Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently

Naoki Sato,1,2 Yuya Nakamura,1,3 Shiho Yamadera,4 Masahiro Inagaki,1,5 Sachiyo Kenmotsu,5 Hiroshi Saito,4,6 Tatsunori Oguchi,1 Mayumi Tsuji,1 Hirokazu Chokki,1 Isao Ohsawa,3 Hiromichi Gotoh,3 Shinichi Iwai,6 Yuji Kiuchi1 1Department of Pharmacology, Showa University School of Medicine, Shinagawa-ku,...

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Autores principales:	Sato N, Nakamura Y, Yamadera S, Inagaki M, Kenmotsu S, Saito H, Oguchi T, Tsuji M, Chokki H, Ohsawa I, Gotoh H, Iwai S, Kiuchi Y
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	linagliptin lipopolysaccharide lipopolysaccharide-binding protein interleukin-6 intranuclear subunit of nuclear factor-κB/p65 intracellular reactive oxygen species Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/71a3fb4bd53e4f08ac724daa0c043192
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id	oai:doaj.org-article:71a3fb4bd53e4f08ac724daa0c043192
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	linagliptin lipopolysaccharide lipopolysaccharide-binding protein interleukin-6 intranuclear subunit of nuclear factor-κB/p65 intracellular reactive oxygen species Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	linagliptin lipopolysaccharide lipopolysaccharide-binding protein interleukin-6 intranuclear subunit of nuclear factor-κB/p65 intracellular reactive oxygen species Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Sato N Nakamura Y Yamadera S Inagaki M Kenmotsu S Saito H Oguchi T Tsuji M Chokki H Ohsawa I Gotoh H Iwai S Kiuchi Y Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently
description	Naoki Sato,1,2 Yuya Nakamura,1,3 Shiho Yamadera,4 Masahiro Inagaki,1,5 Sachiyo Kenmotsu,5 Hiroshi Saito,4,6 Tatsunori Oguchi,1 Mayumi Tsuji,1 Hirokazu Chokki,1 Isao Ohsawa,3 Hiromichi Gotoh,3 Shinichi Iwai,6 Yuji Kiuchi1 1Department of Pharmacology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan; 2Department of Research Center, Tanabe Pharmacy Inc., Tokyo, Japan; 3Department of Nephrology, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan; 4Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan; 5Fuculty of Arts and Sciences at Fujiyoshida, Showa University, Fujiyoshida City, Yamanashi-ken, Japan; 6Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, JapanCorrespondence: Yuya NakamuraDepartment of Pharmacology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, JapanTel +81-3-3784-8125Fax +81-3-3787-4790Email y.nakamura@med.showa-u.ac.jpPurpose: Dipeptidyl peptidase-4 inhibitors, including linagliptin, prevent inflammation. However, the in vitro effects of linagliptin are unclear. Moreover, although linagliptin inhibits lipopolysaccharide (LPS)-induced inflammation, the anti-inflammatory effects of linagliptin in this context are not concentration-dependent. In the absence of LPS-binding protein (LBP), the pro-inflammatory effects of LPS involve pathways other than the Toll-like receptor (TLR) 4 pathway. Here, we aimed to determine the anti-inflammatory mechanisms of linagliptin in an experimental model in which LBP was added to the medium.Methods: Human U937 monocytes were cultured at 1 × 106 cells/mL in Roswell Park Memorial Institute medium and differentiated into macrophages using phorbol myristate acetate. All processes were carried out in medium containing 10% fetal bovine serum (FBS). After 48 hrs of culture, we replaced the medium and pretreated the cells with 100, 250, 500, or 2500 nM linagliptin for 1 hr. We exchanged the medium again, and the cells were treated with 1 ng/mL LPS with or without 100, 250, 500, or 2500 nM linagliptin. Interleukin (IL)-6 and LBP in the supernatant, nuclear factor (NF)-κB/p65 in the nucleus, and reactive oxygen species (ROS) in the cells, as important markers of the mechanism of inflammation induction by LPS, were measured using enzyme-linked immunosorbent assay kits.Results: Linagliptin significantly prevented LPS-stimulated IL-6 production and intranuclear NF-κB/p65 levels in a concentration-dependent manner. LPS-induced intracellular ROS levels were significantly decreased by linagliptin at all concentrations. LBP levels were markedly higher in FBS-containing medium than in medium without FBS. However, LBP levels did not change following administration of linagliptin and/or LPS.Conclusion: Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment in the context of LPS-induced pro-inflammatory responses. Thus, our findings suggested that linagliptin induced two different mechanisms to repress inflammation, i.e., TLR4-dependent and -independent mechanisms.Keywords: linagliptin, lipopolysaccharide-binding protein, interleukin-6, intranuclear subunit of nuclear factor-κB/p65, reactive oxygen species
format	article
