key: cord-0944103-5g1waed3
authors: Hertzog, Paul J.; Bourke, Nollaig M.; de Weerd, Nicole A.; Mangan, Niamh E.
title: New Interferons
date: 2016-05-09
journal: Encyclopedia of Immunobiology
DOI: 10.1016/b978-0-12-374279-7.10007-4
sha: 8837b57f8bf71fdbca83ba67e6e2a055e81774d8
doc_id: 944103
cord_uid: 5g1waed3

New interferons (IFNs) include members of the type I IFN family, such as IFN epsilon (IFNε), IFN tau, IFN omega, and IFN kappa, as well as the type III IFN family, also known as the IFN lambdas. By comparison the classical or ‘old’ IFNs comprise the 14 subtypes of IFN alpha and IFN beta, which are all members of the type I IFN family, as well as type II IFN gamma. In this article, we examine the new IFNs and specifically discuss their discovery, comparative structures, functions in physiology and disease, the signaling pathways they initiate, and their regulatory controls. We highlight IFNε that was discovered in our laboratory and characterized for its role in protecting the female reproductive tract from infections.

Since the discovery of an antiviral activity by Nagano in 1953-54 (Nagano and Kojima, 1954) , named 'the interferon' by Isaacs and Lindenmann in 1957 , we have seen the elaboration of this term to cover a broad family of cytokines with 28 members. This original activity became known as the type I interferon (IFN) family, which grew to comprise 14 IFN alpha (IFNa) subtypes and a single IFN beta (IFNb) (originally called fibroblast IFN). It was later discovered in 1965 (Wheelock, 1965) that lymphocytes stimulated by mitogens also produced an antiviral activity that was eventually distinguished by chemical properties (acid lability), then antigenicity, which was called immune IFN after the cells that produced it; it was subsequently cloned as the type II IFN gamma (IFNg) (Gray and Goeddel, 1982) . For the purpose of this article, these IFNs will be considered as 'the old IFNs,' and we will discuss herein, the subsequently identified 'new' members of the type I IFN family (IFN omega (IFNu) in 1985; IFN tau (IFNs) in 1996; IFN epsilon (IFNε) in 2004; IFN kappa (IFNk) in 2001) and the IFN lambdas (IFNls), the type III IFN family, discovered in 2003.

The IFNs derive their name from their definitive antiviral activity through which they were first described, although their potency varies by three orders of magnitude among the different types. The types of IFNs are distinguished by sequence identity, genomic locus, distinct cognate receptors, and to a lesser extent by cell of origin and stimulus (see Table 1 ). The 'old,' classical type I IFN family comprises the IFNa subtypes and IFNb, all encoded by genes in a genomic locus on HSA chromosome 9p (and the syntenic murine chromosome 4), which also contains the genes encoding the 'new' type I IFNs described below (Hardy et al., 2004) . All type I IFNs bind their cognate cell surface receptors IFNAR1 and IFNAR2 and subsequently activate associated kinases Tyk2 and Jak1, respectively, leading to phosphorylation of the intracellular domains of the receptors and recruitment of signal transducers and activator of transcription (STAT) proteins. The type I (and to some extent type II) IFN signaling has been the prototype system for the discovery and characterization of the JAK/STAT pathway (Stark and Darnell, 2012) . This pathway regulates the expression of thousands of so-called IFN-regulated genes (IRGs) (Rusinova et al., 2013) , which encode the effector molecules of the various type I IFN properties, including the antiviral IRGs, namely 2 0 -5 0 oligoadenylate synthetase, RNase L, PKR, viperin, and many of the so-called 'viral restriction factors.' Additional IRGs that regulate viral infection and replication have been elucidated by the studies of Schoggins et al. (Schoggins, 2014; Schoggins et al., 2014 . Since their discovery as antiviral proteins, the 'older' IFNs have been further characterized as multifaceted cytokines that can modulate cell proliferation; survival; differentiation; and migration, and regulate virtually every effector cell of the innate and adaptive immune responses. They are involved in many pathologies including cancer, infectious, and inflammatory diseases; and IFN modulators are in use or in clinical trials for these conditions. While IFNs have a well-characterized protective role in host defense, excessive signaling is toxic, even lethal. Thus, the well-characterized and diverse pathways driving IFN signaling (Hertzog and Williams, 2013) , are balanced by an intricate array of negative regulators to control potential side effects (Porritt and Hertzog, 2015) . The large number of negative regulators and the nature of their targets, which function in many stages of the IFN production and action system, suggest the need to tightly regulate the response in a temporal and tissue-specific manner. It will be interesting to determine whether the 'controls' on signaling are the same for the 'new' IFNs as the older, well-characterized ones.

