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Interferon-s: the modulators of antivirus, antitumor, and immune responses
Mingcai Li, Xiaojin Liu, Yanchun Zhou, and Shao Bo Su1
Institute of Inﬂammation 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
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 ﬁndings 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: 23–32; 2009.
IFN was the ﬁrst cytokine identiﬁed in 1957 by Isaacs and Lindenmann  during their seminal studies on virus interference. It was also the ﬁrst cytokine to be puriﬁed to homogeneity, cloned, sequenced completely, and produced in recombinant form and in extensive clinical application . With the discovery of more isoforms, IFNs are classiﬁed into three distinct groups based on amino acid sequences and recognition by speciﬁc receptors  (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 ﬁrst ﬁve are found in human  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 . IFN-␦ is pro-
duced by trophoblasts of pig . IFN- (limitin) is found only in mice [7, 8]. Type II IFN consists of a single type, IFN-␥ . Recently, a novel group of IFNs was discovered independently by two groups of scientists led by Kotenko and Gallagher  of the University of Medicine and Dentistry, New Jersey (Newark, NJ, USA) group and Klucher  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 [12–14]. Therefore, they have been described independently as IL-29 (IFN1), IL-28A (IFN-2), and IL-28B (IFN-3) . 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-
The genes encoding three members of the IFN- family are clustered on human chromosome 19 (19q13ϩ13 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 ﬁve exons . 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 . The conserved cysteine pattern and amphipathic proﬁle of the IFN-s suggest that they belong to the helical cytokine family . IFN-s represent an evolutionary link between IL-10 and type I IFNs . 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- . The chicken IFN- has antiviral properties similar
1. Correspondence: Institute of Inﬂammation and Immune Diseases, Shantou University Medical College, 22 Xinling Rd., Shantou 515041, China. E-mail: email@example.com
Abbreviations: 2Ј,5Ј-OASϭ2Ј,5Ј-oligoadenylate synthetase, APEUVϭApeu virus, CMVϭcytomegalovirus, EMCVϭencephalomyocarditis virus, Foxp3 ϭforkhead box p3, GAFϭIFN-␥ activated factor, GASϭgamma interferonactivated site, HBVϭhepatitis B virus, HCVϭhepatitis C virus, HTNVϭHantaan hantavirus, IAVϭinﬂuenza A virus, IEϭimmediate-early, INFARϭIFN-␣ receptor, IRFϭIFN regulatory factor, ISGF3ϭINF-␥-activated factor 3, ISREϭIFN-stimulated response elements, MD-DCϭmonocyte-derived dendritic cells, MxAϭmyxovirus resistance A, pDCϭplasmacytoid DC, PKRϭdoublestranded RNA activated serine/threonine protein kinase, VSVϭvesicular stomatitis virus, SOCSϭsuppressor of cytokine signaling proteins, Tyk2ϭtyrosine kinase, VVϭvaccinia virus
0741-5400/09/0086-0023 © Society for Leukocyte Biology
Volume 86, July 2009
Journal of Leukocyte Biology 23
TABLE 1. such as inhibition of viral replication. in the liver. which is also part of the receptors for IL-10. which translocates to the nucleus and binds to the GAS element.jleukbio. thus resembling IFN-␣ genes . ␣-4. IFNs activate STAT-dependent and STAT-independent pathways. 1). Although virtually any cell type following viral infection can express IFN-. lung. Collectively. brain. IFN-␣ has a positive regulatory effect on the expression of IFN-s. which is speciﬁc for the IFN-s. ␣-14. have been shown to produce and secrete IFN-s following stimulation with TLR agonists [25. and p38 kinases [24. The mouse IFN-1 gene ortholog contains a stop codon in the ﬁrst exon and is therefore predicted not to encode an intact protein. leading to intracellular signaling and activation of biologic activities . binding of IFN-␥ to its receptor leads to tyrosine phosphorylation of Jak1 and Jak2 Tyks. which translocate to the nucleus. IFN-␣ pretreatment strongly enhanced poly(I:C)-induced activation of IFN-␤ and IFN- genes also in HUVECs . In contrast. Sendai virus infection readily activates the expression of IFN-␣. 22. IFN-. 42] (Fig. even under conditions of high IFN-␣ and IFN-␤ expression. 