Structure-activity of type I interferons

Type I IFNs constitute a family of proteins exhibiting high homology in primary, secondary, and tertiary structures. They interact with the same receptor and transmit signals to cellular nucleus through a similar mechanism, eliciting roughly homogeneous biological activity. Nevertheless, the members of that family, IFNα species, IFNβ and IFNω, due to local differences in the structure sometime show distinct properties. From the reported data it results that even minute changes or differences in the primary sequences could be responsible for a significant variety of biological actions, thus inducing to the hypothesis that Type I IFNs, rather than to be the result of a redundant replication during the evolution, play definite roles in the defense of living organisms to foreign agents.     

Functional antagonism between type I and type II interferons on human macrophages

A three-day treatment with IFN-gamma enhanced up to 300% the capacity of human monocytes and macrophages to produce H2O2 during the respiratory burst. IFN-alpha or -beta (type I IFNs), which did not by themselves influence the burst, were found to antagonize the enhancing effect of IFN-gamma (type II IFN). The antagonism was concentration-dependent and required the presence of type I IFNs during the whole period of IFN-gamma pretreatment. These results suggest that the host defense function of mononuclear phagocytes may be controlled by the relative local concentrations of type I and type II IFNs.     

Adjuvant activity of type I interferons

Type I interferons (IFNs) produced primarily by plasmacytoid dendritic cells (pDCs) as part of the innate immune response to infectious agents induce the maturation of myeloid DCs and enhance antigen presentation. Type I IFNs also enhance apoptosis of virus-infected cells, stimulate cross priming and enhanced presentation of viral peptides. Type I IFNs are powerful polyclonal B-cell activators that induce a strong primary humoral immune response characterized by isotype switching and protection against virus challenge. Type I IFNs stimulate an IgG2a antibody response characteristic of Th1 immunity when ad-mixed with influenza virus vaccine and injected intramuscurarly (i.m.) or administered intranasally. The adjuvant activity of type I IFNs has been shown to involve direct effects of IFN on B-cells, effects on T-cells, as well as effects on antigen presentation. Oromucosal administration of type I IFNs concomitantly with i.m. injection of vaccine alone can also enhance the antibody response to influenza vaccination by enhancing trafficking of antigen-presenting cells towards the site of vaccination. Recombinant IFNs are potent adjuvants that may find application in both parenterally and mucosally administered vaccines.     

Immunomodulatory functions of type I interferons

Interferon-α (IFNα) and IFNβ, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases.     

Signal transduction by type I interferons

The two classes of interferons, type I (IFNalpha, IFNbeta, IFNomega, and IFNtau) and type II (IFNgamma) are pleiotropic cytokines that exhibit antiviral, antiproliferative, and immunomodulatory effects on their target cells. This article summarizes the advances made in elucidating the molecular events that mediate the biological responses to type I interferons.     

Induction of type I interferons by bacteria

Type I interferons (IFNs) are secreted cytokines that orchestrate diverse immune responses to infection. Although typically considered to be most important in the response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. Although diverse mechanisms have been described, bacterial induction of type I IFNs occurs upon stimulation of two main pathways: (i) Toll‐like receptor (TLR) recognition of bacterial molecules such as lipopolysaccharide (LPS); (ii) TLR‐independent recognition of molecules delivered to the host cell cytosol. Cytosolic responses can be activated by two general mechanisms. First, viable bacteria can secrete stimulatory ligands into the cytosol via specialized bacterial secretion systems. Second, ligands can be released from bacteria that lyse or are degraded. The bacterial ligands that induce the cytosolic pathways remain uncertain in many cases, but appear to include various nucleic acids. In this review, we discuss recent advances in our understanding of how bacteria induce type I interferons and the roles type I IFNs play in host immunity.     

Human primary immunodeficiencies of type I interferons

Type I interferons (IFN-alpha/beta and related molecules) are essential for protective immunity to experimental infection by numerous viruses in the mouse model. In recent years, human primary immunodeficiencies affecting either the production of (UNC-93B deficiency) or the response to (STAT1 and TYK2 deficiencies) these IFNs have been reported. Affected patients are highly susceptible to certain viruses. Patients with STAT1 or TYK2 deficiency are susceptible to multiple viruses, including herpes simplex virus-1 (HSV-1), whereas UNC-93B-deficient patients present isolated HSV-1 encephalitis. However, these immunological defects are not limited to type I IFN-mediated immunity. Impaired type II IFN (IFN-gamma)-mediated immunity plays no more than a minor role in the pathogenesis of viral diseases in these patients, but the contribution of impaired type III IFN (IFN-lambda)-mediated immunity remains to be determined. These novel inherited disorders strongly suggest that type I IFN-mediated immunity is essential for protection against natural infections caused by several viruses in humans.     

Inhibition of ornithine decarboxylase in human fibroblast cells by type I and type II interferons

Dilution of human fibroblast GM2767 cell cultures into fresh serum-containing growth medium induces ornithine decarboxylase activity 45-fold over a six-hour interval. When the fibroblast cultures are supplemented with human fibroblast α-, β-, or γ-interferon at the time of dilution into fresh growth medium, the induction of ornithine decarboxylase is inhibited 61%, 90%, and 65%, respectively. β-Interferon is the most effective type of interferon to inhibit induction of ornithine decarboxylase.     

