Review

Interferon-s: the modulators of antivirus, antitumor, and immune responses

Mingcai Li, Xiaojin Liu, Yanchun Zhou, and Shao Bo Su1
Institute of Inammation and Immune Diseases, Shantou University Medical College, Shantou, China
RECEIVED DECEMBER 22, 2008; REVISED FEBRUARY 12, 2009; ACCEPTED FEBRUARY 28, 2009. DOI: 10.1189/jlb.1208761

ABSTRACT
IFN-s, including IFN-1, IFN-2, and IFN-3, also known as IL-29, IL-28A, or IL-28B, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. The IFN-R complex consists of a unique ligand-binding chain, IFN-R1 (also designated IL-28R), and an accessory chain, IL-10R2, which is shared with receptors for IL-10-related cytokines. IFN-s signal through the IFN-R and activate pathways of JAK-STATs and MAPKs to induce antiviral, antiproliferative, antitumor, and immune responses. In this review, we summarize recent ndings about the biology of IFN-s and their pathophysiological roles in viral infection, cancer, and immune responses of the innate and adaptive arms. J. Leukoc. Biol. 86: 2332; 2009.

Introduction
IFN was the rst cytokine identied in 1957 by Isaacs and Lindenmann [1] during their seminal studies on virus interference. It was also the rst cytokine to be puried to homogeneity, cloned, sequenced completely, and produced in recombinant form and in extensive clinical application [2]. With the discovery of more isoforms, IFNs are classied into three distinct groups based on amino acid sequences and recognition by specic receptors [3] (Table 1). Mammalian type I IFNs constitute a multigene family with at least eight subclasses: IFN-, IFN-, IFN-, IFN-, IFN-, IFN-, IFN-, and IFN- (limitin), and the rst ve are found in human [4] of which there is only one IFN- but 13 IFN- subtypes. IFN- is produced in trophoectoderm of ruminants and appears to be important in early pregnancy [5]. IFN- is pro-

duced by trophoblasts of pig [6]. IFN- (limitin) is found only in mice [7, 8]. Type II IFN consists of a single type, IFN- [9]. Recently, a novel group of IFNs was discovered independently by two groups of scientists led by Kotenko and Gallagher [10] of the University of Medicine and Dentistry, New Jersey (Newark, NJ, USA) group and Klucher [11] of the ZymoGenetics (Seattle, WA, USA) group. The new IFN- family has three members: IFN-1, IFN-2, and IFN-3. The IFN- genomic structures resemble that of the IL-10 family [1214]. Therefore, they have been described independently as IL-29 (IFN1), IL-28A (IFN-2), and IL-28B (IFN-3) [11]. However, at the amino acid level and functionally, IFN-s are more related to type I IFNs than IL-10. They activate ISRE and induce antiviral activity. IFN-s are now collectively referred to as type III IFNs [10, 15]. Several comprehensive reviews have been published in recent years about IFN- signaling pathways and the antiviral activities [3, 16 18]. Here, we will focus on the current knowledge of the role of the IFN- family in diseases.

BIOLOGICAL CHARACTERISTICS OF IFN-

Genes
The genes encoding three members of the IFN- family are clustered on human chromosome 19 (19q1313 region) [10, 11]. This location differs from the type I IFN family clustered on chromosome 9. Like the IL-10 gene family, IFN-s contain multiple exons, and IFN-2 and IFN-3 have six and IFN-1 ve exons [11]. This is in contrast to the type I IFNs, which are encoded within a single exon. IFN-2 and IFN-3 are virtually identical, sharing 96% amino acid identity, whereas IFN-1 has 81% homology to IFN-2/3 [11]. The conserved cysteine pattern and amphipathic prole of the IFN-s suggest that they belong to the helical cytokine family [11]. IFN-s represent an evolutionary link between IL-10 and type I IFNs [19]. In mammals, IFN- genes are duplicated but only to two to four copies in each species (frog, dog, mouse, rat, and human). In chicken, there appears to be only a single copy of IFN- [4]. The chicken IFN- has antiviral properties similar
1. Correspondence: Institute of Inammation and Immune Diseases, Shantou University Medical College, 22 Xinling Rd., Shantou 515041, China. E-mail: shaobosu@yahoo.com

Abbreviations: 2,5-OAS2,5-oligoadenylate synthetase, APEUVApeu virus, CMVcytomegalovirus, EMCVencephalomyocarditis virus, Foxp3 forkhead box p3, GAFIFN- activated factor, GASgamma interferonactivated site, HBVhepatitis B virus, HCVhepatitis C virus, HTNVHantaan hantavirus, IAVinuenza A virus, IEimmediate-early, INFARIFN- receptor, IRFIFN regulatory factor, ISGF3INF--activated factor 3, ISREIFN-stimulated response elements, MD-DCmonocyte-derived dendritic cells, MxAmyxovirus resistance A, pDCplasmacytoid DC, PKRdoublestranded RNA activated serine/threonine protein kinase, VSVvesicular stomatitis virus, SOCSsuppressor of cytokine signaling proteins, Tyk2tyrosine kinase, VVvaccinia virus

