PMID- 29630425 OWN - NLM STAT- MEDLINE DCOM- 20190218 LR - 20190219 IS - 1532-4206 (Electronic) IS - 0743-5800 (Linking) VI - 43 IP - 4 DP - 2018 Nov TI - Suppressive effects of metformin on T-helper 1-related chemokines expression in the human monocytic leukemia cell line THP-1. PG - 228-234 LID - 10.1080/07435800.2018.1460605 [doi] AB - PURPOSE OF THE STUDY: Type 1 and type 2 diabetes mellitus (DM) are chronic T-cell-mediated inflammatory diseases. Metformin is a widely used drug for type 2 DM that reduces the need for insulin in type 1 DM. However, whether metformin has an anti-inflammatory effect for treating DM is unknown. We investigated the anti-inflammatory mechanism of metformin in the human monocytic leukemia cell line THP-1. MATERIALS AND METHODS: The human monocytic leukemia cell line THP-1 was pretreated with metformin and stimulated with lipopolysaccharide (LPS). The production of T-helper (Th)-1-related chemokines including interferon-gamma-induced protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), Th2-related chemokine macrophage-derived chemokine, and the proinflammatory chemokine tumor necrosis factor-alpha was measured using enzyme-linked immunosorbent assay. Intracellular signaling pathways were investigated using Western blot analysis and chromatin immunoprecipitation assay. RESULTS: Metformin suppressed LPS-induced IP-10 and MCP-1 production as well as LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B (NF-kappaB). Moreover, metformin suppressed LPS-induced acetylation of histones H3 and H4 at the IP-10 promoter. CONCLUSIONS: Metformin suppressed the production of Th1-related chemokines IP-10 and MCP-1 in THP-1 cells. Suppressive effects of metformin on IP-10 production might be attributed at least partially to the JNK, p38, ERK, and NF-kappaB pathways as well as to epigenetic regulation through the acetylation of histones H3 and H4. These results indicated the therapeutic anti-inflammatory potential of metformin. FAU - Chen, Yen-Chun AU - Chen YC AD - a Department of Pediatrics , Kaohsiung Municipal Hsiao-Kang Hospital , Kaohsiung , Taiwan. AD - b Department of Pediatrics, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. FAU - Kuo, Chang-Hung AU - Kuo CH AD - c Ta-Kuo Clinic , Kaohsiung , Taiwan. AD - d Department of Pediatrics , Kaohsiung Municipal Ta-Tung Hospital , Kaohsiung , Taiwan. FAU - Tsai, Ying-Ming AU - Tsai YM AD - e Department of Internal Medicine , Kaohsiung Municipal Ta-Tung Hospital , Kaohsiung , Taiwan. AD - f Graduate Institute of Clinical Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan. FAU - Lin, Yi-Ching AU - Lin YC AD - b Department of Pediatrics, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. AD - f Graduate Institute of Clinical Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan. AD - g Department of Laboratory Medicine, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. FAU - Hsiao, Hui-Pin AU - Hsiao HP AD - a Department of Pediatrics , Kaohsiung Municipal Hsiao-Kang Hospital , Kaohsiung , Taiwan. AD - b Department of Pediatrics, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. AD - h Department of Pediatrics, Faculty of Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan. FAU - Chen, Bai-Hsiun AU - Chen BH AD - b Department of Pediatrics, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. AD - g Department of Laboratory Medicine, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. AD - h Department of Pediatrics, Faculty of Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan. FAU - Chen, Yi-Ting AU - Chen YT AD - b Department of Pediatrics, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. FAU - Wang, Shih-Ling AU - Wang SL AD - b Department of Pediatrics, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. FAU - Hung, Chih-Hsing AU - Hung CH AD - a Department of Pediatrics , Kaohsiung Municipal Hsiao-Kang Hospital , Kaohsiung , Taiwan. AD - b Department of Pediatrics, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan. AD - h Department of Pediatrics, Faculty of Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan. AD - i Research Center for Environmental Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan. LA - eng PT - Journal Article DEP - 20180409 PL - England TA - Endocr Res JT - Endocrine research JID - 8408548 RN - 0 (Chemokine CCL2) RN - 0 (Chemokines) RN - 0 (Hypoglycemic Agents) RN - 0 (Lipopolysaccharides) RN - 0 (Tumor Necrosis Factor-alpha) RN - 9100L32L2N (Metformin) SB - IM MH - Acetylation MH - Chemokine CCL2/metabolism MH - Chemokines/*metabolism MH - Humans MH - Hypoglycemic Agents/*pharmacology MH - Lipopolysaccharides/pharmacology MH - Metformin/*pharmacology MH - Monocytes/*drug effects/metabolism MH - Phosphorylation/drug effects MH - Promoter Regions, Genetic MH - Signal Transduction/drug effects MH - THP-1 Cells MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - Diabetes mellitus OT - T-helper 1-related chemokine OT - interferon-gamma-induced protein-10 OT - metformin OT - monocyte EDAT- 2018/04/10 06:00 MHDA- 2019/02/20 06:00 CRDT- 2018/04/10 06:00 PHST- 2018/04/10 06:00 [pubmed] PHST- 2019/02/20 06:00 [medline] PHST- 2018/04/10 06:00 [entrez] AID - 10.1080/07435800.2018.1460605 [doi] PST - ppublish SO - Endocr Res. 2018 Nov;43(4):228-234. doi: 10.1080/07435800.2018.1460605. Epub 2018 Apr 9.