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, Sung Jae Shin

Index: J. Leukoc. Biol. 97(2) , 351-62, (2015)

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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 up-regulated 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-κB 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 Cl-amidine-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. © Society for Leukocyte Biology.