26. Following nuclear translocation. The IFN-1 gene is regulated by virus-activated IRF3 and IRF7. and the accessory receptor chain. Although there are three genes encoding closely related but distinct human IFN-s. however IFN-R1 demonstrates a more restricted pattern of expression. MD-DC express low levels of IFN- when stimulated with TLR agonists such as LPS or polyinosinic:polycytidylic acid [poly(I:C)]. PBMC [10. IAV. IFNGR1 and IFNGR2. and STAT5 to a lesser extent [14. and translocate to the nucleus to bind to speciﬁc sequences in the promoter of target genes . ␣-10.9% amino acid identity) and are clearly related to other mouse IFNs and to human IFN-s (59 – 60% amino acid identity) . IFN-s. such as DC and macrophages. Sommereyns et al. 38]. IL-10R2 (also termed as IL-10R␤ or CRF2-4) chain. 11] and MD-DC appear to be major producers of IFN- [10. ␣-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. TLR3 ligand poly(I:C) up-regulated IFN-␤. July 2009 www. resulting in the phosphorylation of STAT1. After recruitment to the receptor. Similarly. The receptor for type II IFN (IFN-␥) contains two chains. Regulation IFN- expression was detected at low levels in human blood. VSV . IFNAR1 and IFNAR2. pituitary. and IFN- genes. like type I IFNs. 1). where pretreatment with IFN-␣ was shown to enhance the production of IFN-s by macrophages stimulated with TLR3 and TLR4 agonists. however. ovary. the ISGF3 complex binds to the cis element ISRE in the promoter of target genes and induces the transcription of ISGs. Respiratory syncytial virus induces expression of IFN- in monocyte-derived macrophages  and MD-DC . JNK. Phosphorylated STAT1 homodimerizes to form the GAF complex. Although types I and III IFNs act through a distinct receptor system [10. 40]. The APC. limiting the response to type III IFNs to primarily epitheliumlike tissues [35. the search of the mouse genome revealed the existence of only two intact mouse genes. thereby generating binding sites for two IFNGR2 chains. 11. 11. and testis . 18. b Found in ruminants. IFN- mRNA was readily expressed after lactate dehydrogenase-elevating virus and mouse hepatitis virus infections . ␣-2. Found in pig. IL-10R2 gene polymorphism is associated with susceptibility to systemic sclerosis . measles virus .org . and apoptosis . cellular growth inhibition. Phosphorylated STAT1 and STAT2 combine with IRF9 (or p48) to form the trimeric ISGF3 complex. and IL-26 [10 –12. 33]. as observed after infection by La Crosse virus or Theiler’s virus. Receptors The receptor complex for type I IFNs consists of two subunits. 11. Sindbis virus. STAT4. can be induced in various cell lines and primary cells by dsRNA or after infection with EMCV [10. It is therefore 24 Journal of Leukocyte Biology Volume 86. they activate the same signaling pathway and induce common ISGs [3. Type I IFNRs are expressed in most cell types. In addition. 22]. placenta. STATs become phosphorylated. ␣-7. IL-22. whereas IFN-2/3 gene expression is mainly controlled by IRF7. present in most IFN-␥inducible genes. these ISGs mediate the biological effects of IFNs. 11].  demonstrated recently that the expression of IFN- in the CNS is minimal. ␣-8. Functionally active IFN-␥ is a homodimer that binds two IFNGR1 subunits. Jak1 and Tyk2 . IFN-␤. pancreas. to those of human IFN- . CMV . and Sendai virus [25–27]. form homo. Classiﬁcation of IFNs Type I IFNs IFN-␣: ␣-1. ␣-13. Dengue virus 2. 42]. ␣-5. ␣-16. Mouse IFN-2 and IFN-3 are similar to each other (98% similarity and 96. ␣-17. prostate.or heterodimers. including ERK. Binding of IFN-␣/␤ or IFN- to their receptor leads to the activation of two receptor-associated Tyks. 18. ␣-6. c Found in mice. In addition to the Jak/STAT pathways. IFN- mRNA are coexpressed with IFN-␣ and IFN-␤ in virally infected cells [10. 41]. and TLR3 expression in HUVECs but not in A549 cells. 36] (Fig. thus resembling the regulation of the IFN-␤ gene. representing mouse IFN-2 and IFN-3 gene orthologs . 10.  demonstrated this clearly. pDC express high levels of IFN- following viral infection . However. Type III IFNR is composed of IFN-R1 [also designated IL-28R␣ or cytokine receptor family 2 member 12 (CRF2-12)]. Siren et al. 26]. whereas IAV-induced activation of these genes is mainly dependent on pretreatment of A549 lung epithelial carcinoma cells with IFN-␣ or TNF-␣ . Types I and III IFNs also induce the formation of phosphorylated STAT1 homodimers. 31]. types I and III IFNs trigger different MAPK pathways. This is followed by tyrosine phosphorylation of STAT1 and STAT2 proteins as well as STAT3.
