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 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.
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Byungki
authors.initials: B
authors.lastname: Jang
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Ho Won
authors.initials: HW
authors.lastname: Kim
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Kim
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Bo Ryeong
authors.initials: BR
authors.lastname: Lee
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Sojeong
authors.initials: S
authors.lastname: Kim
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Kim
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Seung Jung
authors.initials: SJ
authors.lastname: Han
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.affiliation: *Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea sjshin@yuhs.ac.
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000494:pharmacology; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000076342:Protein-Arginine Deiminases; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D016207:Cytokines; D008070:Lipopolysaccharides; C558727:N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide; D016328:NF-kappa B; D051193:Toll-Like Receptors; D009952:Ornithine; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases
keywords: Cl-amidine; citrullination; cytokine