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Lipopolysaccharide-Induced Nitric Oxide and Prostaglandin E2 Production Is Inhibited by Tellimagrandin II in Mouse and Human Macrophages.

ABSTRACT: Sepsis develops from a serious microbial infection that causes the immune system to go into overdrive. The major microorganisms that induce sepsis are Gram-negative bacteria with lipopolysaccharide (LPS) in their cell walls. Nitric oxide (NO) and cyclooxygenase-2 (COX-2) are the key factors involved in the LPS-induced pro-inflammatory process. This study aimed to evaluate the effects of polyphenol Tellimagrandin II (TGII) on anti-inflammatory activity and its underlying basic mechanism in murine macrophage cell line RAW 264.7 and human monocyte-derived macrophages. Macrophages with more than 90% cell viability were found in the cytotoxicity assay under 50 μM TGII. Pre- or post-treatment with TGII significantly reduced LPS-induced inducible nitric oxide synthase (NOS2) protein and mRNA expression, reducing LPS-induced COX-2 protein. Downstream of NOS2 and COX-2, NO and prostaglandin E2 (PGE2) were significantly inhibited by TGII. Upstream of NOS2 and COX-2, phospho-p65, c-fos and phospho-c-jun were also reduced after pre-treatment with TGII. Mitogen-activated protein kinases (MAPKs) are also critical to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) stimulation, and phospho-p38 expression was found to have been blocked by TGII. TGII efficiently reduces LPS-induced NO production and its upstream regulatory factors, suggesting that TGII may be a potential therapeutic agent for sepsis and other inflammatory diseases.

SUBMITTER: Lin CY

PROVIDER: S-EPMC8146495 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Marantodes pumilum is traditionally used for dysentery, gonorrhea, and sickness in the bones. Previous studies revealed its antibacterial and xanthine oxidase inhibitory activities. Objective:To evaluate the inhibitory effects of three M. pumilum varieties on the secretion of lipopolysaccharide (LPS)- and monosodium urate crystal (MSU)-induced cytokines and plasma prostaglandin E2 (PGE2) in vitro. Materials and Methods:The leaves and roots of M. pumilum var. alata (MPA), M. pumilum var. pumila (MPP), and M. pumilum var. lanceolata (MPL) were successively extracted with dichloromethane (DCM), methanol, and water. Human peripheral blood mononuclear cells and ELISA technique were used for the cytokine assay, whereas human plasma and radioimmunoassay technique were used in the PGE2 assay. Flavonoids content was determined using a reversed-phase high-performance liquid chromatography. Results:DCM extract of MPL roots showed the highest inhibition of LPS-stimulated cytokine secretion with IC50 values of 29.87, 7.62, 5.84, 25.33, and 5.40 ?g/mL for interleukin (IL)-1?, IL-1?, IL-6, IL-8, and tumor necrosis factor (TNF)-?, respectively; while that of plasma PGE2 secretion was given by DCM extract of MPP roots (IC50 31.10 ?g/mL). Similarly, the DCM extract of MPL roots demonstrated the highest inhibition against MSU-stimulated IL-1?, IL-1?, IL-6, IL-8, TNF-?, and PGE2 secretion with IC50 values of 11.2, 8.92, 12.29, 49.51, 9.60, and 31.58 ?g/mL, respectively. Apigenin in DCM extracts of MPL (0.051 mg/g) and MPP (0.064 mg/g) roots could be responsible for the strong inhibitory activity against IL-1?, IL-6, TNF-?, and PGE2. Conclusion:The results suggested that DCM extracts of MPL and MPP roots are potential anti-inflammatory agents by inhibiting the secretion of LPS- and MSU-stimulated pro-inflammatory cytokines and PGE2. SUMMARY:Amongst 18 tested extracts, DCM extracts of MPL and MPP roots remarkably inhibited LPS- and MSU-stimulated pro-inflammatory cytokines and PGE2 secretionPhytochemical analysis was performed for the active extracts using RP-HPLC systemThe presence of flavonoids particularly apigenin could be responsible for the anti-inflammatory activity. Abbreviations used: BSA: Bovine serum albumin, COX-2: Cyclooxygenase-2, CPM: Count per minute, DAMP: Danger-associated molecular pattern, DCM: Dichloromethane, DMSO: Dimethyl sulfoxide, ELISA: Enzyme-linked immunosorbent assay, FBS: Fetal bovine serum, H2O: Water, HEPES: 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, HMC-1: Human mast cell-1, HMGB1: High-mobility group box 1, ICAM: Intercellular adhesion molecule, IFN: Interferon, IgG: Immunoglobulin G, IKK: IkB kinase, IL: Interleukin, iNOS: Inducible nitric oxide synthase, LPS: Lipopolysaccharide, MeOH: Methanol, MPA: Marantodes pumilum var. alata, MPL: Marantodes pumilum var. lanceolata, MPP: Marantodes pumilum var. pumila, MSU: Monosodium urate, MTT: Methylthiazole tetrazolium, NF-?B: Nuclear factor-kappa B, NLR: NOD-like receptor, NLRP3: NLR family pyrin domain containing protein 3, NO: Nitric oxide, NOD: Nucleotide-binding oligomerization domain, NSAID: Nonsteroidal anti-inflammatory drug, PAMP: Pathogen-associated molecular pattern, PBMC: Peripheral blood mononuclear cell, PBS: Phosphate buffered saline, PGE2: Prostaglandin E2, PMACI: Phorbol-12-myristate 13-acetate and calcium ionosphere A23187, PRR: Pathogen recognition receptor, PTFE: Polytetrafluoroethylene, RIA: Radioimmunoassay, RIG: Retinoic acid-inducible gene I, RLR: RIG I-like receptor, RP-HPLC: Reversed-phase high-performance liquid chromatography, RPMI-1640: Roswell Park Memorial Institute-1640, TLR: Toll-like receptor, TNF: Tumor necrosis factor, VCAM: Vascular cell adhesion molecule.

