DPP-4 Inhibitors Repress NLRP3 Inflammasome and Interleukin-1beta via GLP-1 Receptor in Macrophages Through Protein Kinase C Pathway
Abstract
Background Anti-atherosclerotic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown in many studies. Since inflammation and immune response play a key role in atherogenesis, we examined the effect of DPP-4 inhibitors on the expression of nod-like receptor family, pyrin domain containing 3 (NLRP3) Inflammasome and Interleukin-1beta (IL-1β) in human macrophages. Methods and results THP-1 macrophages were incubated with oxidized low density lipoprotein (ox-LDL) with or without DPP-4 inhibitors (sitagliptin and NVPDPP728). The effects of DPP-4 inhibitors on the expression of NLRP3, toll-like receptor 4 (TLR4) and pro-inflammatory cytokine IL-1β were studied. Both DPP-4 inhibitors induced a significant reduction in NLRP3, TLR4 and IL-1β expression; concurrently, there was an increase in glucagon like peptide 1 receptor (GLP-1R) expression. Simultaneously, DPP-4 inhibitors reduced phosphorylated-PKC, but not PKA, levels. To determine the role of PKC activation in the effects of DPP-4 inhibitors, cells were treated with PMA- which blocked the effect of DPP-4 inhibitors on NLRP3 and IL-1β as well as TLR4 and GLP-1R. Over-expression of GLP-1R in macrophages with its agonist liraglutide also blocked the effects of PMA. Conclusion DPP-4 inhibitors suppress NLRP3, TLR4 and IL-1β in human macrophages through inhibition of PKC activity. This study provides novel insights into the mechanism of inhibition of inflammatory state and immune response in atherosclerosis by DPP-4 inhibitors.
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Sitagliptin (25 μM), NVP-DPP728 (270 μM), or liraglutide (1000 ng/mL) treatment significantly reduced oxidized-LDL-induced or PKC activator-induced protein expression of NLRP3, TLR4, and IL-1β in a human monocytic cell line, THP-1, by decreasing phosphorylated-PKC.
“Sitagliptin (25 μM), NVP-DPP728 (270 μM), or liraglutide (1000 ng/mL) treatment significantly reduced oxidized-low-density lipoprotein-induced or PKC activator-induced protein expression of nucleotide-binding domain-like receptor with a pyrin domain 3 (NLRP3), toll-like receptor 4 (TLR4), and IL-1β in a human monocytic cell line, THP-1, by decreasing phosphorylated-protein kinase C (PKC) [64].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [64]
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“OxLDL binds to the scavenger receptors on membrane of macrophages, and stimulates a number of proinflammatory cytokines such as IL-1β that play a role in the progression of atherosclerosis [3,4].”
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“Sitagliptin (25 𝜇M), NVP-DPP728 (270 𝜇M), or liraglutide (1000 ng/mL) treatment significantly reduced oxidizedlow-density lipoprotein-induced or PKC activator-induced protein expression of nucleotide-binding domain-like receptor with a pyrin domain 3 (NLRP3), toll-like receptor 4 (TLR4), and IL-1𝛽 in a human monocytic…”
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- Authors
- Dai, Y., Dai, D., Wang, X., Ding, Z., & Mehta, J. L.
- Affiliations
- Central Arkansas Veterans Healthcare System (US)
- First Affiliated Hospital of Anhui Medical University (CN)
- Corresponding author
- Dai, Dongsheng
- Mehta, Jawahar L.
- Venue
- Cardiovascular Drugs and Therapy
- Published
- 2014-07-15
- Volume
- 28
- Issue
- 5
- Pages
- 425-432
- ISSN
- 0920-3206 (ISSN-L)
- 1573-7241
- OpenAlex
- W2068938067
- Cited by
- 116
- References
- 1
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 11 · 2021: 12 · 2020: 15 · 2019: 6 · 2018: 11 · 2017: 13 · 2016: 14 · 2015: 10
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cardiovascular Drugs and Therapy (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- U.S. Department of Veterans Affairs (I01 BX000282)
- Office of Research and Development
- Anhui University
- Anhui Medical University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- DPP-4 inhibitors, NLRP3 inflammasome, IL-1β, GLP-1 receptor, protein kinase C, macrophages, atherosclerosis, inflammation, TLR4, sitagliptin, liraglutide, oxidized LDL, anti-inflammatory activity
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Sitagliptin Phosphate, Liraglutide, NLR Family, Pyrin Domain-Containing 3 Protein, Carrier Proteins, Gene Expression Regulation, Humans, Macrophages, Nitriles, Phosphorylation, Protein Kinase C, Pyrazines, Pyrrolidines, Tetradecanoylphorbol Acetate, Triazoles, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Receptors, Glucagon, Cell Culture Techniques, Toll-Like Receptor 4, Glucagon-Like Peptide 1, Interleukin-1beta, Dipeptidyl-Peptidase IV Inhibitors, Inflammasomes
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