46 – 48]. such as pDC and epithelial cells . and HaCaT (keratinocyte) cells . TLR-activated antiviral defense requires the expression of IFNR1 only on nonhemopoietic cells. MxA is transcriptionally up-regulated Journal of Leukocyte Biology 25 EMCV and VSV IFN-1 protects HT29 (colorectal adenocarcinoma). which include up-regulation of MHC class I antigen expression and induction of antiviral protection. The antiviral potency of IFN-1 was comparable with that of IFN-␣ . IFN-3 was the most potent of the IFN- subtypes in an in vitro antiviral assay. and p38. which mediate antiviral protection . The ability of cells to respond to IFN- was restricted to a narrow subset of cells. including ERKs. Relatively higher concentrations of IFN-1 and especially IFN-2. Stoltz et al. were able to protect human hepatocellular carcinoma cell line HepG2 cells from the virusmediated cytopathogenic effect of EMCV. as demonstrated in bone marrow chimeric mice . exhibiting a twofold higher activity than IFN-1 and a 16-fold higher activity than IFN-2 in HepG2 cells when challenged with EMCV.  have recently produced all of the three subtypes of human IFN- in Escherichia coli and tested their antiviral activity. However. The studies by our group have also demonstrated that IFN-1 and IFN-2. In this model. and HaCaT (keratinocyte) cells from infection by VSV and HT29 cells also by EMCV. JNK. However. epithelial cells responded to IFN- and directly restricted virus replication. as compared with type I IFNs. ng/ml IFN-2 compared with 0. type I and type III IFNs induce similar intracellular signals and gene expression proﬁles. However.jleukbio. Surprisingly. there was a signiﬁcant reduction in the antiviral activity evoked by treatment with TLR3 or TLR9 agonists in IFNR1-deﬁcient mice compared with normal mice. Signaling pathways of IFNs. IFN-s and IFN-␣ induce overlapping signaling and biological activities. and MxA (also known as MX1) proteins. which is maintained in nature by an alternative cycle involving blood-feeding arthropods and susceptible small mammals. even at a concentration of 400 ng/ml. MxA gene belongs to the class of ISGs involved in resistance against inﬂuenza viruses. suggesting IFN-1 and IFN-2 act as “weak” type I IFNs . In particular. Dellgren et al. A549 (lung carcinoma).  have found recently that pretreatment of A549 cells with IFN- alone inhibited HTNV replication. like IFN-␣2a. similar to IFN-␣2b.5Ј-OAS. types I and III IFNRs activate MAPK pathways. their results also showed that an established hantavirus infection resists treatment with all antiviral IFNs. HTNV and APEUV HTNV and APEUV are members of the Bunyaviridae family. HeLa S3 (cervical adenocarcinoma).Li et al. July 2009 . IFN-s in antivirus. and IFN- combined with IFN-␥ induced additive antiviral effects. IFN-s are capable of inducing the expression by cells infected with virus of many antiviral proteins. ANTIVIRAL RESPONSES The antiviral activity of type III IFNs is summarized in Table 2. IFN-2 was also less active than IFN-1. and immunity Figure 1. However.org Volume 86. The half-maximal protection (EC50) was achieved with ϳ2 ng/ml IFN-1 and 30 www. as well as induction of ISGs in HT29 (colorectal adenocarcinoma). In addition to the JAK/STAT pathway. are able to protect the human immortalized amnion epithelial cell line (WISH cells) against VSV infection [15. which activate STAT-dependent and -independent pathways. A549 (lung carcinoma). there were no antiviral effects of IFN-3 in bovine kidney cell line Madin-Darby bovine kidney cells against VSV. IFN-R1-deﬁcient mice were indistinguishable from wild-type mice with respect to clearance of a panel of different viruses.5 ng/ml IFN-␣2a . Although using distinct receptor complexes. 2Ј. thereby preventing IFN-induced clearance of virus from infected cells. are necessary to generate comparable antiviral responses. antitumor. such as dsRNA-activated serine/threonine protein kinase. IFN-1 and IFN-2. IFN-s are generally less effective than type I IFNs and induce antiviral activity in fewer cell lines .