IFNu was discovered in 1985 during a low-stringency hybridization screen of the bovine genome with a human IFNa cDNA probe (Capon et al., 1985) . The same study subsequently identified human IFNu (Capon et al., 1985) . There is limited functional data available in the literature for IFNu. While it is induced after viral infection in human peripheral blood leukocytes (Adolf et al., 1990) , it has been shown to have a role in protecting cats against parvovirus (Paltrinieri et al., 2007) . Interestingly, while humans and mice have only one functional IFNu gene each, over 12 IFNu genes have been identified in each of bats, cats, and cattle (Walker and Roberts, 2009; Yang et al., 2007; Kepler et al., 2010) .

The endogenous form of human IFNu was purified from peripheral blood leukocytes after Sendai virus infection (Adolf et al., 1990) . The human IFNu protein shares 61% amino acid identity with human IFNa2 but only 26.2% and 28.21% with human IFNb and human IFNε, respectively (see Table 2 ), but despite relative similarities in primary protein sequence, structural modeling predicts human IFNu is more similar to IFNb than IFNa (Figure 1 (a) and 1(b)). However, of the limited studies reported for IFNu, this cytokine demonstrates binding affinities for both IFNAR1 and IFNAR2 comparable to human IFNb, and a 5-to 10-fold more potent antiproliferative activity compared to human IFNa subtypes (Jaks et al., 2007) , with demonstrated antitumor activities in human cancer models (Horton et al., 1999) . Beside activation of the canonical ISGF3 signaling pathway (Jaks et al., 2007) , IFNu along with IFNa and IFNb has been shown to induce tyrosine phosphorylation of CrkL (Ahmad et al., 1997) , an SH3/SH2 domain-containing signaling adapter involved in signal transduction in chronic myeloid leukemia (ten Hoeve et al., 1994) . IFNu also has disease associations, with reports of serum autoantibodies to this cytokine being a marker for autoimmune polyendocrine syndrome type I, a multifaceted autoimmune disease (Husebye et al., 2009; Cervato et al., 2010) . The crystal structure of IFNu in complex with the extracellular domains of IFNAR2 and a truncated form of IFNAR1 has been determined (Thomas et al., 2011) . When compared to these structures, it is clear that the ligand-receptor interfaces consist of anchor points that are residues conserved across IFN subtypes. Both the high-affinity interface (between IFNu and IFNAR2) and the low-affinity interface (with IFNAR1) are similar to the structure of a mutant IFNa2-IFNAR2 and IFNb-IFNAR1, respectively (Thomas et al., 2011; de Weerd et al., 2013) . The mostly hydrophobic interface with IFNAR2 is localized around the 'elbow' between the two extracellular subdomains of IFNAR2; while the interface of IFNu with IFNAR1 is diffuse over the surface of the receptor with only two receptor residues on IFNAR1 identified as energetically critical for ligand binding, namely Tyr70 and Phe238 (Thomas et al., 2011) . It has been shown recently that in the mouse system, IFNb can bind to and signal through IFNAR1 independently of IFNAR2 . Given that IFNu has a similar IFNAR1 binding affinity and similar antiproliferative potency as IFNb, it may be Cell and organ distribution of the ubiquitous type I IFNAR1 and IFNAR2 receptors and the more restricted expression of type III IL-10Rb and IL-28Ra receptors is reviewed in d .

c Classical functions of IFNs include antiviral, antiproliferative, antitumor, and immunomodulatory functions.

interesting to investigate whether IFNu also binds IFNAR1 directly and signals independently of IFNAR2.

