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Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function.

ABSTRACT: Scavenger receptor class B type I (SR-B1) binds pathogen-associated molecular patterns participating in the regulation of the inflammatory reaction but there is no information regarding potential interactions between SR-B1 and the interferon system. Herein, we report that SR-B1 ligands strongly regulate the transcriptional response to interferon α (IFNα) and enhance its antiviral and antitumor activity. This effect was mediated by the activation of TLR2 and TLR4 as it was annulled by the addition of anti-TLR2 or anti-TLR4 blocking antibodies. In vivo, we maximized the antitumor activity of IFNα co-expressing in the liver a SR-B1 ligand and IFNα by adeno-associated viruses. This gene therapy strategy eradicated liver metastases from colon cancer with reduced toxicity. On the other hand, genetic and pharmacological inhibition of SR-B1 blocks the clathrin-dependent interferon receptor recycling pathway with a concomitant reduction in IFNα signaling and bioactivity. This effect can be applied to enhance cancer immunotherapy with oncolytic viruses. Indeed, SR-B1 antagonists facilitate replication of oncolytic viruses amplifying their tumoricidal potential. In conclusion, SR-B1 agonists behave as IFNα enhancers while SR-B1 inhibitors dampen IFNα activity. These results demonstrate that SR-B1 is a suitable pharmacology target to enhance cancer immunotherapy based on IFNα and oncolytic viruses.

SUBMITTER: Vasquez M

PROVIDER: S-EPMC5007953 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function.

Vasquez Marcos M Fioravanti Jessica J Aranda Fernando F Paredes Vladimir V Gomar Celia C Ardaiz Nuria N Fernandez-Ruiz Veronica V Méndez Miriam M Nistal-Villan Estanislao E Larrea Esther E Gao Qinshan Q Gonzalez-Aseguinolaza Gloria G Prieto Jesus J Berraondo Pedro P

Oncoimmunology 20160629 8

Scavenger receptor class B type I (SR-B1) binds pathogen-associated molecular patterns participating in the regulation of the inflammatory reaction but there is no information regarding potential interactions between SR-B1 and the interferon system. Herein, we report that SR-B1 ligands strongly regulate the transcriptional response to interferon α (IFNα) and enhance its antiviral and antitumor activity. This effect was mediated by the activation of TLR2 and TLR4 as it was annulled by the additio ...[more]

PMID: 27622065

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Project description:BackgroundScavenger receptor class B type I (SR-BI) plays a key role in high density lipoproteins (HDL) metabolism. SR-BI deficiency in mice results in enhanced susceptibility to atherosclerosis with abnormal large, cholesterol enriched, and functional impaired HDL. This study was to characterize the protein markers of dysfunctional HDL in SR-BI deficient (SR-BI-/-) mice and to test if the defective of HDL might be affected by probucol treatment.MethodsShotgun proteomics and 2-D gel electrophoresis were performed to examine the profile of HDL protein and distribution of HDL particles isolated from SR-BI-/- mice. HDL's cell-function, paraoxonase 1 (PON1) and myeloperoxidase activity were assessed. The mice were treated with 1.2 mg/g/day probucol for 6 weeks and the impact on HDL protein markers was analyzed. The differential proteins were quantified by Western blotting.ResultsThe relative amount of protein in SR-BI-/- HDL was decreased by about 25% compared to that in HDL from wild type (WT) mice. Compared to WT HDL, relative protein abundance of representative apoAI and PON1 in SR-BI-/- HDL were significantly reduced, whereas acute-phase protein serum amyloid A (SAA) and apoAIV, proteinase inhibitor proteins α-1-antitrypsin (A1AT) were increased. The distribution of plasma apoAI-containing HDL particles in SR-BI-/- mice was also dramatically altered, although plasma apoAI level was no difference. The protein alterations were accompanied with dysfunction of SR-BI-/- HDL, evidenced by impaired cholesterol homeostasis in macrophages, and reduced anti-oxidative and anti-inflammatory effects. Probucol treatment of SR-BI-/- mice could restored the relative contents of critical proteins including apoAI, PON1, SAA, apoAIV and A1AT on HDL, and improve HDL dysfunction despite decreased HDL-C level.ConclusionSR-BI deficiency leading to dysfunctional HDL is closely related to alteration of HDL protein, suggesting that identification of apoAI, PON1, SAA, apoAIV, and A1AT may serve as the valuable protein markers for diagnosis and therapeutics of dysfunctional HDL-related metabolic diseases.

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Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function.

Publications

Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function.

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