Peptidylarginine deiminase inhibition impairs toll-like receptor agonist-induced functional maturation of dendritic cells, resulting in the loss of T cell–proliferative capacity: A partial mechanism with therapeutic potential in inflammatory settings

Byungki Jang, Ho Won Kim, Jong Seok Kim, Woo Sik Kim, Bo Ryeong Lee, Sojeong Kim, Hongmin Kim, Seung Jung Han, Sang-Jun Ha, SungJae Shin

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Cl-amidine, which is a small-molecule inhibitor of PAD, has therapeutic potential for inflammation-mediated diseases. However, little is known regarding the manner by which PAD inhibition by Cl-amidine regulates inflammatory conditions. Here, we investigated the effects of PAD inhibition by Cl-amidine on the functioning of DCs, which are pivotal immune cells that mediate inflammatory diseases. When DC maturation was induced by TLR agonists, reduced cytokine levels (IL-6, IL-1β, and IL- 12p70) were observed in Cl-amidine-treated DCs. Cl-amidine-treated, LPS-activated DCs exhibited alterations in their mature and functional statuses with upregulated antigen uptake, down-regulated CD80, and MHC molecules. In addition, Cl-amidine-treated DCs dysregulated peptide-MHC class formations. Interestingly, the decreased cytokines were independent of MAPK/NF-kB signaling pathways and transcription levels, indicating that PAD inhibition by Cl-amidine may be involved in post-transcriptional steps of cytokine production. Transmission electron microscopy revealed morphotypical changes with reduced dendrites in the Clamidine- treated DCs, along with altered cellular compartments, including fragmented ERs and the formation of foamy vesicles. Furthermore, in vitro and in vivo Cl-amidine treatments impaired the proliferation of naïve CD4+ and CD8+ T cells. Overall, our findings suggest that Cl-amidine has therapeutic potential for treating inflammation-mediated diseases.

Original languageEnglish
Pages (from-to)351-362
Number of pages12
JournalJournal of Leukocyte Biology
Volume97
Issue number2
DOIs
Publication statusPublished - 2015 Jan 1

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Toll-Like Receptors
Dendritic Cells
Therapeutics
Cytokines
Inflammation
protein-arginine deiminase
N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide
NF-kappa B
Dendrites
Transmission Electron Microscopy
Interleukin-1
Interleukin-6
T-Lymphocytes
Antigens
Peptides

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Cite this

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title = "Peptidylarginine deiminase inhibition impairs toll-like receptor agonist-induced functional maturation of dendritic cells, resulting in the loss of T cell–proliferative capacity: A partial mechanism with therapeutic potential in inflammatory settings",
abstract = "Cl-amidine, which is a small-molecule inhibitor of PAD, has therapeutic potential for inflammation-mediated diseases. However, little is known regarding the manner by which PAD inhibition by Cl-amidine regulates inflammatory conditions. Here, we investigated the effects of PAD inhibition by Cl-amidine on the functioning of DCs, which are pivotal immune cells that mediate inflammatory diseases. When DC maturation was induced by TLR agonists, reduced cytokine levels (IL-6, IL-1β, and IL- 12p70) were observed in Cl-amidine-treated DCs. Cl-amidine-treated, LPS-activated DCs exhibited alterations in their mature and functional statuses with upregulated antigen uptake, down-regulated CD80, and MHC molecules. In addition, Cl-amidine-treated DCs dysregulated peptide-MHC class formations. Interestingly, the decreased cytokines were independent of MAPK/NF-kB signaling pathways and transcription levels, indicating that PAD inhibition by Cl-amidine may be involved in post-transcriptional steps of cytokine production. Transmission electron microscopy revealed morphotypical changes with reduced dendrites in the Clamidine- treated DCs, along with altered cellular compartments, including fragmented ERs and the formation of foamy vesicles. Furthermore, in vitro and in vivo Cl-amidine treatments impaired the proliferation of na{\"i}ve CD4+ and CD8+ T cells. Overall, our findings suggest that Cl-amidine has therapeutic potential for treating inflammation-mediated diseases.",
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Peptidylarginine deiminase inhibition impairs toll-like receptor agonist-induced functional maturation of dendritic cells, resulting in the loss of T cell–proliferative capacity : A partial mechanism with therapeutic potential in inflammatory settings. / Jang, Byungki; Kim, Ho Won; Kim, Jong Seok; Kim, Woo Sik; Lee, Bo Ryeong; Kim, Sojeong; Kim, Hongmin; Han, Seung Jung; Ha, Sang-Jun; Shin, SungJae.

In: Journal of Leukocyte Biology, Vol. 97, No. 2, 01.01.2015, p. 351-362.

Research output: Contribution to journalArticle

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AU - Kim, Ho Won

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AU - Ha, Sang-Jun

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