IFNk was discovered in 2001 following screening of the Human Genome Services expressed sequence tags database for homologs within the IFN family (LaFleur et al., 2001) . IFNk is distinguishable from the IFNa and IFNb subtypes by its constitutive expression in the absence of exogenous stimuli, particularly in dendritic cells, monocytes, and human epidermal keratinocytes (LaFleur et al., 2001; Nardelli et al., 2002) . IFNk is also inducible in monocytes following IFNg stimulation (Nardelli et al., 2002) , and in keratinocytes following viral infection, or IFNg or IFNb stimulation (LaFleur et al., 2001) . Besides the five helical bundle structure characteristic of all type I IFNs, IFNk shares only limited amino acid identity with human IFNa2 (27.66%), IFNb (34.22%), or human IFNε (28.02%) (see Table 2 ). Furthermore, it has an insertion of 13 amino acids (residues 135-147) leading to an extension of the loop between helices C and D of IFNk that may protrude into the IFNAR1 binding domain, and thus could alter signaling (Figure 1(c) ). Regardless, IFNk has been shown to utilize both IFNAR1 and IFNAR2 to induce an IFN-stimulated response element-driven response, and the expression of IRGs characteristic of cellular responses to treatment with other type I IFNs (LaFleur et al., 2001) . IFNk has also been shown to induce production of tumor necrosis factor (TNF) and IL-10, suggesting a role for this cytokine in regulating immune cell function (Nardelli et al., 2002) . Application of recombinant IFNk has been shown to protect human cells from two types of viral infection in vitro (LaFleur et al., 2001) . Interestingly, two studies have investigated IFNk expression in keratinocytes infected with human papillomavirus (HPV) (DeCarlo et al., 2010; Reiser et al., 2011) with one group finding that HPV represses IFNk expression in human keratinocytes in vitro and in vivo (Reiser et al., 2011; DeCarlo et al., 2010) . The other study showed compartmentalized expression, in that keratinocytes from patients infected with HPV lacked IFNk expression, whereas the stroma of cervical biopsy specimens showed elevated IFNk expression that increased in relation to disease progression (DeCarlo et al., 2010) .

Due to its constitutive expression in keratinocytes, the role of IFNk has been investigated in skin diseases. Compared to samples from healthy controls, IFNk is elevated in skin samples from patients with allergic contact dermatitis (Scarponi et al., 2006) , psoriasis and atopic dermatitis (Nardelli et al., 2002) , and in a cohort of patients with increased susceptibility to melanoma and skin cancer (Puig-Butille et al., 2014) . There is also a report of an association between a single nucleotide polymorphism (SNP) upstream of the promoter of IFNk and systemic lupus erythematosus in males, reportedly in the absence of additional SNPs associated with the type I IFN locus (Harley et al., 2010) .

IFNε is a novel type I IFN discovered and characterized by the Hertzog laboratory (Hardy et al., 2004; Fung et al., 2013) . It is found in the same genetic locus as the other type I IFNs and has approximately 30% or 37% amino acid identity with IFNa or b (Table 2) , respectively, and subtle differences in 3D structure based on modeling (Figure 1) . The regulation and expression of IFNε are different to the other type I IFNs suggesting a different function for this type I IFN. Whereas 'classical' type I IFNs are not expressed constitutively and are induced by pathogens via pathogen recognition receptor pathways, IFNε is constitutively and most abundantly expressed in the glandular endometrial epithelium of the female reproductive tract (FRT) where expression is not inducible by pathogens, but is regulated by the hormone changes of the menstrual cycle. IFNε gene expression levels are highest when estrogen is highest and lowest when progesterone levels are prominent. IFNε levels are significantly reduced at embryo implantation (day 4.5) in the mouse, consistent with progesterone regulation of IFNε. IFNε expression is barely detectable in postmenopausal women consistent with the other hormonal regulation data . Interestingly, IFNε is weakly, but significantly induced in human ectocervical epithelial cells following exposure to seminal fluid (Sharkey et al., 2007) and 8 h postcoitus in the mouse . Additionally, Matsumiya et al. (2007) determined that in the HeLa (human cervical cancer) cell line, the TNF cytokine can stabilize IFNε mRNA thus increasing IFNε synthesis to result in increased TNF-mediated STAT1 phosphorylation. This group has since demonstrated a posttranslational regulation of IFNε expression under basal conditions by the importin 9 transporter protein, as identified by mass spectrometry on proteins in HeLa cell extracts that are bound to the 5 0 UTR of IFNε (Matsumiya et al., 2013) .

