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PLoS One. 2016 Feb 16;11(2):e0147509. doi: 10.1371/journal.pone.0147509. eCollection 2016.

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

Author information

1
Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, United States of America.
2
Department of Molecular Biology, Chonbuk National University, Jeon-Ju, Republic of Korea.
3
Loma Linda University School of Medicine, Department of Basic Sciences, Division of Physiology, Loma Linda, California, United States of America.
4
Loma Linda University School of Medicine, Department of Basic Sciences, Division of Biochemistry, Loma Linda, California, United States of America.
5
Loma Linda University School of Medicine, Department of Earth and Biological Sciences, Loma Linda, California, United States of America.
6
Endocrinology Section, JL Pettis Memorial VA Medical Center, Loma Linda, California, United States of America.

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 autoimmunity.

PMID:
26881431
PMCID:
PMC4755608
DOI:
10.1371/journal.pone.0147509
[Indexed for MEDLINE]
Free PMC Article

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