Bernardetta Nardelli

The tumor necrosis factor (TNF) superfamily of cytokines includes both soluble and membrane-bound proteins that regulate immune responses. A member of the human TNF family, BLyS (B lymphocyte stimulator), was identified that induced B cell proliferation and immunoglobulin secretion. BLyS expression on human monocytes could be up-regulated by interferon-γ. Soluble BLyS functioned as a potent B cell growth factor in costimulation assays. Administration of soluble recombinant BLyS to mice disrupted splenic B and T cell zones and resulted in elevated serum immunoglobulin concentrations. The B cell tropism of BLyS is consistent with its receptor expression on B-lineage cells. The biological profile of BLyS suggests it is involved in monocyte-driven B cell activation.

B-lymphocyte stimulator (BLyS) is a recently identified novel member of the tumor necrosis factor ligand superfamily shown to exist in a membrane-bound and soluble form. BLyS was found to be specifically expressed on cells of myeloid lineage and to selectively stimulate B-lymphocyte proliferation and immunoglobulin production. The expression of a cytokine involved in potentiation of humoral immune responses, such as BLyS, is expected to be strictly controlled. The goal of the present study was to examine regulation of BLyS levels in monocytic cells in response to cytokines and during their differentiation to macrophages and dendritic cells. The presence of BLyS on the cell surface and in the culture medium of both normal blood monocytes and on tumor cells of myelomonocytic origin was demonstrated. BLyS gene expression and levels of membrane-associated and soluble BLyS were found to be regulated by cytokines, in particular interferon (IFN)-gamma and to a lesser extent interleukin-10 (IL-10). The expression of BLyS on monocyte membranes was retained following differentiation into macrophages, but detection on the surface of monocyte-derived dendritic cells required stimulation with IFN-gamma. Both IFN-gamma and IL-10 enhanced the release of soluble BLyS that was active in B-cell proliferation assays. Cells transfected with BLyS complementary DNA mutated in a predicted cleavage site failed to release BLyS into the culture medium, thereby suggesting that soluble BLyS was derived from the membrane form. These results provide further support for an important role for BLyS expressed in myeloid cells in B-cell expansion and antibody responses.

B lymphocyte stimulator (BLyS) is a novel member of the TNF ligand superfamily that is important in B cell maturation and survival. We demonstrate that human neutrophils, after incubation with G-CSF or, less efficiently, IFN gamma, express high levels of BLyS mRNA and release elevated amounts of biologically active BLyS. In contrast, surface expression of the membrane-bound BLyS was not detected in activated neutrophils. Indeed, in neutrophils, uniquely among other myeloid cells, soluble BLyS is processed intracellularly by a furin-type convertase. Worthy of note, the absolute capacity of G-CSF-stimulated neutrophils to release BLyS was similar to that of activated monocytes or dendritic cells, suggesting that neutrophils might represent an important source of BLyS. In this regard, we show that BLyS serum levels as well as neutrophil-associated BLyS are significantly enhanced after in vivo administration of G-CSF in patients. In addition, serum obtained from two of these patients induced a remarkable accumulation of neutrophil-associated BLyS in vitro. This effect was neutralized by anti-G-CSF antibodies, indicating that G-CSF, present in the serum, stimulated neutrophils to produce BLyS. Collectively, our findings suggest that neutrophils, through the production of BLyS, might play an unsuspected role in the regulation of B cell homeostasis.