While most functional studies to date have assessed the importance of IFNε in mice, IFNε is highly conserved and the protein has been studied recently in several species, including humans , rhesus macaques (Demers et al., 2014) , dogs (Yang et al., 2013) , and bovine cells (Guo et al., 2015) . IFNε signals through IFNAR1 and IFNAR2 to induce typical IRGs such as ISG15, 2 0 -5 0 oligoadenylate synthetase, and IFN regulatory factor (IRF) 7. Whether IFNε also utilizes the novel IFNAR1-only signaling axis as shown for IFNb or initiates novel downstream signaling mechanisms in specific mucosal cell types remains to be determined.

Mice lacking IFNε are healthy and fertile suggesting the expression of IFNε in the FRT is not necessary for reproduction and development, but may be important in the immune defense of this important site. The importance of IFNε in inflammatory conditions of the FRT (e.g., endometriosis, pelvic inflammatory disease, or chorioamnionitis in pregnancy) has not been determined. IFNε À/À mice are more susceptible to infection with Chlamydia muridarum bacteria and treatment of mice with recombinant IFNε can protect against vaginal infection . These results are in stark contrast to previous studies that indicated that other type I IFNs exacerbated the pathogenesis of C. muridarum disease by activating cytotoxic T cells, which were largely responsible for the inflammatory cell damage in infection (Nagarajan et al., 2008) . Thus IFNε performs different, and in this case opposite, functions to other type I IFNs. This difference in activity is difficult to explain for IFN ligands that act via the same receptors. The unique expression pattern, regulation, and impacts on localized mucosal infections suggest a unique biological function for IFNε.

The epithelial expression of IFNε Demers et al., 2014) represents an important innate factor in mucosal immune defense against pathogens as is seen for Chlamydia and herpes simplex virus 2 infection of mice . As mentioned, however, IFNε levels are not directly affected by these pathogens but rather by hormones that alterimmune system in the FRT and can increase susceptibility to sexually transmitted infections (reviewed in Wira et al., 2015) . While type I IFNs are well characterized for their antipathogen effects, many pathogens have developed mechanisms to evade the type I IFN response and thus, IFNε, with its unusual induction and expression patterns, may circumvent such strategies and thus offer an avenue for the development of novel therapies in FRT infections.

IFNε has recently been reported to be expressed in the epithelium of the lungs and intestines (Demers et al., 2014) in nonhuman primate studies and in the male reproductive tract of rhesus macaques and mice (Demers et al., 2014; Hermant et al., 2013) . Once verified, any functional significance of these expression patterns will require further investigation. Of note, a SNP (rs2039381) resulting in a truncated IFNε protein has a significant association with the autoimmune skin disorder vitiligo (Cho et al., 2013) , again indicating a possible function of IFNε outside the FRT.

