Interferon System

Interferons are the cytokines, which are produced initially to defend the host against infection, through mechanisms that inhibit the replication of a number of viruses. There are two main types of interferon. Type I interferons include interferon-alpha, interferon-beta, interferon-omega, and interferon-delta. Interferon-gamma is a Type II interferon. Interferon-alpha is mainly produced by leukocytes (dendritic cells and macrophages). Interferon-beta is produced by most of the epithelial cells and fibroblasts. Cells of immune system, including T cells and natural killer cells, produce interferon-gamma. Once stimulated by a viral infection, these cells go through a series of signaling events that leads to rapid production of interferons and other cytokines. Interferon is, therefore, an important cytokine during innate host defense against viral infection. It is believed that the interferon system is transcriptionally activated intracellularly within a few hours of virus infection through a cascade of signaling pathways that involve NF-kB, ATF2-c-Jun, and interferon-regulatory factors (IRF 3) and IRF-7 (Kawai & Akira, 2006). In humans, Type I interferons are encoded by 14 functional genes that form the interferon-alpha family. Single genes encode for interferon-beta and -omega, and three genes encodes for interferon-lambda (Sen, 2001; Bekisz et al., 2004). The biological significance of having multiple genes for interferon-alpha and only one for interferon-beta is not clear. The genes for different Type I interferons are all located together on human chromosome 9 (Diaz et al., 1994), and the Type II interferon gene is located on chromosome 12 (Schroder et al., 2004). The commercially available recombinant interferon used against HCV is interferon-a2a, interferon-a2b, or a consensus interferon (Blatt et al., 1996). The consensus interferon is a recombinant protein that has the most common amino acid sequences derived from several natural interferon-alpha subtypes (Heathcote et al., 1998). All Type I interferons bind to the human interferonalpha receptor (IFNAR), which consists of an IFNAR-1 and IFNAR-2 subunit (Uze et al., 1990, 1995; Novick et al., 1994; Colamonici et al., 1994; Domanski and Colamonici, 1996; Platanias et al., 1996). IFNAR-1 has a relative molecular weight of 110 kDa, while IFNAR-2 occurs as two forms due to differential splicing of the same gene. These include the IFNAR-2c protein of molecular weight 90-100 kDa and the IFNAR2b protein of molecular weight 51 kDa. There are two distinct interferon-gamma receptors (IFNGR-1 and IFNGR-2). IFNGR-1 has a major binding subunit protein with a molecular weight of 90 kDa; IRNGR-2, a 62-kDa protein, plays a minimal role in ligand binding and is important in downstream signaling pathways (Stark et al., 1998; Bach et al. 1997; Hemmi et al., 1994). All interferons activate a cascade of signal transduction pathways through its receptors that stimulate synthesis of numerous antiviral genes. The differences and similarities between the signaling pathways of Type I interferon and Type II interferon are summarized in Figure 2. Interferon binding to the cell surface receptors activates the intracellular signaling pathways, which involve Janus kinase (JAK1) and tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription (STAT1 and STAT2) proteins. The JAKs phosphorylate the STAT proteins, which either homo-or heterodimerize and then translocate to the nucleus to induce the expression of the IFN-stimulated genes (ISG). The phosphorylated STAT1 and STAT2 combine with IRF-9 (interferon regulatory factor 9) to form a trimeric ISGF-3 complex. This complex enters the nucleus and binds to a consensus DNA sequence [GAAAN (N) GAAA] called the "interferon stimulated response element" (ISRE) (Goodbourn et al., 2000). This regulatory sequence is present upstream of most interferonalpha and interferon-beta responsive genes. These cascades of molecular signaling are essential for stimulation of interferon-mediated gene transcription. In contrast, binding of interferon-gamma to its receptors leads to tyrosine phosphorylation of STAT1, but not STAT2. The phosphorylated STAT1 protein forms a homodimer called "gamma-activated factor" (GAF) that translocates to the nucleus and binds to a consensus sequence [TTNCNNNAA] called "gamma activation sequence" (GAS) elements. This DNA sequence is present in the upstream regulatory region of the interferon-gamma inducible genes. These cascades of biochemical reactions

Ifn Gamma Ifn Alpha Beta Signalling

Fig. 2 Comparison of signaling pathways activated in a mammalian cell after addition of exogenous interferon. IFN-alpha/beta (type IIFN) and IFN-gamma (type II) binds to separate cell surface receptors. IFN-alpha or IFN-beta binding to their receptors activates two receptor associated tyrosine kinases, Jakl and Tyk2, which then phosphorylate the STAT1 and STAT2 proteins. These two phosphorylated proteins combine with IRF-9 to form the trimeric ISGF3 complex. This complex enters the nucleus and binds to a regulatory consensus DNA sequence called ISRE (interferon sensitive response element) present in most of the type I interferon responsive genes, whereas IFN-gamma binding to its receptor leads to activation of Jak-1 and Jak-2 tyrosine kinases, resulting only in phosphorylation of STAT1 protein. The phosphorylated STAT1 protein forms a homodimer called "gamma-activated factor" (GAF). This complex enters the nucleus and binds to the consensus DNA sequence called the GAS (gamma activated sequence), which regulates the induction of type II responsive genes

Fig. 2 Comparison of signaling pathways activated in a mammalian cell after addition of exogenous interferon. IFN-alpha/beta (type IIFN) and IFN-gamma (type II) binds to separate cell surface receptors. IFN-alpha or IFN-beta binding to their receptors activates two receptor associated tyrosine kinases, Jakl and Tyk2, which then phosphorylate the STAT1 and STAT2 proteins. These two phosphorylated proteins combine with IRF-9 to form the trimeric ISGF3 complex. This complex enters the nucleus and binds to a regulatory consensus DNA sequence called ISRE (interferon sensitive response element) present in most of the type I interferon responsive genes, whereas IFN-gamma binding to its receptor leads to activation of Jak-1 and Jak-2 tyrosine kinases, resulting only in phosphorylation of STAT1 protein. The phosphorylated STAT1 protein forms a homodimer called "gamma-activated factor" (GAF). This complex enters the nucleus and binds to the consensus DNA sequence called the GAS (gamma activated sequence), which regulates the induction of type II responsive genes occurring in normal cells due to interferon treatment have been termed the Jak-Stat pathways (Darnell, 1998). The Jak-Stat pathways activate a large number of genes in the IFN-treated hepatocyte, which are normally quiescent or present at low levels (William, 1991).

The roles of the interferon-stimulated genes have been well established while studying interferon action against different viruses (Katze et al., 2002). These include the double-stranded RNA-activated protein kinase PKR, which inhibits protein synthesis via eIF2alpha phosphorylation, the 2'-5' oligoadenylate synthatase (2'-5' OAS) (which activates RNAse L to degrade viral RNA), the MX GTPase (which blocks viral transport inside the cell), p56 (which inhibits translation via eIF3), and P-200 family proteins that impair cell proliferation through cellular factors such as NFkB, E2F, P53, and c-Myc. However, the exact mechanism by which interferon activates intracellular pathways to inhibit HCV replication is not fully understood. A detailed understanding of this intracellular signaling pathway is important to improve the success of interferon therapy against chronic HCV.

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