High throughput cDNA sequencing has led to the identification of interferon-κ, a novel subclass of type I interferon that displays ∼30% homology to other family members. Interferon-κ consists of 207 amino acids, including a 27-amino acid signal peptide and a series of cysteines conserved in type I interferons. The gene encoding interferon-κ is located on the short arm of chromosome 9 adjacent to the type I interferon gene cluster and is selectively expressed in epidermal keratinocytes. Expression of interferon-κ is significantly enhanced in keratinocytes upon viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-γ or interferon-β. Administration of interferon-κ recombinant protein imparts cellular protection against viral infection in a species-specific manner. Interferon-κ activates the interferon-stimulated response element signaling pathway and a panel of genes similar to those regulated by other type I interferons including anti-viral mediators and transcriptional regulators. An antibody that neutralizes the type I interferon receptor completely blocks interferon-κ signaling, demonstrating that interferon-κ utilizes the same receptor as other type I interferons. Interferon-κ therefore defines a novel subclass of type I interferon that is expressed in keratinocytes and expands the repertoire of known proteins mediating host defense. High throughput cDNA sequencing has led to the identification of interferon-κ, a novel subclass of type I interferon that displays ∼30% homology to other family members. Interferon-κ consists of 207 amino acids, including a 27-amino acid signal peptide and a series of cysteines conserved in type I interferons. The gene encoding interferon-κ is located on the short arm of chromosome 9 adjacent to the type I interferon gene cluster and is selectively expressed in epidermal keratinocytes. Expression of interferon-κ is significantly enhanced in keratinocytes upon viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-γ or interferon-β. Administration of interferon-κ recombinant protein imparts cellular protection against viral infection in a species-specific manner. Interferon-κ activates the interferon-stimulated response element signaling pathway and a panel of genes similar to those regulated by other type I interferons including anti-viral mediators and transcriptional regulators. An antibody that neutralizes the type I interferon receptor completely blocks interferon-κ signaling, demonstrating that interferon-κ utilizes the same receptor as other type I interferons. Interferon-κ therefore defines a novel subclass of type I interferon that is expressed in keratinocytes and expands the repertoire of known proteins mediating host defense. interferon double-stranded RNA type I IFN receptor complex signal transducer and activator of transcription interferon-stimulated response element expressed sequence tag polymerase chain reaction base pair(s) encephalomyocarditis virus enzyme-linked immunosorbent assay 2–5A oligoadenylatesynthetase dsRNA-dependent protein kinase kilobase pair human embryonic kidney Interferons (IFNs)1 are a family of functionally related cytokines that confer a range of cellular responses including antiviral, antiproliferative, antitumor, and immunomodulatory activities (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google Scholar, 2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar). They are classified as type I or type II according to their structural and functional properties. Although the sole member of the type II family is IFN-γ, there are multiple members of the type I interferon class, which is divided into the IFN-α, IFN-β, and IFN-ω subclasses (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google Scholar, 2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar). In humans, excluding psuedogenes, there are 13 non-allelic IFN-α genes, a single β gene, and a single ω gene. Members of the IFN-α family display greater than 80% identity to each other, IFN-ω displays ∼60% identity to IFN-α, and IFN-β is ∼40% identical to the other family members. The evolutionary conservation of the type I IFN genes is reflected in their common intron-less structure and their co-localization to the short arm of chromosome 9, which suggest that type I IFNs arose by gene duplication (3Diaz M.O. Pomykala H.M. Bohlander S.K. Maltepe E. Malik K. Brownstein B. Olapade O.I. Genomics. 