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TABLE 1. Classication of IFNs Type I IFNs IFN-: -1, -2, -4, -5, -6, -7, -8, -10, -13, -14, -16, -17, -21 IFN- IFN- IFN- IFN- IFN-a IFN-b IFN- (limitin)c
a

Type II IFN IFN-

Type III IFNs IFN-1/IL-29 IFN-2/IL-28A IFN-3/IL-28B

hypothesized that types III and I IFN genes are regulated by a common mechanism [25, 33]. The IFN-1 gene is regulated by virus-activated IRF3 and IRF7, thus resembling the regulation of the IFN- gene, whereas IFN-2/3 gene expression is mainly controlled by IRF7, thus resembling IFN- genes [34]. Sommereyns et al. [35] demonstrated recently that the expression of IFN- in the CNS is minimal, even under conditions of high IFN- and IFN- expression, as observed after infection by La Crosse virus or Theilers virus. In contrast, in the liver, IFN- mRNA was readily expressed after lactate dehydrogenase-elevating virus and mouse hepatitis virus infections [35].

Found in pig. b Found in ruminants. c Found in mice.

Receptors
The receptor complex for type I IFNs consists of two subunits, IFNAR1 and IFNAR2. The receptor for type II IFN (IFN-) contains two chains, IFNGR1 and IFNGR2. Functionally active IFN- is a homodimer that binds two IFNGR1 subunits, thereby generating binding sites for two IFNGR2 chains, leading to intracellular signaling and activation of biologic activities [3]. Type III IFNR is composed of IFN-R1 [also designated IL-28R or cytokine receptor family 2 member 12 (CRF2-12)], which is specic for the IFN-s, and the accessory receptor chain, IL-10R2 (also termed as IL-10R or CRF2-4) chain, which is also part of the receptors for IL-10, IL-22, and IL-26 [10 12, 36] (Fig. 1). IL-10R2 gene polymorphism is associated with susceptibility to systemic sclerosis [37]. Type I IFNRs are expressed in most cell types, however IFN-R1 demonstrates a more restricted pattern of expression, limiting the response to type III IFNs to primarily epitheliumlike tissues [35, 38]. IFNs activate STAT-dependent and STAT-independent pathways. After recruitment to the receptor, STATs become phosphorylated, form homo- or heterodimers, and translocate to the nucleus to bind to specic sequences in the promoter of target genes [14]. Binding of IFN-/ or IFN- to their receptor leads to the activation of two receptor-associated Tyks, Jak1 and Tyk2 [39]. This is followed by tyrosine phosphorylation of STAT1 and STAT2 proteins as well as STAT3, STAT4, and STAT5 to a lesser extent [14, 18, 22, 40]. Phosphorylated STAT1 and STAT2 combine with IRF9 (or p48) to form the trimeric ISGF3 complex. Following nuclear translocation, the ISGF3 complex binds to the cis element ISRE in the promoter of target genes and induces the transcription of ISGs. However, binding of IFN- to its receptor leads to tyrosine phosphorylation of Jak1 and Jak2 Tyks, resulting in the phosphorylation of STAT1. Phosphorylated STAT1 homodimerizes to form the GAF complex, which translocates to the nucleus and binds to the GAS element, present in most IFN-inducible genes. Types I and III IFNs also induce the formation of phosphorylated STAT1 homodimers, which translocate to the nucleus. In addition to the Jak/STAT pathways, types I and III IFNs trigger different MAPK pathways, including ERK, JNK, and p38 kinases [24, 41]. Although types I and III IFNs act through a distinct receptor system [10, 42], they activate the same signaling pathway and induce common ISGs [3, 10, 11, 18, 42] (Fig. 1). Collectively, these ISGs mediate the biological effects of IFNs, such as inhibition of viral replication, cellular growth inhibition, and apoptosis [43].

to those of human IFN- [20]. Although there are three genes encoding closely related but distinct human IFN-s, the search of the mouse genome revealed the existence of only two intact mouse genes, representing mouse IFN-2 and IFN-3 gene orthologs [21]. The mouse IFN-1 gene ortholog contains a stop codon in the rst exon and is therefore predicted not to encode an intact protein. Mouse IFN-2 and IFN-3 are similar to each other (98% similarity and 96.9% amino acid identity) and are clearly related to other mouse IFNs and to human IFN-s (59 60% amino acid identity) [21].