Overview of the biology of type I interferons

Type I interferons are pleiotropic cytokines with antiviral, antitumor and immunoregulatory functions. An aspect of their complex biology is the paradox that, depending on context, type I interferons can be anti-inflammatory and tissue protective or can be proinflammatory and promote autoimmunity. Along these lines, the activation of type I interferon pathways is effective in suppressing disease activity in patients with multiple sclerosis and in animal models of arthritis and colitis, while there is an expectation that blockade of the same pathways will be beneficial in the treatment of patients with systemic lupus erythematosus.     

Viral transformation for production of personalized type I interferons

Type I interferons (IFN) are cytokines with many functions and have been widely used to treat many human diseases such as hepatitis C virus infection. Using the viral transformation and priming properties of Epstein-Barr virus, we have developed a system that can produce high levels of “personalized” IFNs, which are produced from the cells of the patient to whom the IFNs are to be administrated. We demonstrate the feasibility of the system. This seems to be the first report for the establishment of a personalized IFN-production system. The personalized IFNs could have a longer circulation time, fewer side effects but higher efficacy. We anticipate that the system can provide an improved form of IFN for medical uses.     

Effects of phenytoin on the production of interferons: differential effects on type I and type II interferons

The relative effects of treatment with an anticonvulsant, phenytoin, on the production of interferons were determined for both the murine and human systems. Phenytoin treatment was found to have differential effects on the in vitro production of Type I and Type II interferons. Phenytoin had either no effect (HuIFN-alpha) or an enhancing effect (MuIFN-alpha/beta) on the in vitro production of Type I interferons. In contrast, phenytoin pretreatment had an inhibitory effect on the in vitro production of Type II interferons (IFN-gamma) for both the murine and human systems. Phenytoin appeared to exert its inhibitory effect directly on the IFN-gamma-producing cell and was active even when added as late as 6 h after IFN-gamma induction. This inhibition was not related to a toxic effect of the phenytoin and occurred at phenytoin concentrations which were pharmacologically relevant (10-20 micrograms/ml). The effects of phenytoin on the in vivo production of MuIFN-gamma were also examined. In parallel to the in vitro observations, phenytoin treatment of mice significantly reduced the in vivo induction of MuIFN-gamma. The results raise the possibility that phenytoin therapy in humans may significantly affect the production of HuIFN-gamma.     

Regulation of immune cell homeostasis by type I interferons

Although initially identified and best characterized for their role in innate antiviral defence, type I interferons (IFN-I) are also known to have an important impact on the adaptive immune response. In part, this is linked to another long-recognised property of IFN-I, namely their ability to modify cellular proliferation and survival. Here, we review the influence of IFN-I on immune cell homeostasis, focusing on their effects on T cells and antigen-presenting cells.     

The role of type I interferons in TLR responses

Recent advances in unravelling the complexities of the signalling pathways that constitute innate immunity have highlighted type I interferon as a key component in the response to infection. Here we focus on the emerging field of pattern-recognition receptor signalling, specifically Toll-like receptors and retinoic acid inducible gene-like helicases, from the perspective of this 50-year-old cytokine. The type I interferon gene family encompasses more than 20 subtypes, whose nature and properties have been extensively studied during its relatively long history. In this review we update and integrate available data on the mechanics of activation of the interferon genes and the role of this cytokine family in the innate immune response.     

Effects of type I interferons on Friend retrovirus infection

The type I interferon (IFN) response plays an important role in the control of many viral infections. However, since there is no rodent animal model for human immunodeficiency virus, the antiviral effect of IFN-alpha and IFN-beta in retroviral infections is not well characterized. In the current study we have used the Friend virus (FV) model to determine the activity of type I interferons against a murine retrovirus. After FV infection of mice, IFN-alpha and IFN-beta could be measured between 12 and 48 h in the serum. The important role of type I IFN in the early immune defense against FV became evident when mice deficient in IFN type I receptor (IFNAR(-/-)) or IFN-beta (IFN-beta(-/-)) were infected. The levels of FV infection in plasma and in spleen were higher in both strains of knockout mice than in C57BL/6 wild-type mice. This difference was induced by an antiviral effect of IFN-alpha and IFN-beta and was most likely mediated by antiviral enzymes as well as by an effect of these IFNs on T-cell responses. Interestingly, the lack of IFNAR and IFN-beta enhanced viral loads during acute and chronic FV infection. Exogenous IFN-alpha could be used therapeutically to reduce FV replication during acute but not chronic infection. These findings indicate that type I IFN plays an important role in the immediate antiviral defense against Friend retrovirus infection.     