1994; 22: 540-552Crossref PubMed Scopus (138) Google Scholar). The subtypes were initially categorized further by their cell of origin. IFN-α and IFN-ω genes were thought to be produced predominantly by leukocytes and IFN-β by fibroblasts. However, upon appropriate induction, most human cell types can generate type I IFNs (2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar). Exposure to a variety of agents triggers the rapid and transient production of type I IFNs, with viruses being the most efficient natural inducers (4Cavalieri R.L. Havell E.A. Vileck J. Pestka S. Proc. Natl. Acad. Sci. 1977; 74: 4415-4419Crossref PubMed Scopus (103) Google Scholar, 5Raj N.B.K. Pitha P.M. Proc. Natl. Acad. Sci. 1983; 80: 3923-3927Crossref PubMed Scopus (85) Google Scholar). Certain bacteria can also induce expression, as can double-stranded RNA (dsRNA) and endotoxin. In contrast, trophoblast IFNs or IFN-τ, which are found only in ruminant ungulate species, are not induced by viral challenge (6Roberts R.M. Ealy A.D. Alexenko A.P. Han C.S. Ezashi T. Placenta. 1999; 20: 259-264Crossref PubMed Scopus (130) Google Scholar). These genes are expressed by the embryonic trophoectoderm at a specific time during early pregnancy, and though they have the typical properties of other type I IFNs, their major function is to create conditions for the completion of pregnancy (6Roberts R.M. Ealy A.D. Alexenko A.P. Han C.S. Ezashi T. Placenta. 1999; 20: 259-264Crossref PubMed Scopus (130) Google Scholar). Despite the diversity in their sequence, all type I IFNs employ a common type I IFN receptor complex (IFNAR) that is composed of two chains, a 135-kDa subunit (IFNAR1) and a 115-kDa subunit (IFNAR2c) (7Uze G. Lutfalla G. Gresser I. Cell. 1990; 60: 225-234Abstract Full Text PDF PubMed Scopus (508) Google Scholar, 8Soh J. Mariano T.M. Lim J.K. Izotova L. Mirochnitchenko O. Schwartz B. Langer J.A. Pestka S. J. Biol. Chem. 1994; 269: 18102-18110Abstract Full Text PDF PubMed Google Scholar, 9Domanski P. Witte M. Kellum M. Rubinstein M. Hackett R. Pitha P. Colamonici O.R. J. Biol. Chem. 1995; 270: 21606-21611Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). IFN-induced receptor dimerization of the IFNAR1 and IFNAR2c chains initiates a signaling cascade that involves tyrosine phosphorylation of the Tyk2 and Jak1 tyrosine kinases and subsequent phosphorylation of the STAT1 and STAT2 proteins (10Schindler C. Darnell J.E. Ann. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1642) Google Scholar, 11Stark G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3365) Google Scholar). Association of the phosphorylated STAT proteins with the p48 DNA binding subunit forms the interferon stimulated gene factor 3 multisubunit complex, which translocates to the nucleus and binds to interferon-stimulated response elements (ISRE) found upstream of interferon-inducible genes. IFN signaling culminates in the modulation of a wide range of cellular responses including anti-viral activity, tumor anti-proliferation, enhancement of natural killer cell activity, and induction of major histocompatibility complex antigen expression (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google Scholar, 2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar, 10Schindler C. Darnell J.E. Ann. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1642) Google Scholar, 11Stark G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3365) Google Scholar). The cellular activities of IFNs have attracted much interest for clinical applications, with IFNs now being used to treat a broad range of diseases including multiple sclerosis, leukemia, and hepatitis (2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar, 12Gutterman J.U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1198-1205Crossref PubMed Scopus (678) Google Scholar). We report here the identification and characterization of a novel subclass of the type I IFN family that we have named IFN-κ, which is expressed in keratinocytes, signals through the type I receptor complex, and mediates anti-viral activity. The Human Genome Sciences expressed sequence tag (EST) data base of ∼3 million cDNA sequences derived from over 900 human cDNA libraries was screened for homologues of the interferon family using the BLAST algorithm. A single EST (HKAPI15) with significant type I interferon homology was identified and sequenced completely to reveal an open reading frame of 207 amino acids. The amino acid sequence has been deposited in GenBankTM under accession numberAF315688. The was in two The sequence that the was from human DNA using and that to and in The upstream was by from a human using a and and that to and in The sequence of the including and sequence has been deposited in GenBankTM under accession The open reading frame was using sequences that the with a a sequence M. J. Cell. PubMed Scopus Google and a The was with and into a expression derived from S. R. P. Cell. Biol. PubMed Scopus Google which a the virus and the and signals of the gene. The IFNAR1 cDNA sequence was as into the IFNAR2c open reading frame was and and The cDNA the cDNA the