Regulation
IFN- expression was detected at low levels in human blood, brain, lung, ovary, pancreas, pituitary, placenta, prostate, and testis [11]. IFN-s, like type I IFNs, can be induced in various cell lines and primary cells by dsRNA or after infection with EMCV [10, 11, 22], Sindbis virus, Dengue virus 2, VSV [10], measles virus [23], CMV [24], IAV, and Sendai virus [2527]. Respiratory syncytial virus induces expression of IFN- in monocyte-derived macrophages [28] and MD-DC [29]. IFN- mRNA are coexpressed with IFN- and IFN- in virally infected cells [10, 11]. Sendai virus infection readily activates the expression of IFN-, IFN-, and IFN- genes, whereas IAV-induced activation of these genes is mainly dependent on pretreatment of A549 lung epithelial carcinoma cells with IFN- or TNF- [30]. Although virtually any cell type following viral infection can express IFN-, PBMC [10, 11] and MD-DC appear to be major producers of IFN- [10, 11, 26, 31]. The APC, such as DC and macrophages, have been shown to produce and secrete IFN-s following stimulation with TLR agonists [25, 26]. MD-DC express low levels of IFN- when stimulated with TLR agonists such as LPS or polyinosinic:polycytidylic acid [poly(I:C)]; however, pDC express high levels of IFN- following viral infection [26]. In addition, IFN- has a positive regulatory effect on the expression of IFN-s. Siren et al. [25] demonstrated this clearly, where pretreatment with IFN- was shown to enhance the production of IFN-s by macrophages stimulated with TLR3 and TLR4 agonists. TLR3 ligand poly(I:C) up-regulated IFN-, IFN-, and TLR3 expression in HUVECs but not in A549 cells. Similarly, IFN- pretreatment strongly enhanced poly(I:C)-induced activation of IFN- and IFN- genes also in HUVECs [32]. It is therefore 24 Journal of Leukocyte Biology
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Figure 1. Signaling pathways of IFNs, which activate STAT-dependent and -independent pathways. Although using distinct receptor complexes, type I and type III IFNs induce similar intracellular signals and gene expression proles. In addition to the JAK/STAT pathway, types I and III IFNRs activate MAPK pathways, including ERKs, JNK, and p38.

ANTIVIRAL RESPONSES
The antiviral activity of type III IFNs is summarized in Table 2. IFN-s and IFN- induce overlapping signaling and biological activities, which include up-regulation of MHC class I antigen expression and induction of antiviral protection, as well as induction of ISGs in HT29 (colorectal adenocarcinoma), HeLa S3 (cervical adenocarcinoma), A549 (lung carcinoma), and HaCaT (keratinocyte) cells [10]. IFN-s are capable of inducing the expression by cells infected with virus of many antiviral proteins, such as dsRNA-activated serine/threonine protein kinase, 2,5-OAS, and MxA (also known as MX1) proteins, which mediate antiviral protection [53]. The ability of cells to respond to IFN- was restricted to a narrow subset of cells, such as pDC and epithelial cells [60]. IFN-R1-decient mice were indistinguishable from wild-type mice with respect to clearance of a panel of different viruses. However, there was a signicant reduction in the antiviral activity evoked by treatment with TLR3 or TLR9 agonists in IFNR1-decient mice compared with normal mice. In particular, TLR-activated antiviral defense requires the expression of IFNR1 only on nonhemopoietic cells, as demonstrated in bone marrow chimeric mice [60]. In this model, epithelial cells responded to IFN- and directly restricted virus replication.

ng/ml IFN-2 compared with 0.5 ng/ml IFN-2a [11]. Dellgren et al. [44] have recently produced all of the three subtypes of human IFN- in Escherichia coli and tested their antiviral activity. Surprisingly, IFN-3 was the most potent of the IFN- subtypes in an in vitro antiviral assay, exhibiting a twofold higher activity than IFN-1 and a 16-fold higher activity than IFN-2 in HepG2 cells when challenged with EMCV. However, there were no antiviral effects of IFN-3 in bovine kidney cell line Madin-Darby bovine kidney cells against VSV, even at a concentration of 400 ng/ml. The studies by our group have also demonstrated that IFN-1 and IFN-2, similar to IFN-2b, are able to protect the human immortalized amnion epithelial cell line (WISH cells) against VSV infection [15, 46 48]. However, IFN-s are generally less effective than type I IFNs and induce antiviral activity in fewer cell lines [45]. IFN-2 was also less active than IFN-1. Relatively higher concentrations of IFN-1 and especially IFN-2, as compared with type I IFNs, are necessary to generate comparable antiviral responses, suggesting IFN-1 and IFN-2 act as weak type I IFNs [45].

HTNV and APEUV

HTNV and APEUV are members of the Bunyaviridae family, which is maintained in nature by an alternative cycle involving blood-feeding arthropods and susceptible small mammals. Stoltz et al. [57] have found recently that pretreatment of A549 cells with IFN- alone inhibited HTNV replication, and IFN- combined with IFN- induced additive antiviral effects. However, their results also showed that an established hantavirus infection resists treatment with all antiviral IFNs, thereby preventing IFN-induced clearance of virus from infected cells. MxA gene belongs to the class of ISGs involved in resistance against inuenza viruses. MxA is transcriptionally up-regulated
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EMCV and VSV

