Jmjd3 contributes to the control of gene expression in LPS-activated macrophages.
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ABSTRACT:
SUBMITTER: De Santa F
PROVIDER: S-EPMC2752025 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Siglec-E is a murine CD33-related siglec that functions as an inhibitory receptor and is expressed mainly on neutrophils and macrophage populations. Recent studies have suggested that siglec-E is an important negative regulator of lipopolysaccharide (LPS)-toll-like receptor 4 (TLR4) signaling and one report (1) claimed that siglec-E is required for TLR4 endocytosis following uptake of Escherichia coli by macrophages and dendritic cells (DCs). Our attempts to reproduce these observations using cells from wild-type (WT) and siglec-E-deficient mice were unsuccessful. We used a variety of assays to determine if siglec-E expressed by different macrophage populations can regulate TLR4 signaling in response to LPS, but found no consistent differences in cytokine secretion in vitro and in vivo, comparing three different strains of siglec-E-deficient mice with matched WT controls. No evidence was found that the siglec-E deficiency was compensated by expression of siglecs-F and -G, the other murine inhibitory CD33-related siglecs. Quantitative proteomics was used as an unbiased approach and provided additional evidence that siglec-E does not suppress inflammatory TLR4 signaling. Interestingly, proteomics revealed a siglec-E-dependent alteration in macrophage protein composition that could be relevant to functional responses in host defense. In support of this, siglec-E-deficient mice exhibited enhanced growth of Salmonella enterica serovar Typhimurium in the liver following intravenous infection, but macrophages lacking siglec-E did not show altered uptake or killing of bacteria in vitro. Using various cell types including bone marrow-derived DCs (BMDCs), splenic DCs, and macrophages from WT and siglec-E-deficient mice, we showed that siglec-E is not required for TLR4 endocytosis following E. coli uptake or LPS challenge. We failed to see expression of siglec-E by BMDC even after LPS-induced maturation, but confirmed previous studies that splenic DCs express low levels of siglec-E. Taken together, our findings do not support a major role of siglec-E in regulation of TLR4 signaling functions or TLR4 endocytosis in macrophages or DCs. Instead, they reveal that induction of siglec-E by LPS can modulate the phenotype of macrophages, the functional significance of which is currently unclear.
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Project description:Studies on natural products that can alleviate the inflammatory response of macrophages caused by endotoxin (lipopolysaccharide) continue. This study investigated the anti-inflammatory activity of baicalin related to macrophage activation caused by lipopolysaccharide (LPS). Baicalin is a flavone glycoside found in plants such as Scutellaria baicalensis and Scutellaria lateriflora belonging to the genus Scutellaria. The multiplex cytokine assay (MCA), Griess reagent assay, fluo-4 calcium assay, dihydrorhodamine 123 (DHR123) assay, quantitative RT-PCR, and flow cytometry were performed using RAW 264.7 mouse macrophages. The MCA revealed that baicalin significantly decreased the production of interleukin (IL)-6, granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-2, and RANTES in LPS-stimulated RAW 264.7 macrophages at concentrations of 10, 25, and 50 μM. The DHR123 assay showed that baicalin significantly inhibited reactive oxygen species generation in LPS-stimulated RAW 264.7 macrophages. Flow cytometry revealed that baicalin significantly reduced the levels of phosphorylated p38 MAPK and Fas in LPS-stimulated RAW 264.7 macrophages. Baicalin also inhibited the mRNA expression levels of inflammatory genes such as Chop, Fas, Nos2, Ptgs2, Stat1, c-Jun, c-Fos, and At1a. The IC50 values of baicalin for IL-6, TNF-α, G-CSF, VEGF, interferon gamma-induced protein 10 (IP-10), leukemia inhibitory factor (LIF), lipopolysaccharide-induced CXC chemokine (LIX), MIP-1α, MIP-1β, MIP-2, RANTES, nitric oxide, intracellular calcium, and hydrogen peroxide were 591.3, 450, 1719, 27.68, 369.4, 256.6, 230.7, 856.9, 1326, 1524, 378.1, 26.76, 345.1, and 32.95 μM, respectively. Baicalin modulated the inflammatory response of macrophages activated by LPS via the calcium-CHOP pathway.
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