Type I IFNs are known to affect the functions and development of innate and adaptive immune cell responses. Indeed IFNε À/À mice have reduced natural killer cells in the FRT, potentially contributing to the increased susceptibility of these mice to Chlamydia infection. Furthermore, IFNε was claimed to boost the adaptive immune response in vaccine adjuvant studies (Xi et al., 2012; Day et al., 2008) . However, these effects were observed using adenoviral vectors containing the IFNε gene, and since IFNε was not quantified in these experiments, it is difficult to attribute the biological functions to IFNε directly. Furthermore, our data (unpublished) suggest that recombinant murine IFNε has approximately 100-fold less antiviral and antiproliferative activities and reduced immunoregulatory activity, compared with other type I IFNs, an observation which has also been demonstrated for IFNε in other species (Yang et al., 2013; Guo et al., 2015) .

IFNε is not the only type I IFN of importance in the FRT. IFNs is produced by trophoblasts and was first recognized as a pregnancy recognition signal, albeit only in ruminant species such as cattle and sheep (Spencer et al., 1996) . IFNs is located in the type I IFN cluster in the bovine genome on chromosome 8 (Walker and Roberts, 2009 ) and its trophoblast expression can be regulated by ETS2 (Ezashi and Roberts, 2004) though it can also be induced by pathogens. More recently, IFNs has been characterized for anti-inflammatory effects and induction of several ISGs, including IRF2 that may protect the conceptus from the maternal immune system and promote development (Choi et al., 2003 (Choi et al., , 2001 . Similarly, in pigs, IFNd (delta) was identified in trophoblasts during the preimplantation period in the uterus (Lefevre et al., 1998) . Although originally it was thought that IFNε might represent the human and murine equivalents of IFNs, it is notable that ruminant species have both IFNs and IFNε gene expression, suggesting different functions consistent with their expression by different cells and in response to different stimuli.

The existence of a separate antiviral immune system other than the type I IFNs is evident by the observation that antiviral immunity, in some instances, can still be activated in the absence of the type I IFN receptor (Pulit-Penaloza et al., 2012; Peltier et al., 2013) . In 2003, a new family of antiviral IFNs, the type III IFNs, was first described (Kotenko et al., 2003; Sheppard et al., 2003) . This family consisted of three cytokines, IFNl1 (IL-29), IFNl2 (IL-28A), and IFNl3 (IL-28B) identified on human chromosome 19 (q13.13 region) (Kotenko et al., 2003; Sheppard et al., 2003) . A fourth member, IFNl4, was identified later in 2013 and its expression and function is still being fully determined (Prokunina-Olsson et al., 2013) . Although the function of type III IFNs overlaps with type I IFNs, they are structurally more similar to the IL-10 cytokine family and interact with a distinct receptor complex to initiate signaling (Gad et al., 2009) . It is the restricted expression of this receptor complex which gives type III IFNs more specificity than type I IFNs.

Type III IFNs can be produced by many cell types, including by epithelial and immune cells. Similar to the type I IFNs, the type III IFNs are strongly induced in response to viral infection through activation of several pattern recognition receptor pathways, including those initiated by viral nucleic acids, such as Toll-like receptors (TLRs 3, 7/8, 9) and RIG-like receptors (RLRs; RIG-I, Mda5) (Onoguchi et al., 2007) . Their induction is mediated through the activation of the transcription factors IRF3, IRF7, and NF-kB, although subtle differences exist in transcription factor activation in the regulation of type I and III IFN (Osterlund et al., 2007; Thomson et al., 2009; Iversen et al., 2010) . This differential regulation at the transcriptional level may account for the observation that IFNl expression is more tissue-restricted than the type I IFNs: for example, one study found that IFNl expression was highly inducible upon stimulation in liver but not in the brain, whereas IFNa/b were upregulated in both organs (Sommereyns et al., 2008) . Additionally, a recent study identified a unique mechanism whereby intestinal epithelial cells, known to be high IFNl producers, can selectively upregulate type III IFNs, and not type I IFNs, through activation of a novel RLR pathway in a peroxisome-dependent manner and through activation of the transcription factors IRF1, NF-kB, and IRF3 (Odendall et al., 2014) . It is noteworthy that IFNa genes do not have NF-kB sites in their promoters.