IFN-1 protects HT29 (colorectal adenocarcinoma), A549 (lung carcinoma), and HaCaT (keratinocyte) cells from infection by VSV and HT29 cells also by EMCV. The antiviral potency of IFN-1 was comparable with that of IFN- [10]. IFN-1 and IFN-2, like IFN-2a, were able to protect human hepatocellular carcinoma cell line HepG2 cells from the virusmediated cytopathogenic effect of EMCV. The half-maximal protection (EC50) was achieved with 2 ng/ml IFN-1 and 30
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TABLE 2. Antiviral Activity of IFN- Virus EMCV VSV IAV HSV1 IFN subtype Experimental system LN229, HepG2, MG63, SW480, HepC2, T24/83, A549, LN319, and HT29 cells HaCaT, HT29, WISH, and A549 cells MD-DCs Macrophages Proposed mechanisms Reduced CPE Reduced CPE Reduced expression of viral H3N2 Decreased viral IE gene-infected cell protein 27 (ICP27) transcription Reduced CPE, reduced expression of HBV relaxed circle, and ssDNA replication forms Reduced CPE, inhibits HCV subgenomic RNA replication, reduced levels of HCV mRNAs and replicons Induced the expression of 2,5OAS Reduction in cells positive for viral IE gene expression Inhibited HTNV replication Reduced the hepatic viral titer, blocked virus replication Reduced viral load in the brain References [10, 11, 44, 45] [10, 15, 4648] [27, 49] [50]

1, 2, 3 1, 2 1 1

HBV

1, 2

Hepatoma cell, primary hepatocytes, hepatocyte Huh7 cells

[40, 51, 52]

HCV

1, 2

Primary hepatocytes, human hepatoma cells, hepatocyte Huh7 cells

[40, 5255]

APEUV CMV HTNV HSV2 (in vivo) VV (in vivo)

1, 2 1, 2 1, 2 2 2/3

African greenmonkey kidney cell line Vero cells, PBMCs HCT116 cells A549 cells i.p. or intravaginal infection of C57BL/6 mice Intranasal and intradermal infection of BALB/c mice

[56] [24] [57] [58] [21, 59]

CPE, cytopathic effect.

by type I ( and ) and type III () IFNs. MxA is a unique marker for the detection of type I and type III IFN activity during virus infection and IFN therapy [61]. Interestingly, it has been observed that IFN-1 and IFN-2 were able to induce anti-APEUV, a member of the Bunyaviridae family isolated from the Brazilian rain forest, responses in human PBMC. IFN-1 and IFN-2 induced the expression of 2,5-OAS [56].

and IFN- were hypersensitive and even failed to restrict usually nonpathogenic inuenza virus mutants lacking the IFNantagonistic factor NS1. Interestingly, the double-knockout mice were not more susceptible against hepatotropic viruses than IFNAR1 (0/0) mice. These results suggest that IFN- contributes to inborn resistance against viral pathogens infecting the lung but not the liver.

IAV
In human myeloid DC, IFN-1 induced MxA protein expression and possessed activity against IAV, although this activity was lower than that of IFN- or IFN- [27]. Mordstein et al. [49] demonstrated that intranasal administration of IFN- readily induced the antiviral factor MxA in mouse lungs and efciently protected type I IFNR-decient mice [IFNAR1 (0/0)] from lethal inuenza virus infection. By contrast, i.p. application of IFN- failed to induce MxA in the liver of IFNAR1 (0/0) mice and did not protect against hepatotropic virus infections. Mice lacking functional IFN-Rs were only slightly more susceptible to inuenza virus than wild-type mice. However, mice lacking functional receptors for IFN-/ 26 Journal of Leukocyte Biology
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HSV
IFN- and IFN-1 decreased the transcription of viral IE gene ICP27, suggesting that IFN-1 and IFN- possess comparable antiviral activity against HSV-1. Moreover, IFN-1, together with IFN-, amplies the antiviral response against HSV-1 [50]. TLR7-, TLR8-, and TLR9-dependent induction of IFN- and IFN-/ is largely redundant in human antiviral immunity, whereas the TLR3-dependent induction of IFN- and IFN-/ is critical for primary immunity to HSV-1 in the CNS in children but is redundant in immunity to most other viral infections [62]. Experiments in vivo demonstrated that type III IFNs are important mediators of antiviral response in mucosal/epithelial tissues. IFN-s in-

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TABLE 3. Antitumor Activity of IFN-s Subtype Experimental system Human glioblastoma LN319 cell line Human neuroendocrine BON1 tumor cells Murine BW5147 thymoma cell line Human keratinocyte cell line HaCaT, human brosarcoma 2fTGH cell line Murine melanoma Murine brosarcoma Possible mechanism Growth inhibition Decreased cell numbers, induced apoptosis Growth inhibition Induced apoptosis, extended STAT activation, prolonged ISG expression Engaged host mechanisms to exert their antitumor functions Induce innate and adaptive immune responses against tumors, including increase of IFN- production and polymorphonuclear neutrophils, NK cells, and CD8 T cell activity Induced tumor apoptosis and innate immune responses References [45] [63] [22] [43] [38] [64]