IFN-1 induced MxA protein expression and possessed activity against IAV. Antiviral Activity of IFN- Virus EMCV VSV IAV HSV1 IFN subtype Experimental system LN229. 2 Primary hepatocytes. 52–55] APEUV CMV HTNV HSV2 (in vivo) VV (in vivo) 1. reduced levels of HCV mRNAs and replicons Induced the expression of 2Ј. IFN-1.p. Interestingly. 52] HCV 1. 49]  1. Mordstein et al. hepatocyte Huh7 cells [40. HepC2.jleukbio. LN319. TLR8-. Interestingly. hepatocyte Huh7 cells [40.TABLE 2. although this activity was lower than that of IFN-␣ or IFN-␤ . human hepatoma cells. T24/83.p. TLR7-. These results suggest that IFN- contributes to inborn resistance against viral pathogens infecting the lung but not the liver. cytopathic effect. 2 1. or intravaginal infection of C57BL/6 mice Intranasal and intradermal infection of BALB/c mice     [21. and TLR9-dependent induction of IFN- and IFN-␣/␤ is largely redundant in human antiviral immunity. 2 1. and IFN- were hypersensitive and even failed to restrict usually nonpathogenic inﬂuenza virus mutants lacking the IFNantagonistic factor NS1.5ЈOAS Reduction in cells positive for viral IE gene expression Inhibited HTNV replication Reduced the hepatic viral titer. IAV In human myeloid DC. However. PBMCs HCT116 cells A549 cells i.5Ј-OAS . SW480. primary hepatocytes. suggesting that IFN-1 and IFN-␣ possess comparable antiviral activity against HSV-1. 15. by type I (␣ and ␤) and type III () IFNs. and ssDNA replication forms Reduced CPE. 46–48] [27. blocked virus replication Reduced viral load in the brain References [10. ampliﬁes the antiviral response against HSV-1 . MxA is a unique marker for the detection of type I and type III IFN activity during virus infection and IFN therapy . a member of the Bunyaviridae family isolated from the Brazilian rain forest. and HT29 cells HaCaT. Experiments in vivo demonstrated that type III IFNs are important mediators of antiviral response in mucosal/epithelial tissues. WISH. IFN-s in- www. responses in human PBMC. 2. HepG2. IFN-1 and IFN-2 induced the expression of 2Ј. 44. 11.  demonstrated that intranasal administration of IFN- readily induced the antiviral factor MxA in mouse lungs and efﬁciently protected type I IFNR-deﬁcient mice [IFNAR1 (0/0)] from lethal inﬂuenza virus infection. 59] CPE.org . mice lacking functional receptors for IFN-␣/␤ 26 Journal of Leukocyte Biology Volume 86. 2 Hepatoma cell. i. the double-knockout mice were not more susceptible against hepatotropic viruses than IFNAR1 (0/0) mice. application of IFN- failed to induce MxA in the liver of IFNAR1 (0/0) mice and did not protect against hepatotropic virus infections. 2 1 1 HBV 1. it has been observed that IFN-1 and IFN-2 were able to induce anti-APEUV. 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 . reduced expression of HBV relaxed circle. Moreover. inhibits HCV subgenomic RNA replication. Mice lacking functional IFN-Rs were only slightly more susceptible to inﬂuenza virus than wild-type mice. 45] [10. 3 1. By contrast. A549. 51. July 2009 HSV IFN-␣ and IFN-1 decreased the transcription of viral IE gene ICP27. 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. MG63. HT29. 2 2 2/3 African greenmonkey kidney cell line Vero cells. together with IFN-␣.