and of and was used as for the transcription according to the were with using cell as by were and of was was by at was using a of to a protein of of was for that and of were to a and the sequence was using an A panel of cell was from and the of were from The which a of the were used for polymerase chain reaction and of polymerase chain reaction for for and for were on of each in a of the data was using the Human Genome keratinocytes San Diego, were in or keratinocytes at were used in the were with of human IFN-β activity, and of human activity, or with for or RNA were and keratinocytes were with the keratinocytes were for in of RNA from keratinocytes was by The used for and IFN-β to amino and were and to to which were for expression, were as human human human human human cell human and human RNA was used in a a for were The of specific was to using the sequence were at for and for by of for and for were in and were to the human the gene is by the sequences of the two and the STAT1 interferon factor were at the with the and on the with the The was with for expression by of 1990; Google Scholar). The sequence of the that amino and an has been deposited in GenBankTM under accession The gene was by using a and a that the and The was with and into a expression R. and T. A. U. S. and expressed in the E. were to the and a induction in the of of was and of cell was in of The cell was through a and to and was a for IFN-β R. PubMed Scopus Google with were with in of and the was with of The was in and acid was a of The was and the was in of the the of a major at and amino acid sequencing identity to human were to an of in in and were to to of recombinant were to the of was to each an the cell were with and with in of the was by of with by at in a are expressed as protein of the element which mediates type I interferon-inducible expression of the interferon-inducible gene R. Darnell J.E. PubMed Scopus Google and a a the was by using with the and The was by and and into of the gene was into to generate The was into human embryonic kidney using and were and screened for their to human IFN-β and demonstrating were used for further of IFN genes and IFN receptor genes was by were in the and in a antibody and antibody were also in BLAST of a data base of over 3 million human EST sequences identified a single EST derived from a novel homology to the type I interferons. sequence of cDNA an open reading frame of 207 amino with significant homology to the other subclasses of type I IFN and that we have named Although the is as the the that the at amino acid is the be the of with the sequence M. J. Cell. PubMed Scopus Google Scholar). the sequence of the cDNA and to the structure of IFN-κ, the gene was and sequenced In to the of upstream sequence including the sequence and of sequence were The sequence the open reading frame sequence identified in the cDNA sequence and also the of an the the The of an in type I IFN genes has not been (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google Scholar, 2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar). of the the of a element and of the transcriptional elements elements have been to the virus of the IFN-α and IFN-β genes through the binding of members of the interferon factor family P.M. L. J. 1998; 80: PubMed Scopus Google Scholar). of the protein sequence with the of human type I IFNs homology the including the in other type IFNs T. S. J. Biol. 1995; Scopus Google Scholar, R. A. P. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). other IFNs, is to be on and G. PubMed Scopus Google with to be amino and In and of the cDNA a protein that at than the of In the of the protein is to signal peptide that is from the open reading frame was expressed in from cell was to and a protein of the for was acid sequencing of the protein identity to and an of therefore that is and that and Although that utilizes a signal peptide than other type I IFNs as be that is the in a signal peptide in to that of the other type I interferon family members. the acid protein identity to the other type I IFNs and defines a novel subclass of type I the most significant structural and the other type I IFNs is the of the has an of amino also for the of amino with the IFN-α amino IFN-β amino and IFN-ω amino The protein and on the of homology and to other IFNs is that forms a with forms a with as an human IFN-β and in common with most type I IFN-α M. M. S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, S. PubMed Scopus Google not a sequence for the of the gene, a panel of cell was screened using A was in chromosome 9, was in other on chromosome 9, a panel of was We in and of data using the Human Genome to the on chromosome 9, which and on the of chromosome of with the of human chromosome 9 the of to of the deposited human sequence the of to on chromosome has been that the IFN-α, IFN-β, and IFN-ω genes are in the (3Diaz M.O. Pomykala H.M. Bohlander S.K. Maltepe E. Malik K. Brownstein B. Olapade O.I. Genomics. 