1 1, 2 1 1 2 (in vivo) 2 (in vivo)

2 (in vivo)

Murine melanoma, colon cancer

[65]

duced potent antiviral activity against HSV-2 in the vaginal infection model, whereas they were inefcient in systemic infections by EMCV and lymphocytic choriomeningitis virus. Pretreatment with IFN- enhanced protein expression of IFN- after HSV-2 infection in vivo. Furthermore, the antiviral activity of IFN- in a model of vaginal HSV-2 infection surpassed that of IFN-. However, in vitro assays revealed that IFN- have appreciable antiviral activity against EMCV but limited activity against HSV-2 [58]. The discrepancy between the observed antiviral activity in vitro and in vivo suggests that IFN- exerts a signicant portion of its antiviral activity in vivo via stimulation of the immune system rather than through induction of antiviral state mediators.

HBV and HCV

Several reports have shown that IFN-s exhibit antiviral activity toward HBV and HCV by inhibiting viral replication. The replication of HBV in a human hepatoma cell line was reduced by 30% following treatment with a high concentration of IFN-. However, the antiviral activity of IFN- against HBV may be limited in human cells [51]. Interestingly, the IFN-R gene is preferentially expressed on primary hepatocytes in normal liver, and IFN-1 and IFN- induced equivalent levels of 2,5OAS and MxA gene expression in this cell type. IFN-1 also signicantly reduced human HBV load in vitro and reduced the cytopathic effect caused by the fully replicating avivirus, West Nile virus [40]. IFN- inhibits HBV replication in a differentiated murine hepatocyte cell line with kinetics and efciency similar to IFN-/, and the activity does not require the expression of IFN-/ or IFN-. Furthermore, IFN- blocked the replication of a subgenomic and a full-length genomic HCV replicon in human hepatocyte Huh7 cells [52]. Zhu et al. [54] demonstrate that IFN-2 effectively inhibits HCV subgenomic RNA replication. Treatment of human hepatoma cells with IFN-2 activates the JAK-STAT signaling pathway and induces the expression of some ISGs. IFN-2 also induces the expression of HLA class I antigens in human hepatoma cells. Moreover, IFN-2 appears to suppress specically HCV internal ribosome entry segment-mediated translation.

There is a distinction between IFN-- and IFN--induced antiviral states. IFN- mediated dose- and time-dependent HCV inhibition, independent of types I and II IFNRs. The kinetics of IFN--mediated STAT activation and induction of potential effector genes were also distinct from those of IFN-. IFN- induced steady increases in levels of known ISGs, whereas IFN- ISGs peaked early and declined rapidly. IFN- inhibited the replication of HCV genotypes 1 and 2 and enhanced the antiviral efcacy of subsaturating levels of IFN- [55]. IFN-s efciently inhibit HCV replication in vitro with potentially less hematopoietic side-effects than IFN- because of limited receptor expression in hematopoietic cells. Despite antiviral properties of IFN-s, their efcacy as antiviral agents may have similar limitations as IFN- as a result of inhibition by SOCS proteins [53].

CMV and poxvirus

Brand et al. [24] have observed that treatment of intestinal epithelial cell lines in vitro with IFN-s, followed by infection with CMV, reduced the number of cells positive for viral IE gene expression. In contrast, expression of murine IFN-2 or IFN-3 by VV did not affect viral replication in murine PAM212 cells, which do express IFN-R, indicating that IFN-s do not have antiviral activity against VV in vitro. However, in a mouse dermal model, where control virus caused a mild localized infection, IFN-2/3-expressing recombinant VV formed delayed and smaller lesions and displayed potent antiviral activity in vivo, suggesting that type III IFNs are biologically relevant against poxviruses [21]. VV, used as a smallpox vaccine, encodes secreted proteins B18 and Y136, which function as IFN antagonists. B18 protein from VV was unable to interact with type III IFNs and had no effect on their signaling and biological activities, suggesting that type III IFNs may be more potent for the treatment of certain poxvirus infections [59].

