bay-11-7082 and Leukemia--Monocytic--Acute

We investigated whether pancreatitis-associated ascitic fluid (PAAF) could induce the expression of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in THP-1 cells and the mechanism(s) involved.. THP-1 cells were divided into control and PAAF groups. The PAAF group was incubated with different final concentrations of PAAF, whereas the control group was incubated with culture medium. Effects and mechanisms were determined by measuring the levels of TNF-α and IL-6 mRNA expression; phospho-p38-MAPK, nuclear factor κB, peroxisome proliferator-activated receptor γ activation; and the effect on the inhibitory activity of SB203580 and BAY-117082.. In response to PAAF, overexpression of TNF-α and IL-6 mRNA was found in THP-1 cells compared with those of the corresponding control (P < 0.05), and in a dose-dependent manner. The levels of phospho-p38 and nuclear factor κB p65 were also increased in different PAAF groups, whereas low expression of peroxisome proliferator-activated receptor γ was found compared with the control group (P < 0.05). Furthermore, we presented that the inflammatory response could be partly alleviated by inhibitors SB203580 or BAY-117082, whereas it was markedly inhibited by the simultaneous treatment of 2 inhibitors.. Pancreatitis-associated ascitic fluid up-regulated proinflammatory cytokines by interfering with proinflammatory and anti-inflammatory signaling pathways, thus exacerbating activation in acute pancreatitis.

Topics: Acute Disease; Apoptosis; Ascitic Fluid; Blotting, Western; Cell Line, Tumor; Cell Survival; Culture Media; Cytokines; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression; Humans; Imidazoles; Inflammation Mediators; Interleukin-6; Leukemia, Monocytic, Acute; Nitriles; p38 Mitogen-Activated Protein Kinases; Pancreatitis; Phosphorylation; PPAR gamma; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sulfones; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Previous studies have shown that elevated homocysteine (Hcy) levels promote the development of atherosclerotic lesions in atherosclerosis-prone animal models. There is evidence that oxidant stress contributes to Hcy's deleterious effects on the vasculature. The accumulation and adhesion of monocytes to the vascular endothelium is a critical event in the development of atherosclerosis. We investigated the effects of Hcy on the interaction between human endothelial cells (EC) (EC line EA.hy 926 and primary human umbilical vein EC [HUVEC]) and the monocytic cell line THP-1, and the impact of vascular oxidant stress and redox-sensitive signaling pathways on these events.. L-Hcy, but not D-Hcy, increases the production of reactive oxygen species inside EC, enhances nuclear factor(NF)-kappaB activation, and stimulates intercellular adhesion molecule-1 (ICAM-1) RNA transcription and cell surface expression. This leads to a time- and dose-dependent increase in monocyte adhesion to ECs. Pretreatment of ECs with superoxide scavengers (MnTBAP and Tiron) or with an inhibitor of NF-kappaB activation abolished Hcy-induced monocyte adhesion, ICAM-1 expression, and nuclear translocation of NF-kappaB.. These findings suggest that reactive oxygen species produced under hyperhomocysteinemic conditions may induce a proinflammatory situation in the vessel wall that initiates and promotes atherosclerotic lesion development.

Topics: Atherosclerosis; Cell Adhesion; Cell Line, Tumor; Dose-Response Relationship, Drug; Endothelium, Vascular; Homocysteine; Humans; Intercellular Adhesion Molecule-1; Isomerism; Leukemia, Monocytic, Acute; Molecular Conformation; Monocytes; NF-kappa B; Nitriles; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction; Sulfones; Superoxides; Umbilical Veins; Vasculitis