Endogenous type I interferons as a defense against tumors

We have reviewed the experimental results which indicate that endogenous type I interferon (IFN) present either constitutively or possibly induced by the tumor plays an important role in limiting the development of transplantable tumors in mice. Thus, treatment with potent polyclonal neutralizing antibodies to IFN alpha/beta markedly enhanced the subcutaneous growth, invasiveness and metastases of xenogeneic tumor cells (uninfected or infected with RNA or DNA viruses) in athymic nude mice; enhanced the intraperitoneal transplantability of six different syngeneic murine tumors in three strains of immunocompetent mice; and completely abrogated the resistance of allogeneic C57Bl/6 (H-2(b)) or C3H (H-2(k)) mice to the multiplication of Friend erythroleukemia cells (H-2(d)) in the liver and spleen resulting in the death of most mice. The mechanisms by which mice respond to the injection of relatively few tumor cells appear to be multiple, to depend on the site of tumor growth, to occur early and prior to an immunologic response. Endogenous type I IFN appears to constitute an essential component of these defense mechanisms enabling the host to restrict tumor growth.     

Role of type I interferons during macrophage activation by lipopolysaccharide

Activation of macrophages by bacterial lipopolysaccharide (LPS) is accompanied by the secretion of type I interferons (IFNs) which can act in an autocrine manner. We examined the role of type I IFNs in macrophage responses to LPS using bone marrow-derived macrophages (BMM) from IFNAR1-/- mice, which lack a component of the type I IFN receptor and do not respond to type I IFNs. We found that, unlike wild-type (WT) BMM, LPS-treated IFNAR1-/- cells failed to produce nitric oxide (NO), or express inducible NO synthase (iNOS), indicating that type I IFNs are essential for all LPS-stimulated NO production in BMM. Exogenously added type II IFN (IFNgamma) rescued these responses in LPS-treated IFNAR1-/- BMM. In contrast to effects on NO, type I IFNs negatively regulated respiratory burst activity in LPS-primed BMM. We also found that while type I IFNs mediated the anti-proliferative effects of lower concentrations of LPS, at higher concentrations LPS acted in a type I IFNs-independent manner. Finally, we report that type I IFNs are a survival factor for BMM. Despite this, the ability of LPS to also prevent apoptosis in BMM was independent of type I IFNs. These findings highlight the diverse roles of type I IFNs in mediating LPS-stimulated macrophage responses.     

Class III human liver alcohol dehydrogenase: a novel structural type equidistantly related to the class I and class II enzymes

The primary structure of class III alcohol dehydrogenase (dimeric with chi subunits) from human liver has been determined by peptide analyses. The protein chain is a clearly distinct type of subunit distantly related to those of both human class I and class II alcohol dehydrogenases (with alpha, beta, gamma, and pi subunits, respectively). Disregarding a few gaps, residue differences in the chi protein chain with respect to beta 1 and pi occur at 139 and 140 positions, respectively. Compared to class I, the 373-residue chi structure has an extra residue, Cys after position 60, and two missing ones, the first two residues relative to class I, although the N-terminus is acetylated like that for those enzymes. The chi subunit contains two more tryptophan residues than the class I subunits, accounting for the increased absorbance at 280 nm. There are also four additional acidic and two fewer basic side chains than in the class I beta structure, compatible with the markedly different electrophoretic mobility of the class III enzyme. Residue differences between class III and the other classes occur with nearly equal frequency in the coenzyme-binding and catalytic domains. The similarity in the number of exchanges relative to that of the enzymes of the other two classes supports conclusions that the three classes of alcohol dehydrogenase reflect stages in the development of separate enzymes with distinct functional roles. In spite of the many exchanges, the residues critical to basic functional properties are either completely unchanged--all zinc ligands and space-restricted Gly residues--or partly unchanged--residues at the coenzyme-binding pocket.(ABSTRACT TRUNCATED AT 250 WORDS)     

IL-4 suppresses dendritic cell response to type I interferons

Cytokines play an important role in modulating the development and function of dendritic cells (DCs). Type I IFNs activate DCs and drive anti-viral responses, whereas IL-4 is the prototype of a Th2 cytokine. Evidence suggests that type I IFNs and IL-4 influence each other to modulate DC functions. We found that two type I IFNs, IFN-alpha and IFN-beta, stimulated a similar costimulatory profile in myeloid resting DCs. IL-4 suppressed the response of myeloid DCs to both type I IFNs in vitro and in vivo by impairing the up-regulation of MHC and costimulatory molecules and the production of cytokines, such as IL-6 and IL-15, and anti-viral genes, such as Mx-1, upon type I IFN stimulation. In dissecting the mechanism underlying this inhibition, we characterized the positive feedback loop that is triggered by IFN-alpha in primary DCs and found that IL-4 inhibited the initial phosphorylation of STAT1 and STAT2 (the transducers of signaling downstream of IFN-alpha and -beta receptors (IFNARs)) and reduced the up-regulation of genes involved in the amplification of the IFN response such as IRF-7, STAT1, STAT2, IFN-beta, and the IFNARs in vitro and in vivo. Therefore, IL-4 renders myeloid DCs less responsive to paracrine type I IFNs and less potent in sustaining the autocrine positive loop that normally amplifies the effects of type I IFNs. This inhibition could explain the increased susceptibility to viral infections observed during Th2-inducing parasitoses.