ANTITUMOR ACTIVITES
One of the most important properties of IFN-s is their potential in tumor therapy (Table 3). Although type I and type III
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IFNs signal through distinct receptors, they both induce antiproliferative responses. However, IFN- might recapitulate only parts of the effects of type I IFNs. Although receptor genes for type I IFNs are ubiquitously expressed on all cells, receptors for IFN- are only found on most tumor cell lines. Dumoutier et al. [22] have conrmed that type I IFNs, but not IFN-, can inhibit the proliferation of B lymphoma cell line Daudi cells. In addition, IFN- could induce phosphorylation of STAT1 and STAT2 in Daudi cells but to a lesser extent as compared with type I IFN, although a signicant IRF7 promoter induction could still be detected. These observations suggest that Daudi cells express low levels of receptors for IFN-, which are sufcient to up-regulate IRF7 expression but not to inhibit cell proliferation as a result of weaker or less-sustained STAT2. The antiproliferative activity of IFN-1, IFN-2, and IFN- has been assessed in several human astrocytoma/glioblastoma cell lines. The ED50 in the range of 0.04 and 0.20 ng/ml were found for IFN-. In contrast, little or no antiproliferative activity for IFN-1 and IFN-2 could be shown in these cell lines, except in one human glioblastoma cell line, LN319, for which an ED50 of 120 ng/ml was recorded for IFN-1 [45]. Zitzmann et al. [63] have shown recently that in human neuroendocrine BON1 tumor cells, similar to IFN-, incubation of BON1 cells with IFN-2 and IFN-1 induced phosphorylation of STAT1, STAT2, and STAT3, signicantly decreased cell numbers, and induced apoptosis as demonstrated by poly (ADP-ribose) polymerase cleavage, caspase-3 cleavage, and DNA fragmentation. Stable overexpression of SOCS proteins (SOCS1 and SOCS3) abolished the IFN- effects completely, indicating that SOCS proteins act as negative regulators of IFN- signaling in BON1 cells. Maher et al. [43] demonstrated recently that in contrast to IFN-, IFN- extended STAT1 and STAT2 tyrosine phosphorylation in the human keratinocyte cell line HaCaT and the human brosarcoma 2fTGH cell line and prolonged the duration of differentially regulated ISG expression. IFN- could promote apoptosis in cell lines that previously showed only an exhibited antiproliferative response to IFN-. IFN- was more efcient than IFN- in inducing an antiproliferative effect that overlapped with the activation of apoptosis. However, the growth inhibitory effects of IFN- were more pronounced than that of IFN-. Furthermore, the combination of IFN- and IFN- had additive effects on the antiproliferative responses. These results reveal that IFN- could potentially be used, in addition to IFN-, to control tumor growth [43]. The antiproliferative activity of IFN-1 has also been reported recently in a subclone of the murine BW5147 thymoma cell line transfected with human IFN-R [22]. Although constitutive expression of mouse IFN-2 in B16 melanoma cells did not affect their proliferation in vitro, their growth and tumorigenicity (B16.IFN-2 cells) when injected s.c. into mice were retarded or prevented completely, suggesting that IFN- may engage host mechanisms to inhibit melanoma growth [38]. However, direct action of IFN- on the host is rather limited. Several cell types, including primary lymphocytes and macrophages, the major players in specic antitumor immunity, were found to be unresponsive to IFN-, suggesting that immune cells are not the primary targets of IFN- [38]. Therefore, the 28 Journal of Leukocyte Biology
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function of immune cells is unlikely to be altered directly by IFN-. Moreover, the development of long-lasting immunity in this mouse tumor model was relatively weak, suggesting such anti-tumor responses are unlikely to involve adaptive immunity [38]. However, Numasaki et al. [64] have demonstrated recently that IFN- induces innate and adaptive immune responses against tumors. IFN- or retroviral transduction of the IFN- gene into the brosarcoma cell line MCA205 did not affect in vitro growth, whereas in vivo growth of MCA205-IFN- was markedly suppressed along with increased animal survival. The expression of IFN- in MCA205 cells also resulted in potent inhibition of metastases formation in the lungs. IFN--mediated suppression of tumor growth was almost abolished in irradiated mice, indicating that irradiation-sensitive cells, presumably immune cells, are involved in IFN--induced suppression of tumor growth. Cell-depletion experiments revealed that polymorphonuclear neutrophils, NK cells, and CD8 T cells, but not CD4 T cells, play equally important roles in IFN--mediated inhibition of in vivo tumor growth. Consistent with these ndings, inoculation of MCA205-IFN- cells into mice evoked enhanced IFN- production and cytotoxic T cell activity in spleen cells. Antitumor action of IFN- is partially dependent on IFN-. IFN- increased the total number of splenic NK cells in severe combined immunodeciency (SCID) mice, enhanced IL-12-induced IFN- production in vivo, and expanded spleen cells in C57BL/6 mice. Moreover, IL-12 augmented IFN--mediated antitumor activity in the presence or absence of IFN- [64]. Interestingly, it has been described by Sato et al. [65] that IFN- induced tumor apoptosis and NK cell-mediated tumor destruction through innate immune responses. Overexpression of IFN- induced cell surface MHC class I expression and cell cycle arrest and apoptotic cell death in murine B16 melanoma cells in vitro. IFN- expression in tumor cell lines markedly inhibited s.c. and metastatic tumor formation in vivo. Moreover, IFN- expression induced lymphocytic cell inltration in tumor tissue. Antibody-mediated immune cell depletion comrmed that NK cells were critical to IFN--mediated tumor inhibition. Hydrodynamic injection of IFN- cDNA reduced liver metastatic foci of colon cancer Colon26 cells and moderately decreased the mortality of mice with tumors. IFN- overexpression in the liver increased NK/NKT cells and enhanced their tumor-killing activity, suggesting the activation of innate immune responses. Thus, local delivery of IFN- may be a useful adjunctive strategy in the treatment of human malignancies [65].

