Alteration of Interferon-α/β Receptors in Chronic Hepatitis B Patients

Meng, Fanli; Wang, Jiefei; Ge, Jian; Fan, Xinghua; Wang, Bing; Han, Li; Kisseleva, Tatiana; Paik, Yong–Han; Brenner, David A.; Wang, Kai

doi:10.1007/s10875-011-9518-6

Cited by 10 publications

(6 citation statements)

References 26 publications

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“…Our subgroup analyses further observed that during PEG-IFN- α -2a treatment, the expression of NKp46 and IFNAR2 on NK cells in nonresponse group had no significant differences compared with baseline, but in the response group, the expression of NKp46 and IFNAR2 on NK cells significantly enhanced, which suggested that the activation of NKp46 and IFNAR2 was related to the therapeutic effect. These results were consistent with previous findings [ 18 , 31 , 32 ] and further support the direction of using the aforementioned parameters as the early indicator to predict treatment response. This study suggested that NK cell function was not associated with changes in HBV DNA loads and HBeAg levels before treatment and during early treatment, but the HBsAg decrease was positively associated with NKp46 bright NK frequency before treatment and at treatment week 12.…”

Section: Discussionsupporting

confidence: 92%

The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated‐Interferon versus Entecavir Therapy

Cao

et al. 2021

BioMed Research International

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Background. To explore the role of natural killer (NK) cells in the process of hepatitis B virus (HBV) clearance and whether their phenotype is related to antiviral treatment outcome in chronic hepatitis B (CHB) patients. Method. We performed a single-center prospective cohort study to analyze changes of NK cells at weeks 12 and 24 from baseline in CHB patients who received PEGylated-interferon- (PEG-IFN-) α-2a versus entecavir. The frequencies of NK, CD56bright, CD56dim, IFNAR2+, NKp46+, NKp46bright, and NKp46dim NK cells and mean fluorescence intensity (MFI) of receptors NKp46 and IFNAR2 on the surface of NK cells were measured. Subgroup analyses were performed by comparing treatment responders versus nonresponders with aforementioned parameters in each group. Results. In PEG-IFN-α-treated patients, posttreatment CD56bright NK cell frequency increased, but CD56dim NK cell frequency decreased. Additionally, receptor NKp46 and IFNAR2 expression enhanced. In entecavir-treated patients, although NK cell frequency increased, CD56bright and CD56dim NK cell frequencies and IFNAR2 expression did not differ between baseline and posttreatment. In subgroup analyses, posttreatment CD56bright NK cell frequency and IFNAR2 expression significantly increased in PEG-IFN-α responders from baseline, while changes were absent in PEG-IFN-α nonresponders and entecavir treatment responders. Among patients with HBV viremia after entecavir therapy, NK cell frequency significantly increased, whereas NKp46bright and IFNAR2+ NK frequency and IFNAR2 MFI significantly decreased at 12 and 24 weeks from baseline. Conclusions. In CHB patients, PEG-IFN-α treatment significantly enhanced NK cell frequency and function when compared to entacavir. Positive treatment responses to either interferon or entecavir were associated with NK cell function improvement. This trial is registered with clinical trial registration no. NCT03208998.

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Section: Discussionsupporting

confidence: 92%

The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated‐Interferon versus Entecavir Therapy

Cao

et al. 2021

BioMed Research International

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“…It was shown that a decrease in cell surface concentration of one or both of the receptor subunits reduces cell sensitivity and alters signaling (5,25,26,43,49). In addition, a clear correlation between the efficiency of interferon as an antiviral drug or a cancer drug and surface receptor concentration was suggested (7,12,27,49). Using stably transfected cells, it was shown that an increased number of receptors resulted in an overall elevated sensitivity for IFNs, accompanied by a de-* Corresponding author.…”

