title: 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.
authors.affiliation: Section of Periodontology, Kyushu University Faculty of Dental Science, Fukuoka, Japan;
authors.forename: Takanori
authors.initials: T
authors.lastname: Shinjo
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakatsu
authors.affiliation: Section of Periodontology, Kyushu University Faculty of Dental Science, Fukuoka, Japan;
authors.forename: Misaki
authors.initials: M
authors.lastname: Iwashita
authors.affiliation: Department of Dental Science for Health Promotion, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan;
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sano
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan;
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.affiliation: Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Tokyo, Japan;
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.affiliation: Division of Diabetes and Metabolism, Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan; and.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.affiliation: Section of Periodontology, Kyushu University Faculty of Dental Science, Fukuoka, Japan;
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Section of Periodontology, Kyushu University Faculty of Dental Science, Fukuoka, Japan;
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Section of Periodontology, Kyushu University Faculty of Dental Science, Fukuoka, Japan;
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.affiliation: Section of Periodontology, Kyushu University Faculty of Dental Science, Fukuoka, Japan;
authors.forename: Fusanori
authors.initials: F
authors.lastname: Nishimura
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; tasano@hiroshima-u.ac.jp.
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D016207:Cytokines / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D016328:NF-kappa B; D011743:Pyrimidines; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; C583175:anagliptin