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

Naoki Sato; Yuya Nakamura; Shiho Yamadera; Masahiro Inagaki; Sachiyo Kenmotsu; Hiroshi Saito; Tatsunori Oguchi; Mayumi Tsuji; Hirokazu Chokki; Isao Ohsawa; Hiromichi Gotoh; Shinichi Iwai; Yuji Kiuchi

doi:10.2147/JIR.S221761

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

J Inflamm Res. 2019 Oct 21:12:285-291. doi: 10.2147/JIR.S221761. eCollection 2019.

Authors

Naoki Sato^{1

2}, Yuya Nakamura^{1

3}, Shiho Yamadera⁴, Masahiro Inagaki^{1

5}, Sachiyo Kenmotsu⁵, Hiroshi Saito^{4

6}, Tatsunori Oguchi¹, Mayumi Tsuji¹, Hirokazu Chokki¹, Isao Ohsawa³, Hiromichi Gotoh³, Shinichi Iwai⁶, Yuji Kiuchi¹

Affiliations

¹ Department of Pharmacology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan.
² Department of Research Center, Tanabe Pharmacy Inc., Tokyo, Japan.
³ Department of Nephrology, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan.
⁴ Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan.
⁵ Fuculty of Arts and Sciences at Fujiyoshida, Showa University, Fujiyoshida City, Yamanashi-ken, Japan.
⁶ Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan.

Abstract

Purpose: 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: interleukin-6; intranuclear subunit of nuclear factor-κB/p65; linagliptin; lipopolysaccharide-binding protein; reactive oxygen species.