The type III IFNs activate antiviral responses through engagement of their receptor complex, which consists of a subunit of the IL-10 receptor, IL-10Rb, and a unique receptor chain IL-28Ra. Upon engagement with this receptor, receptor-associated JAK kinases (Tyk2 and Jak1, as in the IFNAR complex) are activated, leading to the phosphorylation and activation of members of the STAT family of transcription factors, including ISGF3a, in a mechanism similar to type I IFN-induced signaling (Dumoutier et al., 2004) . This leads to the upregulation of genes with antiviral functions, similar to the type I IFNs. Indeed type I and type III IRG signatures have been shown to be redundant and no distinct type III IFN gene profile has yet been identified (Crotta et al., 2013; Zhou et al., 2007) .

It is the restricted expression of IL-28Ra that makes the type III IFN response more specialized than the more ubiquitous type I IFN response. IL-28Ra is predominantly expressed by epithelial cells at mucosal surfaces, including the gastrointestinal tract, reproductive tract, and respiratory tract, and by some immune cell subsets such as dendritic cells (Mordstein et al., 2010; Sommereyns et al., 2008; Witte et al., 2009 ). Subsequently, the type III IFNs have emerged as major protective factors at mucosal sites. For example, type III IFNs protect airway epithelial cells from respiratory viruses such as influenza A and severe acute respiratory syndrome coronavirus (Mordstein et al., 2008 (Mordstein et al., , 2010 . In the intestine, type III IFNs, and not type I IFNs, protect intestinal epithelium from enteric viruses (Pott et al., 2011; Mahlakõiv et al., 2015) . However, this family of cytokines are proving to have more diverse roles than just antiviral immunity, with a recent focus shifting to their role in allergic asthma, where they not only control bronchial rhinovirus infection, an infection that can trigger asthma exacerbations, but also act directly on local adaptive immune cells to suppress Th2-mediated asthmatic responses (Koch and Finotto, 2015) . Indeed, type III IFNs may play an important anti-inflammatory role in autoimmune diseases, with a recent study finding that type III IFNs block and reverse collagen-induced arthritis via suppression of IL-1bproducing neutrophil infiltration, therefore blocking Th17 and gd T cell responses (Blazek et al., 2015) . Many of these emerging roles for the type III IFNs have been elucidated as a consequence of the recently generated IL-28Ra knockout mouse, and more physiological roles may be revealed as studies continue (Ank et al., 2008; Egli et al., 2014) .

The clinical importance of the type III IFNs was highlighted in 2009 when a genome-wide association study revealed several SNPs in the IFNl gene locus that were highly associated with both spontaneous clearance of hepatitis C virus (HCV) and IFNa treatment induced clearance of HCV (Thomas et al., 2009; Suppiah et al., 2009; Ge et al., 2009) . The SNPs with the strongest associations were identified in the novel IFNl4 gene. One of these SNPs, rs368234815, results in a frameshift mutation that gives rise to the expression of IFNl4 (Prokunina-Olsson et al., 2013) . However, why expression of IFNl4, and strong IFNl4 induced antiviral activity, is a disadvantage in HCV infection is unknown (Hamming et al., 2013; Terczy nska-Dyla et al., 2014) .

The tissue-specific nature of the type III IFNs have made them an attractive therapeutic option as they can elicit similar responses to the type I IFNs, which have been used as therapies against viral infections and cancers for decades, but without inducing the systemic side effects observed with type I IFN treatment. Pegylated IFNl1 has successfully completed Phase II clinical trials for the treatment of HCV (Muir et al., 2014) . Interestingly, type III IFNs can overcome the desensitization to IFNa signaling that occurs in HCV patients treated with therapeutic IFNa, making it an attractive complementary therapy for patients exhibiting IFNa refractoriness (Makowska et al., 2011) . Thus, despite only subtle differences detected between type I and the type III IFN system tested in vitro, there may be major differences in vivo, possibly due to differences in the regulation of signaling cascades activated in vivo. Additionally, IFNl has shown some effectiveness in several murine tumor models (Lasfar et al., 2006; Sato et al., 2006) , which requires additional study.