Project description:Interactions between adipocytes and macrophages are associated with metabolic disorders. Production of pro-inflammatory mediators and the release of free fatty acids (FFAs) increase when these cells are co-cultured; butyrate significantly diminishes these effects by suppressing both the macrophage inflammatory and adipocyte lipolysis pathways. Butyrate is known to up-regulate the expression of prostaglandin E2 (PGE2). Therefore, we hypothesized that PGE2 is associated with the suppression of lipolysis by butyrate in co-culture.Using contact or transwell co-culture methods with differentiated 3T3-L1 adipocytes and RAW264.7 macrophages, we investigated the effects of butyrate on the release of PGE2 into the medium and on lipolysis in adipocytes. To elucidate the underlying mechanism, we examined the effects of butyrate on cyclooxygenase-2 (COX2) and phospholipase A2 (PLA2) in co-cultured cells, and cyclic adenine monophosphate (cAMP) and protein kinase A type 1-? regulatory subunit (PRKAR1A) in co-cultured adipocytes. Silent interfering (si)RNA targeting of G-protein-coupled receptor (GPR)41 and 109A was employed to examine the effect on lipolysis in TNF-?-stimulated adipocytes.Co-culture increased PGE2 release into the medium, compared with cells cultured separately. Butyrate significantly increased PGE2 production. Co-culture elevated COX2 expression in macrophages and adipocytes, and butyrate further enhanced this effect. Co-culture enhanced cytosolic PLA2 activity in macrophages, which was further enhanced by butyrate. As for lipolysis, co-culture increased the release of FFAs and free glycerol into the medium, whereas butyrate (and to a lesser extent, PGE2) suppressed FFAs and free glycerol release. An inhibition study using a prostaglandin E receptor 3-selective antagonist suggested that approximately 40% of the suppressive effect of butyrate depends on the PGE2-mediated pathway, whereas 60% depends on a non-PGE2-mediated pathway. Co-culture increased cAMP and PRKAR1A levels in adipocytes, whereas butyrate restored the levels to those of the control. Similarly, in TNF-?-stimulated adipocytes, butyrate reduced FFAs and free glycerol release. siRNA inhibition of GPR41 and GPR109A suggested that the GPR109A-mediated pathway predominates, but the GPR41-mediated pathway also regulates the effect of butyrate on lipolysis in TNF-?-stimulated 3T3-L1 cells.Butyrate attenuates lipolysis in adipocytes co-cultured with macrophages via non-PGE2-mediated and PGE2-mediated pathways.

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Lipopolysaccharide-Induced Nitric Oxide and Prostaglandin E2 Production Is Inhibited by Tellimagrandin II in Mouse and Human Macrophages.

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