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DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-κB activation.

Abstract
Dipeptidyl peptidase IV (DPP-IV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitate-induced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 μM), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IκBα and phosphorylations of p65, JNK, and p38, as well as NF-κB and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF-κB and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNFα. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 μM concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF-κB transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events.
AuthorsTakanori Shinjo, Yusuke Nakatsu, Misaki Iwashita, Tomomi Sano, Hideyuki Sakoda, Hisamitsu Ishihara, Akifumi Kushiyama, Midori Fujishiro, Toshiaki Fukushima, Yoshihiro Tsuchiya, Hideaki Kamata, Fusanori Nishimura, Tomoichiro Asano
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 309 Issue 3 Pg. E214-23 (Aug 01 2015) ISSN: 1522-1555 [Electronic] United States
PMID26015438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 the American Physiological Society.
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Dipeptidyl-Peptidase IV Inhibitors
  • NF-kappa B
  • Pyrimidines
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse
  • anagliptin
Topics
  • 3T3-L1 Cells
  • Adipocytes, White (drug effects, immunology, metabolism)
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
  • Cell Line, Transformed
  • Coculture Techniques
  • Cytokines (agonists, antagonists & inhibitors, genetics, metabolism)
  • Dipeptidyl Peptidase 4 (chemistry, genetics, metabolism)
  • Dipeptidyl-Peptidase IV Inhibitors (pharmacology, therapeutic use)
  • Gene Expression Regulation (drug effects)
  • Genes, Reporter (drug effects)
  • Liver (drug effects, immunology, metabolism)
  • Macrophages (drug effects, immunology, metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B (agonists, antagonists & inhibitors, genetics, metabolism)
  • Phosphorylation (drug effects)
  • Protein Processing, Post-Translational (drug effects)
  • Pyrimidines (pharmacology, therapeutic use)
  • Response Elements (drug effects)
  • Signal Transduction (drug effects)
  • Systemic Inflammatory Response Syndrome (blood, immunology, metabolism, prevention & control)

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