Procyanidin dimer B2-mediated IRAK-M induction negatively regulates TLR4 signaling in macrophages |
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Authors: | Nak-Yun Sung Mi-So Yang Du-Sub Song Jae-Kyung Kim Jong-Heum Park Beom-Seok Song Sang-Hyun Park Ju-Woon Lee Hyun-Jin Park Jae-Hun Kim Eui-Baek Byun Eui-Hong Byun |
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Institution: | 1. Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185, South Korea;2. Department of Microbiology, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea;3. School of life sciences and Biotechnology, Korea University 5-ka, Anam-Dong, Sungbuk-ku, Seoul 136-701, Republic of Korea;4. Department of Food Science and Technology, Kongju National University, Yesan 340-800, South Korea |
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Abstract: | Polyphenolic compounds have been found to possess a wide range of physiological activities that may contribute to their beneficial effects against inflammation-related diseases; however, the molecular mechanisms underlying this anti-inflammatory activity are not completely characterized, and many features remain to be elucidated. In this study, we investigated the molecular basis for the down-regulation of toll-like receptor 4 (TLR4) signal transduction by procyanidin dimer B2 (Pro B2) in macrophages. Pro B2 markedly elevated the expression of the interleukin (IL)-1 receptor-associated kinase (IRAK)-M protein, a negative regulator of TLR signaling. Lipopolysaccharide (LPS)-induced expression of cell surface molecules (CD80, CD86, and MHC class I/II) and production of pro-inflammatory cytokines (tumor necrosis factor-α, IL-1β, IL-6, and IL-12p70) were inhibited by Pro B2, and this action was prevented by IRAK-M silencing. In addition, Pro B2-treated macrophages inhibited LPS-induced activation of mitogen-activated protein kinases such as extracellular signal-regulated kinase 1/2, p38, and c-Jun N-terminal kinase and the translocation of nuclear factor κB and p65 through IRAK-M. We also found that Pro B2-treated macrophages inactivated naïve T cells by inhibiting LPS-induced interferon-γ and IL-2 secretion through IRAK-M. These novel findings provide new insights into the understanding of negative regulatory mechanisms of the TLR4 signaling pathway and the immune-pharmacological role of Pro B2 in the immune response against the development and progression of many chronic diseases. |
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Keywords: | DTT dithiothreitol FITC fluorescein isothiocyanate IFN interferon Iκ-B inhibitor of κB IL interleukin IRAK IL-1 receptor-associated kinase LPS lipopolysaccharide MAPK mitogen-activated protein kinase MyD88 myeloid differentiation factor 88 NF-κB nuclear factor-κB PBS phosphate-buffered saline PE phycoerythrin PMSF phenylmethanesulfonyl fluoride SDS sodium dodecyl sulfate SOCS1 suppressor of cytokine signaling 1 TIR toll/interleukin-1 receptor homology TLR toll-like receptor TNF-α tumor necrosis factor-α TOLLIP toll-interacting protein TRIF TIR domain-containing adapter-inducing interferon-β |
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