Yi-Ching Lin1,2,3,4, Yen-Chun Chen2,5, Hui-Pin Hsiao2, Chang-Hung Kuo6,7, Bai-Hsiun Chen1,2,4,8, Yi-Ting Chen2, Shih-Ling Wang2, Mei-Lan Tsai2, Chih-Hsing Hung9,10,11,12. 1. Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No.100, Tzyou 1st Road, Sanmin District, Kaohsiung City, 807, Taiwan, Republic of China. 2. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No.100, Tzyou 1st Road, Sanmin District, Kaohsiung City, 807, Taiwan, Republic of China. 3. Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, No.100, Shihchuan 1st Road, Sanmin District, Kaohsiung City, 807, Taiwan, Republic of China. 4. Research Center for Environmental Medicine, Kaohsiung Medical University, No.100, Shihchuan 1st Road, Sanmin District, Kaohsiung City, 807, Taiwan, Republic of China. 5. Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, No.482, Shanming Road, Siaogang District, Kaohsiung City, 812, Taiwan, Republic of China. 6. Ta-Kuo Clinic, No.69, Ziqiang 2nd Road, Cianjin District, Kaohsiung City, 144, Taiwan, Republic of China. 7. Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, No.68, Jhonghua 3rd Road, Cianjin District, Kaohsiung City, 145, Taiwan, Republic of China. 8. Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, No.100, Shihchuan 1st Road, Sanmin District, Kaohsiung City, 807, Taiwan, Republic of China. 9. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No.100, Tzyou 1st Road, Sanmin District, Kaohsiung City, 807, Taiwan, Republic of China. pedhung@gmail.com. 10. Research Center for Environmental Medicine, Kaohsiung Medical University, No.100, Shihchuan 1st Road, Sanmin District, Kaohsiung City, 807, Taiwan, Republic of China. pedhung@gmail.com. 11. Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, No.482, Shanming Road, Siaogang District, Kaohsiung City, 812, Taiwan, Republic of China. pedhung@gmail.com. 12. Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, No.100, Shihchuan 1st Road, Sanmin District, Kaohsiung City, 807, Taiwan, Republic of China. pedhung@gmail.com.
Abstract
BACKGROUND AND OBJECTIVES: Chronic inflammation induced by proinflammatory cytokines and chemokines is postulated to be involved in insulin resistance and β-cell dysfunction in type 2 diabetes mellitus (T2DM). Acarbose, the α-glucosidase inhibitor, is an oral antidiabetic drug for T2DM. Acarbose suppresses inflammatory cytokine production in patients with T2DM, though the underlying mechanisms are unclear. In the present study, we aimed to investigate the anti-inflammatory effects and the exact mechanisms of acarbose in human monocytic THP-1 cells. METHODS: THP-1 cells were pretreated with acarbose and then stimulated with lipopolysaccharide (LPS). The levels of Th1-related chemokines, including interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), Th2-related chemokine macrophage-derived chemokine (MDC), and proinflammatory cytokine tumor necrosis factor-α (TNF-α), were determined by enzyme-linked immunosorbent assay. Intracellular signaling pathways were explored by Western blot analysis and using a chromatin immunoprecipitation assay. RESULTS: Acarbose suppressed the levels of IP-10, MCP-1, MDC, and TNF-α and downregulated phosphorylation of p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B-p65 (NF-κB-p65) in LPS-stimulated THP-1 cells. Acarbose suppressed LPS-induced acetylation of histones H3 (H3) and H4 in the IP-10 and MCP-1 promoter regions. These findings revealed the suppressive effects of acarbose on IP-10, MCP-1, MDC, and TNF-α production in THP-1 cells via, at least partially, the p38, JNK, ERK, and NF-κB-p65 pathways, as well as through epigenetic regulation via histone H3 and H4 acetylation. CONCLUSION: Our study points to the therapeutic anti-inflammatory potential of acarbose.
BACKGROUND AND OBJECTIVES: Chronic inflammation induced by proinflammatory cytokines and chemokines is postulated to be involved in insulin resistance and β-cell dysfunction in type 2 diabetes mellitus (T2DM). Acarbose, the α-glucosidase inhibitor, is an oral antidiabetic drug for T2DM. Acarbose suppresses inflammatory cytokine production in patients with T2DM, though the underlying mechanisms are unclear. In the present study, we aimed to investigate the anti-inflammatory effects and the exact mechanisms of acarbose in human monocytic THP-1 cells. METHODS: THP-1 cells were pretreated with acarbose and then stimulated with lipopolysaccharide (LPS). The levels of Th1-related chemokines, including interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), Th2-related chemokine macrophage-derived chemokine (MDC), and proinflammatory cytokine tumor necrosis factor-α (TNF-α), were determined by enzyme-linked immunosorbent assay. Intracellular signaling pathways were explored by Western blot analysis and using a chromatin immunoprecipitation assay. RESULTS:Acarbose suppressed the levels of IP-10, MCP-1, MDC, and TNF-α and downregulated phosphorylation of p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B-p65 (NF-κB-p65) in LPS-stimulated THP-1 cells. Acarbose suppressed LPS-induced acetylation of histones H3 (H3) and H4 in the IP-10 and MCP-1 promoter regions. These findings revealed the suppressive effects of acarbose on IP-10, MCP-1, MDC, and TNF-α production in THP-1 cells via, at least partially, the p38, JNK, ERK, and NF-κB-p65 pathways, as well as through epigenetic regulation via histone H3 and H4 acetylation. CONCLUSION: Our study points to the therapeutic anti-inflammatory potential of acarbose.