IFN- induced steady increases in levels of known ISGs. There is a distinction between IFN-. VV.  have observed that treatment of intestinal epithelial cell lines in vitro with IFN-s. IFN- mediated dose.org Journal of Leukocyte Biology 27 . IFN-2 also induces the expression of HLA class I antigens in human hepatoma cells. Despite antiviral properties of IFN-s.and time-dependent HCV inhibition. IFN- inhibited the replication of HCV genotypes 1 and 2 and enhanced the antiviral efﬁcacy of subsaturating levels of IFN-␣ .  demonstrate that IFN-2 effectively inhibits HCV subgenomic RNA replication. and IFN-1 and IFN-␣ induced equivalent levels of 2Ј. ANTITUMOR ACTIVITES One of the most important properties of IFN-s is their potential in tumor therapy (Table 3). expression of murine IFN-2 or IFN-3 by VV did not affect viral replication in murine PAM212 cells. IFN-1 also signiﬁcantly reduced human HBV load in vitro and reduced the cytopathic effect caused by the fully replicating ﬂavivirus. induced apoptosis Growth inhibition Induced apoptosis. IFN-2/3-expressing recombinant VV formed delayed and smaller lesions and displayed potent antiviral activity in vivo.5ЈOAS and MxA gene expression in this cell type. Zhu et al. Furthermore. IFN- inhibits HBV replication in a differentiated murine hepatocyte cell line with kinetics and efﬁciency similar to IFN-␣/␤. prolonged ISG expression Engaged host mechanisms to exert their antitumor functions Induce innate and adaptive immune responses against tumors. 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. Moreover. However. in a mouse dermal model. reduced the number of cells positive for viral IE gene expression. IFN-s efﬁciently inhibit HCV replication in vitro with potentially less hematopoietic side-effects than IFN-␣ because of limited receptor expression in hematopoietic cells. NK cells. IFN-2 appears to suppress speciﬁcally HCV internal ribosome entry segment-mediated translation.Li et al. and the activity does not require the expression of IFN-␣/␤ or IFN-␥. Although type I and type III Volume 86. IFN-s in antivirus. However. the antiviral activity of IFN- in a model of vaginal HSV-2 infection surpassed that of IFN-␣. The discrepancy between the observed antiviral activity in vitro and in vivo suggests that IFN- exerts a signiﬁcant portion of its antiviral activity in vivo via stimulation of the immune system rather than through induction of antiviral state mediators. West Nile virus . HBV and HCV Several reports have shown that IFN-s exhibit antiviral activity toward HBV and HCV by inhibiting viral replication. However. and CD8 T cell activity Induced tumor apoptosis and innate immune responses References       1 1. IFN- blocked the replication of a subgenomic and a full-length genomic HCV replicon in human hepatocyte Huh7 cells . encodes secreted proteins B18 and Y136. used as a smallpox vaccine. extended STAT activation. which function as IFN antagonists.jleukbio. the antiviral activity of IFN- against HBV may be limited in human cells . human ﬁbrosarcoma 2fTGH cell line Murine melanoma Murine ﬁbrosarcoma Possible mechanism Growth inhibition Decreased cell numbers. Interestingly. which do express IFN-R. suggesting that type III IFNs are biologically relevant against poxviruses . including increase of IFN-␥ production and polymorphonuclear neutrophils.and IFN-␣-induced antiviral states. antitumor. their efﬁcacy as antiviral agents may have similar limitations as IFN-␣ as a result of inhibition by SOCS proteins . in vitro assays revealed that IFN- have appreciable antiviral activity against EMCV but limited activity against HSV-2 . whereas they were inefﬁcient in systemic infections by EMCV and lymphocytic choriomeningitis virus. July 2009 www. followed by infection with CMV. indicating that IFN-s do not have antiviral activity against VV in vitro. suggesting that type III IFNs may be more potent for the treatment of certain poxvirus infections . B18 protein from VV was unable to interact with type III IFNs and had no effect on their signaling and biological activities. In contrast. Furthermore. the IFN-R gene is preferentially expressed on primary hepatocytes in normal liver. 2 1 1 2 (in vivo) 2 (in vivo) 2 (in vivo) Murine melanoma. independent of types I and II IFNRs. whereas IFN-␣ ISGs peaked early and declined rapidly. CMV and poxvirus Brand et al. and immunity TABLE 3. The kinetics of IFN--mediated STAT activation and induction of potential effector genes were also distinct from those of IFN-␣. Pretreatment with IFN- enhanced protein expression of IFN-␥ after HSV-2 infection in vivo. colon cancer  duced potent antiviral activity against HSV-2 in the vaginal infection model. Treatment of human hepatoma cells with IFN-2 activates the JAK-STAT signaling pathway and induces the expression of some ISGs. where control virus caused a mild localized infection. The replication of HBV in a human hepatoma cell line was reduced by ϳ30% following treatment with a high concentration of IFN-.
