Roles of unphosphorylated ISGF3 in HCV infection and interferon responsiveness

Sung, Pil Soo; Cheon, HyeonJoo; Cho, Chung Hwan; Hong, Seon Hui; Park, Do Youn; Seo, Hyung Il; Park, Su–Hyung; Yoon, Seung Kew; Stark, George R.; Shin, Eui‐Cheol

doi:10.1073/pnas.1513341112

Cited by 77 publications

(127 citation statements)

References 37 publications

(63 reference statements)

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“…In line with this hypothesis, Sung et al recently demonstrated that expression of unphosphorylated ISG-F3 is increased by endogenous IFN in HCV-infected livers, leading to persistent activation of a set of ISGs and a lack of response to IFN-α in chronic HCV infection [41]. …”

Section: Discussionmentioning

confidence: 99%

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C

et al. 2016

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BackgroundImmuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity.MethodsA total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both. NK cell IFN-γ response was analysed by FACS. IL-12 and IL-18 secretion of monocytes was studied by ELISA. In blocking experiments anti-IL-12/anti-IL-18 were used.ResultsFollowing stimulation of total PBMCs with R848 we found NK cell IFN- γ responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)NK cells. When isolated NK cells were studied no such associations were observed, indicating an indirect association between IL-28B genotype and NK cell activity. Accordingly, we found R848-stimulated monocytes of patients with a T/T genotype to be significantly less effective in triggering NK cell IFN- γ production than monocytes from carriers of a non-T/T genotype. In line with these findings we observed monocytes from T/T patients to secrete significantly lower concentrations of IL-12 than monocytes from non-T/T individuals.ConclusionsOur data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, thus, provide a link between IL-28B genotype and NK functions.

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Section: Discussionmentioning

confidence: 99%

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C

et al. 2016

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“…Furthermore, the level of expression of several ISGs was shown to correlate with IFN-λ genotypes, with the unfavorable alleles associated with higher hepatic levels of ISGs (37, 38). Unphosphorylated IFN-stimulated gene factor 3 (ISGF3) is induced by type III IFNs and sustains expression of USP18, a negative regulator of IFN signaling, resulting in unresponsiveness to IFN-α treatment (39). Comparison of levels of ISGs before and after treatment further demonstrated that the high basal expression levels in non-responders did not increase above pretreatment level, whereas there was a strong ISGs induction in the SVR group (40).…”

Section: Mechanisms Underlying the Role Of Ifn-λ Polymorphisms In Hcvmentioning

confidence: 99%

Type III Interferons in Hepatitis C Virus Infection

Boisvert

Shoukry

2016

Front. Immunol.

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The interferon (IFN)-λ family of type III cytokines includes the closely related interleukin (IL)-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1). They signal through the Janus kinases (JAK)-signal transducers and activators of transcription pathway and promote an antiviral state by the induction of expression of several interferon-stimulated genes (ISGs). Contrary to type I IFNs, the effect of IFN-λ cytokines is largely limited to epithelial cells due to the restricted pattern of expression of their specific receptor. Several genome-wide association studies have established a strong correlation between polymorphism in the region of IL-28B gene (encoding for IFN-λ3) and both spontaneous and therapeutic IFN-mediated clearance of hepatitis C virus (HCV) infection, but the mechanism(s) underlying this enhanced viral clearance are not fully understood. IFN-λ3 directly inhibits HCV replication, and in vitro studies suggest that polymorphism in the IFN-λ3 and its recently identified overlapping IFN-λ4 govern the pattern of ISGs induced upon HCV infection of hepatocytes. IFN-λ can also be produced by dendritic cells, and apart from its antiviral action on hepatocytes, it can regulate the inflammatory response of monocytes/macrophages, thus acting at the interface between innate and adaptive immunity. Here, we review the current state of knowledge about the role of IFN-λ cytokines in mediating and regulating the immune response during acute and chronic HCV infections.