This novel and exciting class of type III IFNs are emerging as key effectors in localized antiviral responses and could play a role in the pathogenesis of a variety of other diseases. Already, the discovery that SNPs in the type III IFN locus are highly associated with disease, and therapeutic response in HCV has revolutionized the treatment of this disease. Their ability to act like type I IFNs, yet in a much more localized and specialized manner due to their restricted receptor expression, demonstrates their potential for treating the diseases that respond to type I IFN therapy, albeit in a more precise manner to overcome the issues of tolerance and off-target effects.

The identification of the traditional type I IFNs over 60 years ago revolutionized our understanding of how the immune response was regulated and led to new treatments for a variety of human diseases, including viral infections, cancers, and autoimmune diseases. Despite the side effects associated with the off-target effects of these IFNs, they are still the main therapy for treating many diseases. However, the IFN family has greatly expanded in the past decade, and although some of these novel members have been significantly characterized, there is still much unknown about some of the newer IFNs. So, what do these new IFNs add to our knowledge and perception of the IFN family of cytokines and their roles in physiological and pathological processes? What is clear from recent characterizations of the type III IFN family and IFNε is that these novel IFNs play important functional roles, not only in immune functions, but in normal homeostasis. The clinical relevance of newer IFN research is apparent from the recent example of how further understanding of type III IFNs, especially SNPs in these genes, has changed the way HCV is treated clinically. Indeed, the strong link between SNPs in type III IFN genes and viral infection highlights the possibility that uncharacterized SNPs in other novel IFNs may have potent functional consequences on the immune response and may underlie other human disease pathologies or therapeutic responses. Another exciting aspect of many of these novel IFNs is that although they may exhibit similar functions to the traditional IFNs, they are often produced in a more specialized manner, with some even being expressed constitutively at low levels within some organs. Their signaling occurs through well-characterized receptors, but there may be differences in these signal transduction pathways that are yet to be characterized. This research raises the possibility that the use of some of these novel IFNs therapeutically may be able to harness the wide range of beneficial effects induced by traditional IFNs, while overcoming issues of tolerance and side effects. 

Purification and characterization of natural human interferon omega 1. Two alternative cleavage sites for the signal peptidase

The type I interferon receptor mediates tyrosine phosphorylation of the CrkL adaptor protein

An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity

IFN-l resolves inflammation via suppression of neutrophil infiltration and IL-1b production

Two distinct families of human and bovine interferon-alpha genes are coordinately expressed and encode functional polypeptides

AIRE gene mutations and autoantibodies to interferon omega in patients with chronic hypoparathyroidism without APECED

Association study between nonsense polymorphism (rs2039381, Gln71Stop) of interferon-epsilon and susceptibility to vitiligo in Korean population

Interferon regulatory factor-two restricts expression of interferon-stimulated genes to the endometrial stroma and glandular epithelium of the ovine uterus

Pregnancy and interferon tau regulate major histocompatibility complex class I and beta2-microglobulin expression in the ovine uterus

Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia

Differential effects of the type I interferons alpha4, beta, and epsilon on antiviral activity and vaccine efficacy

IFN-kappa, a novel type I IFN, is undetectable in HPV-positive human cervical keratinocytes

The mucosal expression pattern of interferon-epsilon in rhesus macaques

Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling

The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections

Regulation of interferon-tau (IFN-tau) gene promoters by growth factors that target the Ets-2 composite enhancer: a possible model for maternal control of IFN-tau production by the conceptus during early pregnancy

Interferon-epsilon protects the female reproductive tract from viral and bacterial infection

Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family

Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance

Structure of the human immune interferon gene

Molecular cloning and characterization of a novel bovine IFN-epsilon

Interferon lambda 4 signals via the IFNl receptor to regulate antiviral activity against HCV and coronaviruses

Characterization of the type I interferon locus and identification of novel genes

The role of genetic variation near interferon-kappa in systemic lupus erythematosus

IFN-epsilon is constitutively expressed by cells of the reproductive tract and is inefficiently secreted by fibroblasts and cell lines