1994; 22: 540-552Crossref PubMed Scopus (138) Google Scholar). on the and sequence is located to the to the type I IFN of the Human Genome Sciences data which sequences derived from human cDNA libraries from and and cell expression of only in keratinocytes that a of expression of was in an of a panel of RNA from a wide range of human cell and types including and on a range of cell including and and keratinocytes expression of in keratinocytes and a of expression in and to significant expression not on keratinocytes the expression of a Expression of the was in multiple and also in keratinocytes not In to expression, IFN-β was in keratinocytes of keratinocytes with a known of IFN expression, in the in IFN-β expression and also an of expression keratinocytes of an was for The of the was by an of the or the or to with either recombinant IFN-α or from of keratinocytes for expression of at the In contrast, protein was in cell of or in The that expression that also be upon viral of keratinocytes with that the is induced viral infection expression of is regulated by other human keratinocytes were with or in and IFN-β a significant in the of expression with an in the The of the response to the two is with IFN-β mediating a rapid response in the of with the response to treatment A of all interferons is the to anti-viral protection (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google Scholar, 2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar). has activity, recombinant protein from E. was for to either human or from infection with encephalomyocarditis in human from infection in a with protection in the of In human cell with an expression were also from infection with virus not In contrast, anti-viral on is therefore to anti-viral protection in a species-specific and is of against cellular infection by at two of RNA has been that all type I IFNs signal through a common receptor complex and gene expression through of a of interferon-inducible genes in 10Schindler C. Darnell J.E. Ann. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1642) Google and 11Stark G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3365) Google Scholar). can a of a element upstream of the gene was into the cell A and induction of the signaling pathway was upon treatment of the with recombinant protein was on the type I IFN receptor complex, a antibody that binds to IFNAR2c and signaling through the receptor complex was O.R. P. J. Biol. Chem. Full Text PDF PubMed Google Scholar). binds with to the IFN receptor complex and neutralizes the of human IFN-α species, IFN-β and IFN-ω O.R. P. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The of antibody to signaling on the that signals through the type I IFN receptor signaling for the of the IFNAR2c and IFNAR1 chains in the cellular response to was by the genes encoding the receptor IFNAR1 and IFNAR2c in the cell either or in Although of IFNAR1 or in a in gene in response to treatment with IFN-κ, induction expression of the expression of of the same genes that other IFNs which are to type I IFNs Cell. Biol. 1999; PubMed Scopus Google were with of RNA was and to to the of expression of a of genes to be regulated by type I IFNs The IFN-induced are the anti-viral the the and the pathway (2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar, 10Schindler C. Darnell J.E. Ann. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1642) Google Scholar, 11Stark G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3365) Google Scholar). that are induced at the by interferons and are of and were for their response to in the genes were all by IFN-κ, that also the anti-viral The of two transcription that in the IFN signal pathway were also by and a novel subclass of type I interferon that is selectively expressed in keratinocytes and is ∼30% identical to the other type I interferon family members. The gene encoding is located on the short arm of chromosome 9, adjacent to the type I IFN is to the In to the other which are of (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google an the In the protein is than the other type I IFNs of a acid the and the gene and structure suggest that from the other type I interferons. of cDNA and sequences from other has to an of have to a specific in or of a for of The of the in is cellular with binding with and subsequent Despite sequence and structural employ the common IFN receptor and activates the signal pathway by other type I utilizes to be The of expands the repertoire of human type I IFNs into IFN-α, IFN-β, and An IFN-τ, has been identified in ruminant N.B.K. Pitha P.M. Proc. Natl. Acad. Sci. 1983; 80: 3923-3927Crossref PubMed Scopus (85) Google and a gene related to the type I IFNs that also signals through the common type I IFN was K. J. M. T. K. I. PubMed Scopus Google Scholar). Although the type I IFNs similar they significant in the of their activities and immunomodulatory (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google Scholar, 2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar, 10Schindler C. Darnell J.E. Ann. