TY - JOUR
T1 - Chimeric vaccine stimulation of human dendritic cell indoleamine 2, 3-dioxygenase occurs via the non-canonical NF-kB pathway
AU - Kim, Nan Sun
AU - Mbongue, Jacques C.
AU - Nicholas, Dequina A.
AU - Esebanmen, Grace E.
AU - Unternaehrer, Juli J.
AU - Firek, Anthony F.
AU - Langridge, William H.R.
N1 - Publisher Copyright:
© 2016 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/2
Y1 - 2016/2
N2 - 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-kB-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-kB consensus sequences in the IDO1 promoter, suggesting vaccine stimulation of the non-canonical NF-kB 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-kB signaling pathway resulting in suppression of dendritic cell mediated type 1 diabetes autoimmunity.
AB - 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-kB-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-kB consensus sequences in the IDO1 promoter, suggesting vaccine stimulation of the non-canonical NF-kB 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-kB signaling pathway resulting in suppression of dendritic cell mediated type 1 diabetes autoimmunity.
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U2 - 10.1371/journal.pone.0147509
DO - 10.1371/journal.pone.0147509
M3 - Article
C2 - 26881431
SN - 1932-6203
VL - 11
JO - PLoS ONE
JF - PLoS ONE
IS - 2
M1 - e0147509
ER -