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Interferon-Gamma Increases Endothelial Permeability by Causing Activation of p38 MAP Kinase and Actin Cytoskeleton Alteration

Ng CT, Fong LY, Sulaiman MR, Moklas MA, Yong YK, Hakim MN, et al.

J Interferon Cytokine Res, 2015 Jul;35(7):513-22.
PMID: 25830506 DOI: 10.1089/jir.2014.0188

Interferon-gamma (IFN-γ) is known to potentiate the progression of inflammatory diseases, such as inflammatory bowel disease and atherosclerosis. IFN-γ has been found to disrupt the barrier integrity of epithelial and endothelial cell both in vivo and in vitro. However, the mechanisms of IFN-γ underlying increased endothelial cell permeability have not been extensively elucidated. We reported that IFN-γ exhibits a biphasic nature in increasing endothelial permeability. The changes observed in the first phase (4-8 h) involve cell retraction and rounding in addition to condensed peripheral F-actin without a significant change in the F-/G-actin ratio. However, cell elongation, stress fiber formation, and an increased F-/G-actin ratio were noticed in the second phase (16-24 h). Consistent with our finding from the permeability assay, IFN-γ induced the formation of intercellular gaps in both phases. A delayed phase of increased permeability was observed at 12 h, which paralleled the onset of cell elongation, stress fiber formation, and increased F-/G-actin ratio. In addition, IFN-γ stimulated p38 mitogen-activated protein (MAP) kinase phosphorylation over a 24 h period. Inhibition of p38 MAP kinase by SB203580 prevented increases in paracellular permeability, actin rearrangement, and increases in the F-/G-actin ratio caused by IFN-γ. Our results suggest that p38 MAP kinase is activated in response to IFN-γ and causes actin rearrangement and altered cell morphology, which in turn mediates endothelial cell hyperpermeability. The F-/G-actin ratio might be involved in the regulation of actin distribution and cell morphology rather than the increased permeability induced by IFN-γ.

Matched MeSH terms: Human Umbilical Vein Endothelial Cells/enzymology*
Fulltext Immunomodulatory effects of 17-O-acetylacuminolide in RAW264.7 cells and HUVECs: involvement of MAPK and NF-κB pathways

Achoui M, Heyninck K, Looi CY, Mustafa AM, Haegeman G, Mustafa MR

Drug Des Devel Ther, 2014;8:1993-2007.
PMID: 25349474 DOI: 10.2147/DDDT.S68659

The terpenoid 17-O-acetylacuminolide (AA) was shown to inhibit the production of several inflammatory mediators. However, the mechanisms by which this compound elicited its anti-inflammatory activity remain to be elucidated. In this study, we analyzed the effects of AA on inflammatory gene expression in two different cell types with primordial importance in the inflammatory processes - endothelial cells and macrophages. In human umbilical vein endothelial cells, AA inhibited the expression of inflammatory proteins including the adhesion molecules intercellular adhesion molecule 1; vascular cell adhesion molecule 1; and E-selectin, as well as the release of the chemokine interleukin-8. Additionally, AA hindered the formation of capillary-like tubes in an in vitro model of angiogenesis. AA's effects in endothelial cells can be attributed at least in part to AA's inhibition of tumor necrosis factor alpha-induced nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB)'s translocation. Also, in lipopolysaccharide-stimulated macrophage-like RAW264.7 cells, AA was able to downregulate the expression of the genes cyclooxygenase 2, inducible nitric oxide synthase, interleukin-6, and chemokine (C-C motif) ligand 2. Moreover, AA inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα), IκB kinase (IKK), and the mitogen-activated protein kinases JNK, ERK, and p38. In conclusion, the present results further support the anti-inflammatory potential of AA in different models of inflammation.

Matched MeSH terms: Human Umbilical Vein Endothelial Cells/enzymology
Fulltext In vitro and in vivo anti-angiogenic activities of Panduratin A

Lai SL, Cheah SC, Wong PF, Noor SM, Mustafa MR

PLoS One, 2012;7(5):e38103.
PMID: 22666456 DOI: 10.1371/journal.pone.0038103

BACKGROUND: Targeting angiogenesis has emerged as an attractive and promising strategy in anti-cancer therapeutic development. The present study investigates the anti-angiogenic potential of Panduratin A (PA), a natural chalcone isolated from Boesenbergia rotunda by using both in vitro and in vivo assays.
METHODOLOGY/PRINCIPAL FINDINGS: PA exerted selective cytotoxicity on human umbilical vein endothelial cells (HUVECs) with IC(50) value of 6.91 ± 0.85 µM when compared to human normal fibroblast and normal liver epithelial cells. Assessment of the growth kinetics by cell impedance-based Real-Time Cell Analyzer showed that PA induced both cytotoxic and cytostatic effects on HUVECs, depending on the concentration used. Results also showed that PA suppressed VEGF-induced survival and proliferation of HUVECs. Furthermore, endothelial cell migration, invasion, and morphogenesis or tube formation demonstrated significant time- and dose-dependent inhibition by PA. PA also suppressed matrix metalloproteinase-2 (MMP-2) secretion and attenuated its activation to intermediate and active MMP-2. In addition, PA suppressed F-actin stress fiber formation to prevent migration of the endothelial cells. More importantly, anti-angiogenic potential of PA was also evidenced in two in vivo models. PA inhibited neo-vessels formation in murine Matrigel plugs, and angiogenesis in zebrafish embryos.
CONCLUSIONS/SIGNIFICANCE: Taken together, our study demonstrated the distinctive anti-angiogenic properties of PA, both in vitro and in vivo. This report thus reveals another biological activity of PA in addition to its reported anti-inflammatory and anti-cancer activities, suggestive of PA's potential for development as an anti-angiogenic agent for cancer therapy.

Matched MeSH terms: Human Umbilical Vein Endothelial Cells/enzymology
Fulltext Syzygium campanulatum korth methanolic extract inhibits angiogenesis and tumor growth in nude mice

Aisha AF, Ismail Z, Abu-Salah KM, Siddiqui JM, Ghafar G, Abdul Majid AM

BMC Complement Altern Med, 2013;13:168.
PMID: 23842450 DOI: 10.1186/1472-6882-13-168

Syzygium campanulatum Korth (Myrtaceae) is an evergreen shrub rich in phenolics, flavonoid antioxidants, and betulinic acid. This study sought to investigate antiangiogenic and anti-colon cancer effects of S.C. standardized methanolic extract.

Matched MeSH terms: Human Umbilical Vein Endothelial Cells/enzymology