title: Procyanidin dimer B2-mediated IRAK-M induction negatively regulates TLR4 signaling in macrophages.
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.
authors.affiliation: Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185, South Korea.
authors.forename: Nak-Yun
authors.initials: NY
authors.lastname: Sung
authors.forename: Mi-So
authors.initials: MS
authors.lastname: Yang
authors.forename: Du-Sub
authors.initials: DS
authors.lastname: Song
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Kim
authors.forename: Jong-Heum
authors.initials: JH
authors.lastname: Park
authors.forename: Beom-Seok
authors.initials: BS
authors.lastname: Song
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Park
authors.forename: Ju-Woon
authors.initials: JW
authors.lastname: Lee
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Jae-Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Eui-Baek
authors.initials: EB
authors.lastname: Byun
authors.forename: Eui-Hong
authors.initials: EH
authors.lastname: Byun
mesh_terms: D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D044945:Proanthocyanidins / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D044946:Biflavonoids; D044945:Proanthocyanidins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C479580:procyanidin B2; D002392:Catechin; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse
keywords: Cytokine; DTT; FITC; IFN; IL; IL-1 receptor-associated kinase; IRAK; Iκ-B; LPS; MAPK; Mitogen-activated protein kinases; MyD88; NF-κB; Nuclear factor κB; PBS; PE; PMSF; Procyanidin B2; SDS; SOCS1; TIR; TIR domain-containing adapter-inducing interferon-β; TLR; TNF-α; TOLLIP; TRIF; Toll-like receptor; dithiothreitol; fluorescein isothiocyanate; inhibitor of κB; interferon; interleukin; lipopolysaccharide; mitogen-activated protein kinase; myeloid differentiation factor 88; nuclear factor-κB; phenylmethanesulfonyl fluoride; phosphate-buffered saline; phycoerythrin; sodium dodecyl sulfate; suppressor of cytokine signaling 1; toll-interacting protein; toll-like receptor; toll/interleukin-1 receptor homology; tumor necrosis factor-α