STAT2.  have demonstrated recently that IFN- induces innate and adaptive immune responses against tumors. signiﬁcantly decreased cell numbers. promoting Th1 responses . IFN- increased the total number of splenic NK cells in severe combined immunodeﬁciency (SCID) mice.IFN-2 cells) when injected s. except in one human glioblastoma cell line. into mice were retarded or prevented completely. in addition to IFN-␣. Several cell types. Therefore.  demonstrated recently that in contrast to IFN-␣. However. Cell-depletion experiments revealed that polymorphonuclear neutrophils. the combination of IFN-␣ and IFN- had additive effects on the antiproliferative responses. suggesting such anti-tumor responses are unlikely to involve adaptive immunity . Although receptor genes for type I IFNs are ubiquitously expressed on all cells. indicating that SOCS proteins act as negative regulators of IFN- signaling in BON1 cells. including primary lymphocytes and macrophages. Zitzmann et al. caspase-3 cleavage. Antibody-mediated immune cell depletion comﬁrmed that NK cells were critical to IFN--mediated tumor inhibition. inoculation of MCA205-IFN- cells into mice evoked enhanced IFN-␥ production and cytotoxic T cell activity in spleen cells. Dumoutier et al. IFN--mediated suppression of tumor growth was almost abolished in irradiated mice. IMMUNOREGULATORY FUNCTIONS In addition to their antiviral and antiproliferative activities.  have shown recently that in human neuroendocrine BON1 tumor cells. Although constitutive expression of mouse IFN-2 in B16 melanoma cells did not affect their proliferation in vitro. up-regulating MHC class I molecule expression on tumor cells to promote antigen presentation [10. Moreover. and DNA fragmentation. NK cells. to control tumor growth . their growth and tumorigenicity (B16. IFN- expression induced lymphocytic cell inﬁltration in tumor tissue. enhanced IL-12-induced IFN-␥ production in vivo. Stable overexpression of SOCS proteins (SOCS1 and SOCS3) abolished the IFN- effects completely. it has been described by Sato et al. play equally important roles in IFN--mediated inhibition of in vivo tumor growth. the 28 Journal of Leukocyte Biology Volume 86. and mediating cell apoptosis [43.jleukbio. Hydrodynamic injection of IFN- cDNA reduced liver metastatic foci of colon cancer Colon26 cells and moderately decreased the mortality of mice with tumors.20 ng/ml were found for IFN-␤. IFN- or retroviral transduction of the IFN- gene into the ﬁbrosarcoma cell line MCA205 did not affect in vitro growth.  have conﬁrmed that type I IFNs. and expanded spleen cells in C57BL/6 mice.org . Interestingly. IFN- was more efﬁcient than IFN-␣ in inducing an antiproliferative effect that overlapped with the activation of apoptosis. incubation of BON1 cells with IFN-2 and IFN-1 induced phosphorylation of STAT1. However. www. can inhibit the proliferation of B lymphoma cell line Daudi cells. direct action of IFN- on the host is rather limited. and induced apoptosis as demonstrated by poly (ADP-ribose) polymerase cleavage. local delivery of IFN- may be a useful adjunctive strategy in the treatment of human malignancies . but not CD4 T cells. for which an ED50 of ϳ120 ng/ml was recorded for IFN-1 . whereas in vivo growth of MCA205-IFN- was markedly suppressed along with increased animal survival. These activities include increasing NK and T cell cytotoxicity . These results reveal that IFN- could potentially be used. suggesting that immune cells are not the primary targets of IFN- . 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 . and metastatic tumor formation in vivo. Consistent with these ﬁndings. In contrast. the major players in speciﬁc antitumor immunity. IFN- could promote apoptosis in cell lines that previously showed only an exhibited antiproliferative response to IFN-␣.IFNs signal through distinct receptors. IFN-s exert immunomodulatory effects that overlap type I IFNs in innate and adaptive arms of the immune system. Moreover.c. suggesting that IFN- may engage host mechanisms to inhibit melanoma growth . 11].c. The ED50 in the range of 0. which are sufﬁcient to up-regulate IRF7 expression but not to inhibit cell proliferation as a result of weaker or less-sustained STAT2.  that IFN- induced tumor apoptosis and NK cell-mediated tumor destruction through innate immune responses. IL-12 augmented IFN--mediated antitumor activity in the presence or absence of IFN-␥ . were found to be unresponsive to IFN-. Furthermore. although a signiﬁcant IRF7 promoter induction could still be detected. indicating that irradiation-sensitive cells. but not IFN-. 65. IFN-2. Maher et al. Thus. are involved in IFN--induced suppression of tumor growth. 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. These observations suggest that Daudi cells express low levels of receptors for IFN-. IFN- expression in tumor cell lines markedly inhibited s. Moreover. IFN- extended STAT1 and STAT2 tyrosine phosphorylation in the human keratinocyte cell line HaCaT and the human ﬁbrosarcoma 2fTGH cell line and prolonged the duration of differentially regulated ISG expression. similar to IFN-␣. the development of long-lasting immunity in this mouse tumor model was relatively weak. IFN- could induce phosphorylation of STAT1 and STAT2 in Daudi cells but to a lesser extent as compared with type I IFN. suggesting the activation of innate immune responses.04 and 0. The expression of IFN- in MCA205 cells also resulted in potent inhibition of metastases formation in the lungs. IFN- overexpression in the liver increased NK/NKT cells and enhanced their tumor-killing activity. little or no antiproliferative activity for IFN-1 and IFN-2 could be shown in these cell lines. 66]. July 2009 function of immune cells is unlikely to be altered directly by IFN-. IFN- might recapitulate only parts of the effects of type I IFNs. and CD8 T cells. and IFN-␤ has been assessed in several human astrocytoma/glioblastoma cell lines. In addition. Antitumor action of IFN- is partially dependent on IFN-␥. they both induce antiproliferative responses. receptors for IFN- are only found on most tumor cell lines. The antiproliferative activity of IFN-1. However. Numasaki et al. However. presumably immune cells. and STAT3. LN319. the growth inhibitory effects of IFN- were more pronounced than that of IFN-␣.
