Chimeric Vaccine Stimulation of Human Dendritic Cell Indoleamine 2, 3-Dioxygenase Occurs via the Non-Canonical NF-κB Pathway.

PloS One
Nan-Sun KimWilliam Langridge

Abstract

A chimeric protein vaccine composed of the cholera toxin B subunit fused to proinsulin (CTB-INS) was shown to suppress type 1 diabetes onset in NOD mice and upregulate biosynthesis of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) in human dendritic cells (DCs). Here we demonstrate siRNA inhibition of the NF-κB-inducing kinase (NIK) suppresses vaccine-induced IDO1 biosynthesis as well as IKKα phosphorylation. Chromatin immunoprecipitation (ChIP) analysis of CTB-INS inoculated DCs showed that RelB bound to NF-κB consensus sequences in the IDO1 promoter, suggesting vaccine stimulation of the non-canonical NF-κB pathway activates IDO1 expression in vivo. The addition of Tumor Necrosis Factor Associated Factors (TRAF) TRAF 2, 3 and TRAF6 blocking peptides to vaccine inoculated DCs was shown to inhibit IDO1 biosynthesis. This experimental outcome suggests vaccine activation of the TNFR super-family receptor pathway leads to upregulation of IDO1 biosynthesis in CTB-INS inoculated dendritic cells. Together, our experimental data suggest the CTB-INS vaccine uses a TNFR-dependent signaling pathway of the non-canonical NF-κB signaling pathway resulting in suppression of dendritic cell mediated type 1 diabetes autoimm...Continue Reading

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Citations

Apr 12, 2017·Frontiers in Immunology·Jacques C MbongueWilliam H R Langridge
Mar 16, 2018·Frontiers in Immunology·Emilia VendelovaManfred B Lutz
Jun 6, 2017·Nature Reviews. Immunology·Shao-Cong Sun
May 31, 2017·Vaccines·Christopher ConchaCristian Ibáñez
Dec 10, 2020·BioMed Research International·Jingjing WangGuixiang Tai
Mar 27, 2019·Cellular Immunology·Nan-Sun KimWilliam Langridge

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Methods Mentioned

BETA
ubiquitination
nuclear translocation
phase contrast microscopy
electrophoresis
transfection
fluorescence microscopy
PCR
immunoprecipitation
Chip
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