IMMUNOREGULATORY FUNCTIONS
In addition to their antiviral and antiproliferative activities, IFN-s exert immunomodulatory effects that overlap type I IFNs in innate and adaptive arms of the immune system. These activities include increasing NK and T cell cytotoxicity [64], promoting Th1 responses [64], up-regulating MHC class I molecule expression on tumor cells to promote antigen presentation [10, 11], and mediating cell apoptosis [43, 65, 66].

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TABLE 4. Immunoregulatory Functions of IFN-s Subtype Experimental system PBMC and C8166 T cell line Antiviral function Antitumor function DC Regulatory T cells PBMC, monocytes, and macrophages MD-DCs Asthma Con A-induced hepatitis Possible mechanism Increased HIV binding and replication Up-regulating MHC class I molecule expression to promote antigen presentation Regulating innate and adaptive immune responses Promoted the generation of tolerogenic DC: induced a partial maturation of DC, up-regulation of MHC class I and II molecules, no induction of costimulatory molecules Promoted proliferation of naturally arising Foxp3-expressing CD4CD25 regulatory T cells Up-regulated IL-6, -8, and -10 and chemokines Inhibition of Th2 responses by down-regulating IL-13 production Immunoprotective Induced Th1 cytokine production and T cell-mediated liver injury References [67] [10, 11] [64, 65] [68] [68] [69, 70] [71] [7274] [75]

2 1, 2 1, 2 1, 2 1, 2 1 1 1, 2 2

Moreover, Serra et al. [67] have shown recently that pretreatment of PBMC and the C8166 T cell line with type III and type I IFNs causes increased HIV binding and replication. These effects are likely to be a result of increased expression of HIV receptors and coreceptors on the plasma membrane. The immunoregulatory actions of IFN- are cell type-specic, which depend on the distribution of IFN-Rs, the nature of the signal transduction, and genes activated. IFN- are capable of signaling through almost all STAT molecules, and therefore, they exhibit broader functions as compared with type I IFNs (Table 4).

monokine induced by IFN- (CXCL9), IFN--inducible protein-10 (CXCL10), and IFN--inducible T cell chemoattractant (CXCL11) in human PBMC. This action of IFN-1 was similar to that reported previously for IFN-. However, the IFN-1 activity did not depend on the intermediate induction of IFN- [70].

IFN- in Th1/Th2 response

IFN-1 has important immunoregulatory properties with regard to the Th2 responses. Th2 cytokines consist of IL-4, IL-5, and IL-13. Recently, IFN-1 has been shown to inhibit the production of IL-13 by T cells in an IFN--independent manner, which is mediated in part via MD-DC [71]. Furthermore, IFN-1 preferentially inhibits IL-13 production. IFN-1 decreased IL-4 and IL-5 production signicantly, but its effects were not as consistent as those seen on IL-13. Thus, IFN-1 appears to be an inhibitor of human Th2 responses whose action is directed primarily toward IL-13 but may also affect Th2 responses in general without invoking complementary elevation of IFN- [72]. The inhibition of IL-13 secretion by monocytes can be of clinical relevance, as IL-13 and the Th2 response is important in the development of asthma. In contrast to the Th2 response affected by IFN-1, Siebler et al. [73] described that IFN-2 induced Th1 cytokine production by the CD4T lymphocyte. IFN-2-transgenic mice showed markedly augmented Con A-induced hepatitis with up-regulated IFN- production. In addition, IFN-2-specic antisense phosphorothioate oligonucleotides suppressed liver pathology in Con A-treated wild-type mice. These results suggest IFN-2 as a key regulatory cytokine with pathogenic function in T cell-mediated liver injury. Thus, targeting IFN-2 may represent a novel approach for therapy of Th1-mediated inammatory diseases. We have demonstrated recently that HUVECs treated with IFN- and poly(I:C) express IFN-2 protein. Moreover, macrophage-like cells in colon and lung and alveolar epithelial cells in lung tissue contain IFN-2, suggesting IFN-2 may be used by these for antivirus and antitumor function [74].
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Effects of IFN- on DC, monocytes, and macrophages

IFNs produced by DC in response to TLR stimulation are critical in DC differentiation and maturation, in which IFN- exhibits specic effects [26]. DC acquire IFN- responsiveness through the expression of the IFN-R chain during their differentiation from monocytes. As opposed to the complexity of type I IFN effects on DC, i.v.-injected IFN- in SCID mice induce only a partial maturation, which includes up-regulation of MHC class I and II molecules and the ability to migrate into lymph nodes. However, no induction of costimulatory molecules was observed following IFN- treatment [68]. Interestingly, IFN--treated DC promote the generation of tolerogenic DC and IL-2-dependent proliferation of natural Foxp3expressing CD4CD25 regulatory T cells with contact-dependent suppressive activity on T cell proliferation initiated by fully mature DC [68]. IFN-1 activates monocytes and macrophages to produce a restricted panel of cytokines. Whole PBMC exposed to IFN-1 increase the production of IL-6, -8, and -10. This response was inhibited by IL-10. Examination of puried cell populations isolated from PBMC demonstrated that monocytes rather than lymphocytes were the major IFN-1-responsing subset, producing IL-6, -8, and -10. Human macrophages also responded to IFN-1 by producing cytokines IL-6, -8, and -10 [69]. Induction of IL-6 by IFN- might suggest a role in linking the innate immune response to the adaptive immune response. In a range of chemokines tested, IFN-1 elevated mRNA levels of

