Interferon-κ, a Novel Type I Interferon Expressed in Human Keratinocytes

Abstract

High throughput cDNA sequencing has led to the identification of interferon-, a novel subclass of type I interferon that displays ϳ30% homology to other family members. Interferon-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-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-is significantly enhanced in keratinocytes upon viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-␥ or interferon-␤. Administration of interferon-recombinant protein imparts cellular protection against viral infection in a species-specific manner. Interferon-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-signaling, demonstrating that interferon-utilizes the same receptor as other type I interferons. Interferon-therefore defines a novel subclass of type I interferon that is expressed in keratinocytes and expands the repertoire of known proteins mediating host defense. Interferons (IFNs)1 are a family of functionally related cytokines that confer a range of cellular responses including antiviral, antiproliferative, antitumor, and immunomodulatory activities (1, 2). 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-␥, there are multiple members of the type I interferon class, which is divided into the IFN-␣, IFN-␤, and IFN-subclasses (1, 2). In humans, excluding psuedogenes, there are 13 non-allelic IFN-␣ genes, a single ␤ gene, and a single gene. Members of the IFN-␣ family display greater than 80% identity to each other, IFN-displays ϳ60% identity to IFN-␣, and IFN-␤ is ϳ40% 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 (3). The subtypes were initially categorized further by their cell of origin. IFN-␣ and IFN-genes were thought to be produced predominantly by leukocytes and IFN-␤ by fibroblasts. However, upon appropriate induction, most human cell types can generate type I IFNs (2). Exposure to a variety of agents triggers the rapid and transient production of type I IFNs, with viruses being the most efficient natural inducers (4, 5). Certain bacteria can also induce expression, as can double-stranded RNA (dsRNA) and endotoxin. In contrast, trophoblast IFNs or IFN-, which are found only in ruminant ungulate species, are not induced by viral challenge (6). These genes are expressed by the embryonic trophoecto...

Regulatory Effect of IFN-κ, A Novel Type I IFN, On Cytokine Production by Cells of the Innate Immune System

“…The intriguing observation of IFN-constitutive expression in keratinocytes (15) suggests that this IFN may have a local function in the epidermis. To determine whether IFN-can be retained at its site of production through interaction with the glycosaminoglycans present in many tissues, we developed an ELISA-based assay to measure IFN-binding to heparin.…”

“…Previously, we demonstrated that the IFN-mRNA is present in unstimulated keratinocytes and is inducible by stimulation with a variety of factors, including type I and type II IFNs (15). The aim of the next series of experiments was to determine whether IFN-␥ could also up-regulate IFN-expression in monocytes, known to be a source of IFN-␣␤ following viral or bacterial challenge.…”

“…A distinguishing feature of IFN-is the detectable constitutive expression of its transcript in uninduced cells, particularly keratinocytes (15). The mRNA expression level of IFN-can be upregulated by viral infection, by other type I IFNs and, characteristically, by IFN-␥.…”

“…We recently reported the identification and preliminary biological characterization of IFN-, a 180-aa human cytokine belonging to the type I IFN family (15). The coding sequence of IFN-does not have preferential homology with any of the other family members found in humans, displaying ϳ30% homology to IFN-␣, IFN-␤, or IFN-.…”

Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy

“…On the whole, the coding regions of the 13 IFN-a genes display greater than 80% nucleotide identity to each other, while the IFN-o gene displays approximately 60% identity to any of the IFN-a genes, and the IFN-b gene is about 40% identical to the rest of the cluster. 15 The type I interferons are pleiotropic cytokines with important roles in inflammation, immunoregulation, and T cell responses, 16 making them outstanding candidates for asthma and atopy susceptibility genes. The potent antiviral properties of type I interferons have long been recognized, 17,18 and viral infections, such as respiratory syncytial virus (RSV) and rhinovirus (RV), may be early life triggers of asthma.…”