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“…Many target genes of U-STATs 1, 2, 3, and 6 encode proteins that promote cell survival and resistance to cell death, suggesting that the U-STAT system helps to sustain the survival of cells in stressful environments. U-STAT1 induces its target genes as U-ISGF3, a tripartite complex with U-STAT2 and IRF9, and the expression of all three U-ISGF3 components is increased in response to either type I or type III IFN Sung et al 2015). U-STAT1 does not activate gene expression as a homodimer, because high levels of U-STAT1 do not induce target gene expression if U-STAT2 and IRF9 are not present in sufficient quantities (Cheon and Stark 2009;Cheon et al 2013).…”

Section: U-stats As Positive Regulators Of Gene Expressionmentioning

confidence: 99%

“…Cancer cells that express high levels of U-ISGF3 are more resistant to DNA damage, while IFNs inhibit cancer cell proliferation and increase their apoptosis (Borden et al 2007). Similarly, hepatocytes expressing high levels of U-ISGF3 are more resistant to IFN-a therapy, although U-ISGF3 itself suppresses viral replication by inducing antiviral genes (Sung et al 2015). Phosphorylated STAT3 mediates the induction of U-STAT3 in response to IL-6 and other cytokines that activate gp130-linked receptors (Yang et al 2005).…”

Section: U-stats As Positive Regulators Of Gene Expressionmentioning

confidence: 99%

“…However, the levels of tyrosine-phosphorylated STAT1 and STAT2 are low, and the patients respond poorly to exogenous IFN (Shin et al 2016). The underlying mechanism is complex, revealing some important general principles (Sung et al 2015). The levels of U-ISGF3 are high in these livers because of chronic exposure to IFN-l and, as a result, the downstream gene ISG15 is constitutively activated.…”

Section: Mechanisms Of Misregulation Of Ifn Signalingmentioning

confidence: 99%

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Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Stark

Cheon

Wang

2017

Cold Spring Harb Perspect Biol

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Many cytokines and all interferons activate members of a small family of kinases (the Janus kinases [JAKs]) and a slightly larger family of transcription factors (the signal transducers and activators of transcription [STATs]), which are essential components of pathways that induce the expression of specific sets of genes in susceptible cells. JAK-STAT pathways are required for many innate and acquired immune responses, and the activities of these pathways must be finely regulated to avoid major immune dysfunctions. Regulation is achieved through mechanisms that include the activation or induction of potent negative regulatory proteins, posttranslational modification of the STATs, and other modulatory effects that are cell-type specific. Mutations of JAKs and STATs can result in gains or losses of function and can predispose affected individuals to autoimmune disease, susceptibility to a variety of infections, or cancer. Here we review recent developments in the biochemistry, genetics, and biology of JAKs and STATs. Because the basic biochemistry of Janus kinase -signal transducers and activators of transcription (JAK-STAT) signaling pathways has been frequently and extensively reviewed (see, for example, Stark and Darnell 2012;Cai et al. 2015;O'Shea et al. 2015;Villarino et al. 2015), we present here only a brief summary. After a cytokine or interferon binds to its specific receptor, the receptor forms homodimers, heterodimers, or trimers, depending on the cytokine, thus activating the tightly bound JAKs to cross-phosphorylate each other. The activated JAKs then phosphorylate specific tyrosine residues in the cytoplasmic domains of the receptors, providing binding sites for the STATs through their highly conserved SH2 domains. The receptor-bound STATs are phosphorylated, each on a highly conserved tyrosine residue, after which they leave the receptor as homo-or heterodimers whose association is strengthened by SH2-phosphotyrosine interactions. The phosphorylated STAT dimers are then transported to the nucleus, where they bind to and activate specific promoters. The basic outline of JAK-STAT signaling (Fig. 1) shows that interferon (IFN)-g (type II IFN) and all of the cytokines primarily drive the formation of specific STAT homodimers, which then bind to DNA directly. However, in some cases, heterodimers involving STAT1 and STAT3 or STAT5A and STAT5B can also form. In contrast, IFN-b and the subtypes of IFN-a (collectively type I IFNs) and the subtypes of IFN-l (collectively type III IFNs) drive the formation of STAT1-STAT2 heterodimers, which then associate with the DNA-binding interferon regulatory protein 9 (IRF9) to form in-

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Roles of unphosphorylated ISGF3 in HCV infection and interferon responsiveness

Cited by 77 publications

References 37 publications

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C

Type III Interferons in Hepatitis C Virus Infection

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

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