Interferons and Interferon Inhibitory Activity in Disease and Therapy

Chadha, Kailash C.; Ambrus, Julian L.; Dembinski, Wlodzimierz

doi:10.1177/153537020422900402

Cited by 12 publications

(10 citation statements)

References 36 publications

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“…These include abnormal IFN signalling [46], decreased expression of the IFN type I receptor on the cell surface [47], release of free IFN-alpha/beta type I receptors into the circulation [48,49] and the presence of IFN type I inhibitory proteins [48,50]. Recently it has been shown that two members of the suppressor of cytokine signalling (SOCS) protein family, SOCS-1 and SOCS-3, also inhibit IFN-induced expression of the antiviral proteins 2¢5¢-OAS and MxA [51].…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies

Scagnolari

Duda²,

Bagnato

et al. 2007

J Neurol

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To analyze the in vivo biological effect of anti-interferon beta (IFN-beta) neutralizing antibodies (NABs), blood concentrations of neopterin, beta2microglobulin (Beta2-MG), mRNA-dependent myxovirusresistant protein A (MxA) and dsRNA-dependent protein kinase (PKR) were measured before (predose) and 24 hours after (postdose) IFN-beta administration in 49 patients with multiple sclerosis (MS) with (n = 25) and without (n = 24) NABs. The results indicated that predose levels of MxA-mRNA and PKR-mRNA were highly variable [coefficient of variation (CV) > 100%] among patients. A lower inter-individual variability was observed for pre-dose levels of Beta2-MG and neopterin (CVs of 29% and 44%, respectively). Significantly lower pre- and post-dose blood levels of IFN induced markers, except for postdose PKR-mRNA (p = 0.09), were seen in NAB+ compared with NAB-patients and between patients with high (> 200 t(1/10)) and low ( pound 200 t(1/10)) NAB titers. A significant inverse correlation between NAB titer and pre-dose levels of the above IFN-induced markers was found. In summary, our findings confirm that NABs affect absolute concentrations of IFN-beta induced markers and suggest that such an effect occurs in a titer-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies

Scagnolari

Duda²,

Bagnato

et al. 2007

J Neurol

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“…The ‫ء‬ indicates p Ͻ 0.05 compared with TLR9 ligand. chronic HCV infection that may be linked to reduced IFN-␣ production, including insufficient response of CTLs, low activity of NK cells, and production of Abs with low neutralizing capacity (2,13,(27)(28)(29). It has been reported that IFN-␣ is a potent survival factor of PDCs (30, 31); thus, internal deficit of IFN-␣ may favor a self-destructive loop for loss of PDCs in HCV-infected patients.…”

Section: Discussionmentioning

confidence: 99%

“…IFN-␣ is a naturally occurring protein with distinct antiviral and immunoregulatory effects (13). Healthy individuals produce IFN-␣ in response to infection and stimulation with an Ag or mitogen.…”

Section: Low Ifn-␣ Production Correlates With Reduced Frequency Of Pdmentioning

confidence: 99%

Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection

Dolganiuc

Chang

Kodys

et al. 2006

The Journal of Immunology

206

203

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IFN-α production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-α-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-α production was tested in PBMCs or isolated PDCs after TLR9 stimulation. Treatment-naive patients with chronic HCV infection had reduced frequency of circulating PDCs due to increased apoptosis and showed diminished IFN-α production after stimulation with TLR9 ligands. These PDC defects correlated with the presence of HCV and were in contrast with normal PDC functions of sustained responders. HCV core protein, which was detectable in the plasma of infected patients, reduced TLR9-triggered IFN-α and increased TNF-α and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-α and IL-10 induced apoptosis and inhibited IFN-α production in PDCs. Neutralization of TNF-α and/or IL-10 prevented HCV core-induced inhibition of IFN-α production. We identified CD14+ monocytes as the source of TNF-α and IL-10 in the HCV core-induced inhibition of PDC IFN-α production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-α production. In conclusion, our results suggest that HCV interferes with antiviral immunity through TLR2-mediated monocyte activation triggered by the HCV core protein to induce cytokines that in turn lead to PDC apoptosis and inhibit IFN-α production. These mechanisms are likely to contribute to HCV viral escape from immune responses.

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“…18 IFNs include type I (a, b), type II (c) and IFNl. 19 IFNc was considered pro-inflammatory owing to its increase in the synovium of patients with RA.…”

mentioning

confidence: 99%

Inhibition of interleukin 1-induced matrix metalloproteinase 13 expression in human chondrocytes by interferon

Ahmad

Qureshi

Mabrouk

et al. 2007

Annals of the Rheumatic Diseases

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Background: Despite well-documented immunomodulation by interferon c (IFNc), its role and mechanism of regulation of matrix metalloproteinase 13 (MMP13) gene expression in human chondrocytes is unknown. Objective: To investigate the ability and mechanism of IFNc to suppress interleukin 1 (IL1)-induced MMP13 expression in articular chondrocytes. Methods: Human chondrocytes were treated with IFNc or IL1b alone or in combination. MMP13 mRNA was analysed by semiquantitative reverse transcriptase-PCR. MMP13 protein, phospho-signal transducer and activator of transcription 1 (STAT1) and p44/42 mitogen-activated protein kinase levels were measured by western blotting. MMP13 promoter luciferase, cytomegalovirus cyclic AMP response element-binding protein (CBP)/p300 plasmids and STAT1 small interfering RNA (siRNA) were transfected by the calcium phosphate method. IFNc receptor was also neutralised. Activator protein (AP) 1 activity was monitored by the TransAM transcription factor kit. STAT1-CBP/p300 interaction was studied by immunoprecipitation. Results: IFNc potently suppressed IL1-induced expression of MMP13 and promoter activity. Blockade with neutralising IFNc R1 antibody revealed that MMP13 inhibition by IFNc is mediated by the IFN receptor. IFNcstimulated activation of STAT1 was directly correlated with MMP13 suppression. Knockdown of the STAT1 gene by specific siRNA or its inhibition with fludarabine partially restored the IL1b induction of MMP13 expression and promoter activity. IFNc did not alter AP1 binding ability but promoted physical interaction of STAT1 and CBP/p300 coactivator. p300 overexpression reversed IFNc inhibition of endogenous MMP13 mRNA expression and exogenous MMP13 promoter activity. Conclusion: IFNc, through its receptor, activates STAT1, which binds with CBP/p300 coactivator, sequesters it from the cell system, and thus inhibits transcriptional induction of the MMP13 gene in chondrocytes. IFNc and its signalling pathways could be targeted therapeutically for diminishing IL1-induced cartilage degradation by MMP13 in patients with arthritis.

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Interferons and Interferon Inhibitory Activity in Disease and Therapy

Cited by 12 publications

References 36 publications

Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies

Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies

Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection

Inhibition of interleukin 1-induced matrix metalloproteinase 13 expression in human chondrocytes by interferon

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