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confidence: 99%

Stochastic Receptor Expression Determines Cell Fate upon Interferon Treatment

Levin

Harari

Schreiber

2011

Molecular and Cellular Biology

116

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Type I interferons trigger diverse biological effects by binding a common receptor, composed of IFNAR1 and IFNAR2. Intriguingly, while the activation of an antiviral state is common to all cells, antiproliferative activity and apoptosis affect only part of the population, even when cells are stimulated with saturating interferon concentrations. Manipulating receptor expression by different small interfering RNA (siRNA) concentrations reduced the fraction of responsive cells independent of the interferon used, including a newly generated, extremely tight-binding variant. Reduced receptor numbers increased 50% effective concentrations (EC 50 s) for alpha interferon 2 (IFN-␣2) but not for the tight-binding variant. A correlation between receptor numbers, STAT activation, and gene induction is observed. Our data suggest that for a given cell, the response is binary (؉/؊) and dependent on the stochastic expression levels of the receptors on an individual cell. A low number of receptors suffices for antiviral response and is thus a robust feature common to all cells. Conversely, a high number of receptors is required for antiproliferative activity, which allows for fine-tuning on a single-cell level.Type I interferons (IFNs) form a class of cytokines capable of mediating antiviral, growth inhibitory, and immunoregulatory activities (10,36,46). Consisting of 18 members in humans (32), all IFNs induce their biological activities through binding to the same receptor complex, composed of the two transmembrane proteins IFNAR1 and IFNAR2 (1). Upon formation of the ternary complex, the interferon signal is transduced through receptor-associated Janus kinases (JAK), which activate the signal transducers and activators of transcription (STAT) proteins. These, in turn, form homo-and heterodimers that translocate to the nucleus to promote the expression of interferon-stimulated genes (ISGs) (45).Despite their common biological activities and sequence homologies, type I IFNs are not redundant but rather induce their activities differentially (9, 41). These differences take effect in various ways, most notably in the antiviral (AV) and antiproliferative (AP) potencies of interferon subtypes (16,33) and in their abilities to induce different gene expression patterns (11,14,38,48). The AP activities of IFNs are a result of both apoptosis and cell cycle arrest (17,20,40). A profound example for differential activity is the substantially higher AP response induced by beta interferon (IFN-␤) than by 14,21,41). However, it should be noted that most of the differences between IFN-␣2 and IFN-␤ are quantitative and not qualitative; thus, higher IFN-␣2 concentrations mimic most IFN-␤ activities.IFNAR1 and IFNAR2 receptor subunits make distinct contributions to interferon binding, as IFNAR1 binds IFN-␣ with micromolar affinities, while the IFNAR2 subunit binds at nanomolar affinities (6). Nevertheless, the activation of both receptors is necessary to induce the interferon signal (3, 23).Mutagenesis studies have shown that the binding sites f...

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“…Peripheral IFNAR The mechanisms are not clear and may related to oxidative stress and the disturbance of IFNAR function (37,52).…”

Section: Cytokines Chemokines and Non-coding Rnasmentioning

confidence: 99%

“…Studies showed that IFNAR1 and IFNAR2 in peripheral blood mononuclear cells and lymphocytes increased in CHB patients, but their level had a positive correlation with HBV-DNA in liver tissue ( 37 ). Several negative regulators mainly functioning to suppress IFNs expression or disturb the function or expression of IFNAR, thereby inhibit the JAK-STAT pathway and ISGs production ( Figure 1 ).…”

Section: Negative Regulators In Ifn Induction and Signaling Pathwaymentioning

confidence: 99%

“…However, soluble IFNAR was reported as an inhibitory factor of IFN therapy in both HBV and HCV infection ( 52 , 105 ). The expression of IFNAR1 and IFNAR2 in lymphocytes and monocytes was increased in CHB patients which was negatively correlated to plasma glutathione S-transferase (GST), a class of cytosolic enzyme participated in the protection of cell from reactive oxygen species (ROS), suggesting that oxidative stress play an important role in the upregulation of IFNAR in CHB patients ( 37 , 52 ). Oxidative stress could modulate protein misfolding and then disrupt the biological protein conformation.…”

Section: Role Of Cytokines Chemokines and Mirnas In Negative Regulation Of Ifn-α Therapy In Chb Infectionmentioning

confidence: 99%

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Suppression of Interferon-α Treatment Response by Host Negative Factors in Hepatitis B Virus Infection

Wang

Tang

2021

Front. Med.

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Chronic hepatitis B virus (CHB) infection remains a major global public health issue for which there is still lacking effective curative treatment. Interferon-α (IFN-α) and its pegylated form have been approved as an anti-HBV drug with the advantage of antiviral activity and host immunity against HBV infection enhancement, however, IFN-α treatment failure in CHB patients is a challenging obstacle with 70% of CHB patients respond poorly to exogenous IFN-α treatment. The IFN-α treatment response is negatively regulated by both viral and host factors, and the role of viral factors has been extensively illustrated, while much less attention has been paid to host negative factors. Here, we summarized evidence of host negative regulators and parameters involved in IFN-α therapy failure, review the mechanisms responsible for these effects, and discuss the possible improvement of IFN-based therapy and the rationale of combining the inhibitors of negative regulators in achieving an HBV cure.

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Alteration of Interferon-α/β Receptors in Chronic Hepatitis B Patients

Cited by 10 publications

References 26 publications

The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated‐Interferon versus Entecavir Therapy

The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated‐Interferon versus Entecavir Therapy

Stochastic Receptor Expression Determines Cell Fate upon Interferon Treatment

Suppression of Interferon-α Treatment Response by Host Negative Factors in Hepatitis B Virus Infection

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