Abstract 155: Novel Antioxidant Compounds Reduce Lipopolysaccharide Induction of Tissue Factor and Cytokines in Human Monocytic and Endothelial Cells by Inhibiting Apoptosis Signal-Regulating Kinase-1 and Mitogen Activated Protein Kinases.
Oxidative stress occurs during the pathogenesis of many diseases, including acute (e.g. sepsis) and chronic (e.g. atherosclerosis) inflammatory diseases. Therefore, antioxidants may be beneficial in the treatment of various inflammatory diseases. We have previously shown that two novel antioxidants derived from probucol (AGI-1067 and AGIX-4207) have anti-inflammatory activity. Currently, AGI-1067 is being evaluated in a phase III clinical trial for the treatment of atherosclerosis. The purpose of this study was to determine if three structurally-related antioxidants (AGI-1067, AGIX-4207 and AGI-1095) inhibited bacterial lipopolysaccharide (LPS) induction of tissue factor (TF) and cytokine (IL-6, TNFα and IL-8) expression in human monocytic and endothelial cells. Pretreatment of THP-1 cells, peripheral blood mononuclear cells, and human aortic endothelial cells (HAECs) with each of these antioxidants inhibited LPS induction of TF and cytokines in a concentration-dependent manner. In contrast, a related compound, AGI-1097, which lacks antioxidant activity, did not affect LPS signaling, suggesting that the compounds are acting by inhibiting oxidative stress. The antioxidants inhibited LPS activation of the p38 and JNK1/2 mitogen activated protein kinases (MAPKs) in THP-1 cells and in HAECs, without affecting LPS-induced nuclear translocation of NF-κB. The antioxidants also inhibited LPS activation of ERK1/2 in THP-1 cells. Importantly, AGI-1067 inhibited LPS activation of the redox-sensitive kinase, apoptosis signal-regulating kinase-1 (ASK1). ASK1 has been shown to be required for LPS activation of p38 and JNK but not NF-κB. Finally, LPS induction of the transcription factors AP-1 and Egr-1 was also inhibited by AGI-1095. Our data indicate that this novel class of antioxidant compounds reduces LPS induction of TF and cytokines in monocytic and endothelial cells by inhibiting ASK1 and MAPK signaling pathways and subsequent activation of the transcription factors AP-1 and Egr-1.