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

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 demonstr...

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Bibliographic Details
Published in:PloS one 2016-02, Vol.11 (2), p.e0147509
Main Authors: Kim, Nan-Sun, Mbongue, Jacques C, Nicholas, Dequina A, Esebanmen, Grace E, Unternaehrer, Juli J, Firek, Anthony F, Langridge, William H R
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Autoimmunity
Autoimmunity - drug effects
Base Sequence
Biochemistry
Biology and life sciences
Biosynthesis
Cholera
Cholera toxin
Cholera Toxin - biosynthesis
Cholera Toxin - genetics
Cholera Toxin - immunology
Cholera toxin B subunit
Chromatin
Dendritic cells
Dendritic Cells - drug effects
Dendritic Cells - immunology
Dendritic Cells - pathology
Diabetes
Diabetes mellitus
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 1 - immunology
Diabetes Mellitus, Type 1 - pathology
Diabetes Mellitus, Type 1 - therapy
Dioxygenase
Gene Expression Regulation
Health disparities
Humans
Hyperglycemia
I-kappa B Kinase - genetics
I-kappa B Kinase - immunology
I-kappa B Kinase - metabolism
Immunology
Immunoprecipitation
Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology
Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism
Infections
Insulin
Kinases
Ligands
Mammals
Medicine
Medicine and Health Sciences
Mice
Mice, Inbred NOD
Molecular Sequence Data
NF-kappa B - genetics
NF-kappa B - immunology
NF-kappa B - metabolism
NF-kappaB-Inducing Kinase
NF-κB protein
Peptides
Phosphorylation
Physicians
Proinsulin - biosynthesis
Proinsulin - genetics
Proinsulin - immunology
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - immunology
Protein Serine-Threonine Kinases - metabolism
Proteins
Public health
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - immunology
RelB protein
Research and Analysis Methods
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Signal Transduction
siRNA
Stimulation
TNF Receptor-Associated Factor 2 - pharmacology
TNF Receptor-Associated Factor 3 - pharmacology
TNF Receptor-Associated Factor 6 - pharmacology
TRAF6 protein
Tryptophan
Tumor necrosis factor receptors
Tumor necrosis factor-TNF
Vaccines
Vaccines - administration & dosage
Waterborne diseases
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Summary: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 autoimmunity.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0147509