70]  [72–74]  2 1. and -10. This response was inhibited by IL-10. which includes up-regulation of MHC class I and II molecules and the ability to migrate into lymph nodes. IL-5. and -10. July 2009 Effects of IFN- on DC.  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. which depend on the distribution of IFN-Rs. IFN-2-speciﬁc antisense phosphorothioate oligonucleotides suppressed liver pathology in Con A-treated wild-type mice. 65]   [69. Induction of IL-6 by IFN- might suggest a role in linking the innate immune response to the adaptive immune response. 2 1 1 1. Thus. These effects are likely to be a result of increased expression of HIV receptors and coreceptors on the plasma membrane. However. producing IL-6. -8.-injected IFN- in SCID mice induce only a partial maturation. 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. IFN-␥-inducible protein-10 (CXCL10). as IL-13 and the Th2 response is important in the development of asthma. in which IFN- exhibits speciﬁc effects . These results suggest IFN-2 as a key regulatory cytokine with pathogenic function in T cell-mediated liver injury. Thus. IFN-s in antivirus. and genes activated.org Journal of Leukocyte Biology 29 . Volume 86.Li et al. and therefore. In contrast to the Th2 response affected by IFN-1. the nature of the signal transduction. i. IFN-1 has been shown to inhibit the production of IL-13 by T cells in an IFN-␥-independent manner. but its effects were not as consistent as those seen on IL-13. IFN-1 elevated mRNA levels of www. The inhibition of IL-13 secretion by monocytes can be of clinical relevance. and -10 . -8.  described that IFN-2 induced Th1 cytokine production by the CD4ϩT lymphocyte. the IFN-1 activity did not depend on the intermediate induction of IFN-␥ . 2 1. -8. In addition. Whole PBMC exposed to IFN-1 increase the production of IL-6. This action of IFN-1 was similar to that reported previously for IFN-␥. As opposed to the complexity of type I IFN effects on DC. In a range of chemokines tested.v. Interestingly. IFN- are capable of signaling through almost all STAT molecules. Furthermore. which is mediated in part via MD-DC . targeting IFN-2 may represent a novel approach for therapy of Th1-mediated inﬂammatory diseases.jleukbio. 11] [64. Th2 cytokines consist of IL-4. Immunoregulatory Functions of IFN-s Subtype Experimental system PBMC and C8166 T cell line Antiviral function Antitumor function DC Regulatory T cells PBMC. 2 1. antitumor. suggesting IFN-2 may be used by these for antivirus and antitumor function . no induction of costimulatory molecules Promoted proliferation of naturally arising Foxp3-expressing CD4ϩCD25ϩ regulatory T cells Up-regulated IL-6. and IFN-␥-inducible T cell ␣ chemoattractant (CXCL11) in human PBMC. Serra et al. DC acquire IFN- responsiveness through the expression of the IFN-R chain during their differentiation from monocytes. IFN-1 activates monocytes and macrophages to produce a restricted panel of cytokines. macrophage-like cells in colon and lung and alveolar epithelial cells in lung tissue contain IFN-2. IFN-1 preferentially inhibits IL-13 production. IFN- in Th1/Th2 response IFN-1 has important immunoregulatory properties with regard to the Th2 responses. 2 2 Moreover. monocytes. 2 1. monokine induced by IFN-␥ (CXCL9). and IL-13. no induction of costimulatory molecules was observed following IFN- treatment . IFN--treated DC promote the generation of tolerogenic DC and IL-2-dependent proliferation of natural Foxp3expressing CD4ϩCD25ϩ regulatory T cells with contact-dependent suppressive activity on T cell proliferation initiated by fully mature DC . Examination of puriﬁed cell populations isolated from PBMC demonstrated that monocytes rather than lymphocytes were the major IFN-1-responsing subset. Human macrophages also responded to IFN-1 by producing cytokines IL-6. Recently. However. 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-␥ . and macrophages IFNs produced by DC in response to TLR stimulation are critical in DC differentiation and maturation. Siebler et al. up-regulation of MHC class I and II molecules. Moreover. they exhibit broader functions as compared with type I IFNs (Table 4). -8. The immunoregulatory actions of IFN- are cell type-speciﬁc. We have demonstrated recently that HUVECs treated with IFN-␣ and poly(I:C) express IFN-2 protein. 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  [10. IFN-1 decreased IL-4 and IL-5 production signiﬁcantly. IFN-2-transgenic mice showed markedly augmented Con A-induced hepatitis with up-regulated IFN-␥ production. monocytes. and immunity TABLE 4.