author	Sato N Nakamura Y Yamadera S Inagaki M Kenmotsu S Saito H Oguchi T Tsuji M Chokki H Ohsawa I Gotoh H Iwai S Kiuchi Y
author_facet	Sato N Nakamura Y Yamadera S Inagaki M Kenmotsu S Saito H Oguchi T Tsuji M Chokki H Ohsawa I Gotoh H Iwai S Kiuchi Y
author_sort	Sato N
title	Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently
title_short	Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently
title_full	Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently
title_fullStr	Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently
title_full_unstemmed	Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently
title_sort	linagliptin inhibits lipopolysaccharide-induced inflammation concentration-dependently and -independently
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/71a3fb4bd53e4f08ac724daa0c043192
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spelling	oai:doaj.org-article:71a3fb4bd53e4f08ac724daa0c0431922021-12-02T08:11:42ZLinagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently1178-7031https://doaj.org/article/71a3fb4bd53e4f08ac724daa0c0431922019-10-01T00:00:00Zhttps://www.dovepress.com/linagliptin-inhibits-lipopolysaccharide-induced-inflammation-concentra-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Naoki Sato,1,2 Yuya Nakamura,1,3 Shiho Yamadera,4 Masahiro Inagaki,1,5 Sachiyo Kenmotsu,5 Hiroshi Saito,4,6 Tatsunori Oguchi,1 Mayumi Tsuji,1 Hirokazu Chokki,1 Isao Ohsawa,3 Hiromichi Gotoh,3 Shinichi Iwai,6 Yuji Kiuchi1 1Department of Pharmacology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan; 2Department of Research Center, Tanabe Pharmacy Inc., Tokyo, Japan; 3Department of Nephrology, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan; 4Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan; 5Fuculty of Arts and Sciences at Fujiyoshida, Showa University, Fujiyoshida City, Yamanashi-ken, Japan; 6Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, JapanCorrespondence: Yuya NakamuraDepartment of Pharmacology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, JapanTel +81-3-3784-8125Fax +81-3-3787-4790Email y.nakamura@med.showa-u.ac.jpPurpose: Dipeptidyl peptidase-4 inhibitors, including linagliptin, prevent inflammation. However, the in vitro effects of linagliptin are unclear. Moreover, although linagliptin inhibits lipopolysaccharide (LPS)-induced inflammation, the anti-inflammatory effects of linagliptin in this context are not concentration-dependent. In the absence of LPS-binding protein (LBP), the pro-inflammatory effects of LPS involve pathways other than the Toll-like receptor (TLR) 4 pathway. Here, we aimed to determine the anti-inflammatory mechanisms of linagliptin in an experimental model in which LBP was added to the medium.Methods: Human U937 monocytes were cultured at 1 × 106 cells/mL in Roswell Park Memorial Institute medium and differentiated into macrophages using phorbol myristate acetate. All processes were carried out in medium containing 10% fetal bovine serum (FBS). After 48 hrs of culture, we replaced the medium and pretreated the cells with 100, 250, 500, or 2500 nM linagliptin for 1 hr. We exchanged the medium again, and the cells were treated with 1 ng/mL LPS with or without 100, 250, 500, or 2500 nM linagliptin. Interleukin (IL)-6 and LBP in the supernatant, nuclear factor (NF)-κB/p65 in the nucleus, and reactive oxygen species (ROS) in the cells, as important markers of the mechanism of inflammation induction by LPS, were measured using enzyme-linked immunosorbent assay kits.Results: Linagliptin significantly prevented LPS-stimulated IL-6 production and intranuclear NF-κB/p65 levels in a concentration-dependent manner. LPS-induced intracellular ROS levels were significantly decreased by linagliptin at all concentrations. LBP levels were markedly higher in FBS-containing medium than in medium without FBS. However, LBP levels did not change following administration of linagliptin and/or LPS.Conclusion: Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment in the context of LPS-induced pro-inflammatory responses. Thus, our findings suggested that linagliptin induced two different mechanisms to repress inflammation, i.e., TLR4-dependent and -independent mechanisms.Keywords: linagliptin, lipopolysaccharide-binding protein, interleukin-6, intranuclear subunit of nuclear factor-κB/p65, reactive oxygen speciesSato NNakamura YYamadera SInagaki MKenmotsu SSaito HOguchi TTsuji MChokki HOhsawa IGotoh HIwai SKiuchi YDove Medical Pressarticlelinagliptinlipopolysaccharidelipopolysaccharide-binding proteininterleukin-6intranuclear subunit of nuclear factor-κB/p65intracellular reactive oxygen speciesPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 12, Pp 285-291 (2019)

Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently And -Independently

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