and the use of interferon inducers in veterinary practice. Moreover, a number of theories on the possible mechanism of action of interferons are discussed. The antitumour effect of interferons is examined more closely, the relationship with the antitumour activity of the immune system being a central feature. The part played by 'killer' and 'natural killer' cells is discussed. Finally, a look is taken into the future, and efforts are made to present an actual picture of the future possibilities of the use of interferons in therapy and prevention. A central question is whether it will be possible to produce interferons in sufficient amounts by particular bacteria (recombinant DNA studies) within a certain period.

Important progress has been recently made on the identification, physico-chemical properties, purification and production by recombinant technology of a series of immunoregulatory mediators, including interferons (IFNs). It is now possible to appreciate which part play IFNs in the regulation and activation of monocyte-macrophage (MO) functions. The present review discusses old concepts, such as Macrophage-Activating Factor (MAF) activity, at the light of recent data on the effects of IFN alpha, beta and gamma on four main immunological properties of MO, namely intracellular killing of microorganisms, non specific lysis of tumor cells, antigen presentation and secretion of soluble immunoregulatories molecules such as interleukin 1. All three IFN species enhance such functions, whereas enhancement of membrane class II major histocompatibility complex antigens is a unique property of IFN gamma. The role of IFNs, especially IFN gamma, as major MAF in vitro and in vivo is discussed.

The ability of lymphocytes from newborn infants to produce two types of interferon was compared with that of lymphocytes from older children and adults. Cord blood lymphocytes were as capable of producing both viral interferon (stable at pH 2.0) following stimulation with polyriboinosinic acid-polyribocytidilic acid and immune interferon (unstable at pH 2.0) following stimulation with phytohemagglutinin as lymphocytes from older individuals. In a mixture of mononuclear and polymorphonuclear cells, it was the former that produced the interferon. Interferon may be important in the defense mechanism of the newborn infant against viruses and other microbial agents.

Interaction of lipopolysaccharide (LPS) from enteric and oral bacteria with natural killer (NK) cells enhanced cytotoxicity against NK-sensitive and NK-resistant targets. This activation occurred without expansion of the NK cell population or without changes in the leukocyte function-associated antigen family of cellular adhesion molecule (CAM) expression on NK cells. Significant interferon (IFN) titers were measured in LPS-lymphocyte supernatants, and antibody to IFN-alpha blocked LPS activation. LPS-induced NK cytotoxicity was inhibited by antibodies to individual alpha chains of CAM and, more profoundly, by antibody to the beta chain of CAM. However, LPS, when preincubated with NK cells, did not compete with subsequent anti-CAM antibody binding as detected by flow cytometry. Anti-CAM antibodies had no effect on NK activation by IFN, but antibodies to either CD11a or CD11c abrogated IFN production induced by LPS. These findings suggest that LPS binds NK cells at non-CAM sites, resulting in the release of IFN. IFN then acts in an autocrine manner independent of CAM to enhance NK cytotoxicity. Interaction of anti-CAM antibodies with CAM may provide a negative signal in regulating LPS-induced IFN production.

Mice sensitized with either BCG or cell-wall skeleton of BCG (BCG-CWS) produced interferon in blood after stimulation with specific antigen, purified protein derivative of tuberculin (PPD). Both BCG-infected normal (C57BL/6) and thymic nude (BALB/c, nu/nu) mice showed enhanced activity to produce interferon by stimulation with E. coli endotoxin. However, detectable interferon was not produced in athymic nude mice sensitized with BCG or BCG-CWS by stimulation with PPD. Immune-induced interferon (I-IF) produced by BCG-CWS and PPD in mice was different in biological and physicochemical properties from virus-induced interferon. I-IF showed about 100 times more potent L-cell growth inhibitory activity than virus-induced L-cell interferon (L-IF). Both I-IF and L-IF showed macrophage-activating activity, which renders resting macrphages cytotoxic to L1210 leukemia cells. Antiviral and macrophage-activating activity of interferon preparation was not separated physicochemically in this study.

The interferon-induced Newcastle disease virus (NDV) was shown to augment cytotoxicity attributable to natural killer (NK) cells in all of the major lymphoid organs of W/Fu rats except the thymus. The levels of interferon isolated from the spleen following NDV inoculation correlated with the increase in splenic cytotoxicity from the same spleen. Spleen-derived interferon was shown to augment splenic cytotoxicity following intravenous inoculation, and to augment spleen cell cytotoxicity in vitro. Three major peaks of interferon type I were found in spleen homogenates corresponding to mol. wt of greater than 100,000, 29-33,000 and 19-23,000. All these fractions stimulated spleen cell cytotoxicity when tested in vitro. The rapid drop in splenic cytotoxicity 24 hr after NDV inoculation was associated with a rapid fall in interferon levels in vivo. The need for the continued presence of interferon for the stimulation of cytotoxicity was demonstrated when spleen cells pretreated with interferon for 4 hr in vitro lost their augmented cytotoxicity upon culturing for a further 20 hr in the absence of interferon. Although splenic cytotoxicity returned to control levels within 24 hr of a single 10(7.3) EID50 dose of NDV, repeated doses of NDV maintained augmented cytotoxicity over a longer period. Spleen cells either taken from rats injected with NDV or pretreated in vitro with interferon showed a two-fold increase in the number of cytotoxic cells bound to W/FuG-1 target cells, with no change in the target binding-cell numbers. However, only the cells pretreated with interferon showed an increase in lytic efficiency.

In this paper it is demonstrated that (3H)2'-5'P3A3 can bind to the peritoneal macrophages from Wistar rat. This binding is strongly inhibited by cold 2'-5'P3A3, while the inhibiting capacity of 2'-5'P3I3 and 2'-5'A3 is very small, showing that this binding is highly specific. And the binding of (3H)2'-5'P3A3 is reversible, saturable and with high affinity. A Scatchard analysis of the binding data gives a linear plot, an apparent dissociation constant (Kd) about 1.3 X 10(-7) M and binding sites per cell about 2.1 X 10(7). The above evidence shows the existence of the 2'-5'P3A3 receptor, a fact which, to our knowledge, has not been reported before.