www. goat. 373–379. D. July 2009 ACKNOWLEDGMENTS This project was supported by grants from the National Natural Science Foundation of China (30671932. Interferon Res. A. Immunol. N. The deﬁciency 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 . 5. 79]. R. National Institutes of Health). When prolonged. Chem. Isaacs. as the novel members of the class II cytokine family. S. Oritani. 268. J. Int.... 30770840. Oritani. R. 381– 409. Bullens et al. Because of the low responsiveness of the CNS. 325–331. However. Paludan. Further studies will be necessary to better evaluate the potential of IFN-s as novel therapeutic agents. for instance in the case of hepatitis C treatment. Sputum IFN-1 mRNA (but not IFN-2/3) correlates negatively with asthma symptoms in steroid-naive patients and is signiﬁcantly higher in steroid-treated patients. fever. it has become clear that type I IFNs have beneﬁcial roles in interfering with viruses and in bridging protective innate and adaptive immune responses. F. Schoenborn. Ank. Lewis-Antes. The interferon. cancers. Boulay. 9.. B. Biol. 1–11. 10.. Shah. F. Comparison of Type I IFNs and IFN-s: Receptors and Clinical Effects Receptors IFNAR1/IFNAR2 (ubiquitous expression) Clinical effects Autoimmune and chronic inﬂammatory diseases like multiple sclerosis. (2006) Interferon: the pathways of discovery I. Med. Mol. G. V.. (1993) A novel and atypical type one interferon gene expressed by trophoblast during early pregnancy. 8 –32. Sci. Proc. (1992) Genes for the trophoblast interferons in sheep. Molecular and cellular aspects. S. their importance in viral infection. R. J. B. 147. and chronic HBV and HCV infections  (Table 5).. 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These studies show that asthmatic subjects have substantial type III IFN- mRNA levels in the airways. 3. Lefevre. and musk ox and distribution of related genes among mammals. 41–101. Soc. possess antiviral. and the level of IFN- was correlated with the severity of exacerbation. Dickensheets. 202. type I IFN treatment can lead to neurological or neuropsychiatric adverse effects [82. Walter. such as fatigue. 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. and the murine experimental autoimmune encephalitis .. depression. J. C. and immunoregulatory activity. 4. and their receptors.gov. Donnelly. anorexia. Kanakura. Interferon Cytokine Res. Biol. H. Billiau. and myelosuppression. IFN-2/3 (but not IFN1) mRNA levels correlate with the relative and absolute number of eosinophils present in the sputum sample.. 7.. Tomiyama. J. Rev. (2005) IFN-/limitin: a member of type I IFN with mild lympho-myelosuppression. and IFN-1 could have an immunoprotective role in the lower airways. 17. and asthmatics have increased susceptibility to rhinovirus and the risk of invasive bacterial infection. The major challenge to the treatment of HCV is to improve antiviral efﬁcacy and to reduce the side-effects typically seen in IFN-␣-based therapy. Type I IFNs. MS.IFN- in airway disease Rhinoviruses are the major cause of asthma exacerbation. Cell. 9. Further studies are required to clarify whether administration of IFN- may be beneﬁcial in the treatment of asthma exacerbation and whether similar deﬁciencies are present in children and in subjects with nonatopic asthma and the mechanisms of deﬁcient IFN production in asthma . K. Krause. asthmatic adults have increased sputum IFN-2/3 mRNA but similar IFN-1 mRNA expression. J. and 30772011).. 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