Development and characterization of a high-throughput in vitro cord formation model insensitive to VEGF inhibition.

Background: Anti-VEGF therapy reduces tumor blood vessels, however, some vessels always remain. These VEGF insensitive vessels may help support continued tumor growth and metastases. Many in vitro assays examining multiple steps of the angiogenic process have been described, but the majority of these assays are sensitive to VEGF inhibition.

Post-transcriptional regulation of macrophage ABCA1, an early response gene to IFN-gamma.

Interferon-gamma (IFN-gamma) down-regulates receptors associated with reverse cholesterol transport including ABCA1. In the present study, the kinetics and mechanism of ABCA1 down-regulation were determined in mouse peritoneal macrophages. IFN-gamma decreased ABCA1 mRNA 1h following IFN-gamma addition and was maximally reduced by 3h.

The human Burkitt lymphoma cell line Namalwa represents a homogenous cell system characterized by high levels of Toll-like receptor 9 and activation by CpG oligonucleotides.

Human B cells and plasmacytoid dendritic cells constitutively express Toll-like receptor (TLR)9 and respond to TLR9 ligands, as evidenced by nuclear factor kappa B translocation and cytokine secretion. However, TLR9 expression on B lymphocytes appears to be dependent upon both the state of activation and differentiation of the B cell population. In the current study, TLR9 mRNA expression was evaluated in transformed human B cell lines and correlated with their response to CpG.

Histone deacetylase inhibition results in decreased macrophage CD9 expression.

Histone deacetylase (HDAC) inhibitors have been demonstrated to regulate myeloid cell differentiation. In the present study the effects of the HDAC inhibitor trichostatin A (TSA) on the tetraspanin cell surface antigen CD9 were determined in primary murine macrophages. TSA inhibited CD9 protein and message expression and was optimal by 48 h.

Peroxisome proliferator-activated receptor alpha,gamma coagonist LY465608 inhibits macrophage activation and atherosclerosis in apolipoprotein E knockout mice.

The apolipoprotein E (apoE) knockout mouse has provided an approach to the investigation of the effect of both cellular and humoral processes on atherosclerotic lesion progression. In the present study, pharmacologic modulation of both interferon gamma (IFNgamma)-inducible macrophage effector functions, and atherosclerotic lesions in the apoE knockout mouse were investigated using the peroxisome proliferator-activated receptor (PPAR) alpha,gamma coagonist LY465608. LY465608 inhibited, in a concentration-dependent manner, IFNgamma induction of both nitric oxide synthesis and the beta 2 integrin CD11a in elicited peritoneal macrophages from apoE knockout mice.

Interferon-gamma-mediated downregulation of cholesterol efflux and ABC1 expression is by the Stat1 pathway.

The pathological role of interferon-gamma (IFN-gamma) in atherosclerosis is mediated through effects on macrophages, foam cells, and other vascular cells. Recently, we reported that ATP-binding cassette transporter 1(ABC1) message and protein levels were decreased 3- to 4-fold in foam cells by IFN-gamma. In the present study, the pathway by which IFN-gamma inhibited ABC1 expression was investigated with signal transducers and activators of transcription (Stat1) knockout mice.

Down-regulation of macrophage CD9 expression by interferon-gamma.

CD9, a member of the tetraspanin family is a cell surface marker expressed on myeloid and nonmyeloid as well as on neoplastic cells. The present study has focused on the role of inflammation and macrophage activation in the regulation of CD9 expression. We report that the expression of CD9 on primary cultures of murine peritoneal macrophages was down regulated by Interferon-gamma, IFN-gamma.