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1642) Google Scholar, 11Stark G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3365) Google Scholar, M. Rubinstein M. Pestka S. Biochem. PubMed Scopus Google Scholar, K. Biochem. 1983; Scopus (103) Google Scholar, C. P. B. Pestka S. Proc. Natl. Acad. Sci. PubMed Scopus Google Scholar, G.R. 1995; Google Scholar, S. PubMed Scopus Google Scholar). in signaling from the receptor G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3365) Google Scholar, 12Gutterman J.U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1198-1205Crossref PubMed Scopus (678) Google Scholar, A. Williams B.R. Silverman R.H. Proc. Natl. Acad. Sci. 1998; PubMed Scopus Google with in their and expression of function for each type I IFN most type I IFNs are predominantly expressed only upon viral infection or cellular the expression of protein in keratinocytes and cell types of the and is an of also the of a type I IFN from IFN-α or IFN-β that is expressed in keratinocytes M. J. Biol. PubMed Scopus Google Scholar). In contrast, IFN-α IFN-β are expressed in keratinocytes, IFN-β protein is in of keratinocytes S. B. J. Cytokine PubMed Scopus Google Scholar). In of the by as the expression of in keratinocytes a novel of host that further is of mediating cellular protection against at two of RNA viruses be that the of anti-viral of against infection of is with other type I interferons (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google Scholar, G.R. 1995; Google Scholar). be to other including those that as the and are to viral infection of keratinocytes or treatment with the expression of is further enhanced a in host defense. The that IFN-β and also significantly expression a for in the host interferon An of the including the elements P.M. L. J. 1998; 80: PubMed Scopus Google identified in in the that expression in keratinocytes and response to IFN-β, IFN-γ, and viral In to anti-viral activity, interferons a wide range of other cellular through the of a wide of interferon-inducible genes. These activities of of and tumor of natural killer enhancement of major histocompatibility complex antigen expression, and the of tumor (1Pestka S. Langer J.A. Zoon K.C. Samuel C.E. Annu. Rev. Biochem. 1987; 56: 727-777Crossref PubMed Scopus (1599) Google Scholar, 2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar, Cell. Biol. 1999; PubMed Scopus Google P. Pestka S. J. 1987; PubMed Scopus Google Scholar). The that utilizes the common IFN receptor and activates the as by to transcriptional of the that activities similar to those by other interferons. transcriptional that activates the anti-viral by and also the transcription and which in mediating the interferon response G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3365) Google Scholar). the STAT1 gene have response to either viral or infection to the of the IFN response K.C. E.A. J.K. K. R. M. Schreiber R.D. Cell. Full Text Full Text PDF PubMed Scopus Google the expression of genes including major histocompatibility complex G.R. Kerr I.M. Williams B.R. Silverman R.H. Schreiber R.D. Annu. Rev. Biochem. 1998; 67: 227-264Crossref PubMed Scopus (3365) Google Scholar, T. J. PubMed Scopus Google Scholar). The that is induced by the IFN-γ, and also other type I further of in host defense. further be to the range and of cellular activities by to the of other type I interferons and to the to host and cellular in the and the The of also be type I interferons have been used to treat a range of diseases as forms of leukemia, and multiple (2Maeyer E. Maeyer-Guignard J. Thompson A. The Cytokine Handbook. 3rd Ed. Academic Press, San Diego, CA1998: 491-516Google Scholar, 12Gutterman J.U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1198-1205Crossref PubMed Scopus (678) Google Scholar). However, IFN including and In their be by the production of J.U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1198-1205Crossref PubMed Scopus (678) Google Scholar, C. P. B. Pestka S. Proc. Natl. Acad. Sci. PubMed Scopus Google Scholar, G.R. 1995; Google Scholar). Although be to clinical is that an interferon treatment to type I interferons in the by either by The of and and on the by are