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Journal of Leukocyte Biology 29

IFN- in airway disease

Rhinoviruses are the major cause of asthma exacerbation, and asthmatics have increased susceptibility to rhinovirus and the risk of invasive bacterial infection. The deciency in induction of IFN- by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages was highly correlated with the severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers [75]. Induction by LPS in asthmatic macrophages was also decreased signicantly, and the level of IFN- was correlated with the severity of exacerbation. Thus, replacement or augmentation of IFN- production could be a new approach to treatment or prevention of asthma exacerbation. Bullens et al. [76] demonstrated recently that in comparison with healthy subjects, asthmatic adults have increased sputum IFN-2/3 mRNA but similar IFN-1 mRNA expression. IFN-2/3 (but not IFN1) mRNA levels correlate with the relative and absolute number of eosinophils present in the sputum sample. Sputum IFN-1 mRNA (but not IFN-2/3) correlates negatively with asthma symptoms in steroid-naive patients and is signicantly higher in steroid-treated patients. These studies show that asthmatic subjects have substantial type III IFN- mRNA levels in the airways, and IFN-1 could have an immunoprotective role in the lower airways. Further studies are required to clarify whether administration of IFN- may be benecial in the treatment of asthma exacerbation and whether similar deciencies are present in children and in subjects with nonatopic asthma and the mechanisms of decient IFN production in asthma [77]. IFNs

TABLE 5. Comparison of Type I IFNs and IFN-s: Receptors and Clinical Effects Receptors IFNAR1/IFNAR2 (ubiquitous expression) Clinical effects Autoimmune and chronic inammatory diseases like multiple sclerosis, experimental autoimmune encephalitis, cancers, chronic HBV and HCV infections HBV and HCV infections

Type I IFNs: IFN-/

IFN-s: IFN-1, IFN-2, IFN3

IFNLR1 (limited expression)/ IL-10R2 (ubiquitous expression)

biological functions [84]. As the receptor for IFN- has a restricted pattern of expression, the IFN- may serve as an alternative therapeutic choice to type I IFNs and reduce the adverse side-effects of type I IFN therapy. IFN-s also inhibit HCV replication efciently and control tumor growth with less hematopoietic side-effects than IFN- because of limited receptor expression [53]. Because of the low responsiveness of the CNS, it will be of interest to test whether IFN-s would exhibit less neurological toxicity than IFN-/ [35]. However, despite all we have learned about IFN-s, their importance in viral infection, cancer, and immune responses remains to be fully elucidated. Further studies will be necessary to better evaluate the potential of IFN-s as novel therapeutic agents.

CONCLUSIONS
From studies in patients and in mouse models of disease, it has become clear that type I IFNs have benecial roles in interfering with viruses and in bridging protective innate and adaptive immune responses. Type I IFNs proved to be advantageous against autoimmune disorders such as multiple sclerosis (MS), a chronic inammatory disease of the CNS [78, 79], and the murine experimental autoimmune encephalitis [80]. Phase III clinical trials have shown the efcacy of IFN- in the treatment of relapsing-remitting MS. Type I IFNs, IFN- in particular, are often used in the treatment of various cancers, MS, and chronic HBV and HCV infections [81] (Table 5). However, treatment with type I IFNs also causes signicant side-effects, such as fatigue, fever, anorexia, depression, and myelosuppression. When prolonged, for instance in the case of hepatitis C treatment, type I IFN treatment can lead to neurological or neuropsychiatric adverse effects [82, 83]. The major challenge to the treatment of HCV is to improve antiviral efcacy and to reduce the side-effects typically seen in IFN--based therapy. Phase I clinical trials are currently sponsored by ZymoGenetics to assess the safety and antiviral activity of pegylated IFN-1 (or PEG-recombinant IL-29) in subjects with relapsed, chronic HCV infection (ClinicalTrials.gov, identier: NCT00565539). IFN-s, as the novel members of the class II cytokine family, possess antiviral, antitumor, and immunoregulatory activity. IFN-s appear to activate the same set of genes as type I IFNs, and they share most 30 Journal of Leukocyte Biology
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ACKNOWLEDGMENTS
This project was supported by grants from the National Natural Science Foundation of China (30671932, 30770840, and 30772011). We are grateful for the critical comments by Dr. Ji Ming Wang (National Cancer Institute, National Institutes of Health).
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KEY WORDS: IFN- IL-28 IL-29 immunoregulation

32 Journal of Leukocyte Biology

Volume 86, July 2009

www.jleukbio.org