Fine tuning type I interferon responses

Antitumor effects of interferon-omega: in vivo therapy of human tumor xenografts in nude mice

Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I

Cellular interactions of CRKL, and SH2-SH3 adaptor protein

Virus interference. I. The interferon

Expression of type III interferon (IFN) in the vaginal mucosa is mediated primarily by dendritic cells and displays stronger dependence on NF-kappaB than type I IFNs

Differential receptor subunit affinities of type I interferons govern differential signal activation

Chiropteran types I and II interferon genes inferred from genome sequencing traces by a statistical gene-family assembler

Role of Interferon-l in allergic asthma

IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex

Interferon-kappa, a novel type I interferon expressed in human keratinocytes

Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma

Interferon-delta: the first member of a novel type I interferon family

Leukocyte-derived IFN-a/b and epithelial IFN-l constitute a compartmentalized mucosal defense system that restricts enteric virus infections

Interferonb and interferon-l signaling is not affected by interferon-induced refractoriness to interferon-a in vivo

IFN-epsilon mediates TNF-alpha-induced STAT1 phosphorylation and induction of retinoic acid-inducible gene-I in human cervical cancer cells

Novel role for molecular transporter importin 9 in posttranscriptional regulation of IFN-epsilon expression

Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses

Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections

A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection

Pouvoir immunisant du virus vaccinal inactivé par des rayons ultraviolets

Type I interferon signaling exacerbates Chlamydia muridarum genital infection in a murine model

Regulatory effect of IFN-kappa, a novel type I IFN, on cytokine production by cells of the innate immune system

Diverse intracellular pathogens activate type III interferon expression from peroxisomes

Viral infections activate types I and III interferon genes through a common mechanism

IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes

Evaluation of inflammation and immunity in cats with spontaneous parvovirus infection: consequences of recombinant feline interferon-omega administration

Neurotropic arboviruses induce interferon regulatory factor 3-mediated neuronal responses that are cytoprotective, interferon independent, and inhibited by Western equine encephalitis virus capsid

Dynamic control of type I IFN signalling by an integrated network of negative regulators

IFN-lambda determines the intestinal epithelial antiviral host defense

A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus

Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer

Type 1 IFN-independent activation of a subset of interferon stimulated genes in West Nile virus Eg101-infected mouse cells

High-risk human papillomaviruses repress constitutive kappa interferon transcription via E6 to prevent pathogen recognition receptor and antiviral-gene expression

Interferome v2.0: an updated database of annotated interferon-regulated genes

Antitumor activity of IFN-lambda in murine tumor models

Analysis of IFN-kappa expression in pathologic skin conditions: downregulation in psoriasis and atopic dermatitis

Interferon-stimulated genes: roles in viral pathogenesis

Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity

Interferon-stimulated genes and their antiviral effector functions

A diverse range of gene products are effectors of the type I interferon antiviral response

Seminal plasma differentially regulates inflammatory cytokine gene expression in human cervical and vaginal epithelial cells

IL-28, IL-29 and their class II cytokine receptor IL-28R

IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo

tau-Interferon: pregnancy recognition signal in ruminants

The JAK-STAT pathway at twenty

IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy

Reduced IFNl4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Structural linkage between ligand discrimination and receptor activation by type I interferons

Genetic variation in IL28B and spontaneous clearance of hepatitis C virus

The role of transposable elements in the regulation of IFN-lambda1 gene expression

Structural basis of a unique interferon-beta signaling axis mediated via the receptor IFNAR1

Characterization of the bovine type I IFN locus: rearrangements, expansions, and novel subfamilies

Interferon-like virus-inhibitor induced in human leukocytes by phytohemagglutinin

The role of sex hormones in immune protection of the female reproductive tract

Despite IFN-lambda receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

Role of novel type I interferon epsilon in viral infection and mucosal immunity

Molecular and functional characterization of canine interferon-epsilon

Cloning and characterization of a novel feline IFN-omega

Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases