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- Title
Anti-inflammatory Effects of Empagliflozin and Gemigliptin on LPS-Stimulated Macrophage via the IKK/NF- B, MKK7/JNK, and JAK2/STAT1 Signalling Pathways.
- Authors
Nami Lee; Yu Jung Heo; Choi, Sung-E.; Ja Young Jeon; Seung Jin Han; Dae Jung Kim; Yup Kang; Kwan Woo Lee; Hae Jin Kim; Lee, Nami; Heo, Yu Jung; Jeon, Ja Young; Han, Seung Jin; Kim, Dae Jung; Kang, Yup; Lee, Kwan Woo; Kim, Hae Jin
- Abstract
<bold>Background: </bold>Sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs whose anti-inflammatory properties have recently become useful in tackling metabolic syndromes in chronic inflammatory diseases, including diabetes and obesity. We investigated whether empagliflozin (SGLT2 inhibitor) and gemigliptin (DPP-4 inhibitor) improve inflammatory responses in macrophages, identified signalling pathways responsible for these effects, and studied whether the effects can be augmented with dual empagliflozin and gemigliptin therapy.<bold>Methods: </bold>RAW 264.7 macrophages were first stimulated with lipopolysaccharide (LPS), then cotreated with empagliflozin, gemigliptin, or empagliflozin plus gemigliptin. We conducted quantitative RT-PCR (qRT-PCR) to determine the most effective anti-inflammatory doses without cytotoxicity. We performed ELISA and qRT-PCR for inflammatory cytokines and chemokines and flow cytometry for CD80, the M1 macrophage surface marker, to evaluate the anti-inflammatory effects of empagliflozin and gemigliptin. NF-κB, MAPK, and JAK2/STAT signalling pathways were examined via Western blotting to elucidate the molecular mechanisms of anti-inflammation.<bold>Results: </bold>LPS-stimulated CD80+ M1 macrophages were suppressed by coincubation with empagliflozin, gemigliptin, and empagliflozin plus gemigliptin, respectively. Empagliflozin and gemigliptin (individually and combined) inhibited prostaglandin E2 (PGE2) release and COX-2, iNOS gene expression in LPS-stimulated RAW 264.7 macrophages. These three treatments also attenuated the secretion and mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, and proinflammatory chemokines, such as CCL3, CCL4, CCL5, and CXCL10. All of them blocked NF-κB, JNK, and STAT1/3 phosphorylation through IKKα/β, MKK4/7, and JAK2 signalling.<bold>Conclusions: </bold>Our study demonstrated the anti-inflammatory effects of empagliflozin and gemigliptin via IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 pathway downregulation in macrophages. In all cases, combined empagliflozin and gemigliptin treatment showed greater anti-inflammatory properties.
- Subjects
EMPAGLIFLOZIN; MACROPHAGES; SODIUM-glucose cotransporter 2 inhibitors; WESTERN immunoblotting; FLOW cytometry; TYPE 2 diabetes
- Publication
Journal of Immunology Research, 2021, p1
- ISSN
2314-8861
- Publication type
journal article
- DOI
10.1155/2021/9944880