Angiotensin II (ANG II)-induced interleukin (IL)-6 synthesis requires NAD(P)H-oxidase-derived superoxide anions. Since NAD(P)H-oxidase activation by cytokines involves 5-lipoxygenase (LOX)-derived leukotriene B-4 (LTB4) formation, we postulated that LTB4 is involved in the ANG II-dependent NAD(P)H-oxidase activation. Therefore, 5-LOX expression and LTB4 formation following ANG II (100 nM) stimulation were determined in rat aortic smooth muscle cells (SMC). Reactive oxygen species (ROS)-formation and IL-6 mRNA expression were analyzed following ANG II and LTB4 (0.6 muM) stimulation. 5-LOX mRNA and protein were detected in SMC. ANG II-induced LTB4 formation at 2.5 min and was followed by an increase in ROS-formation and IL-6 mRNA expression. Blockade of 5-LOX by MK886 (200 nM) abrogated LTB4-formation, ROS-formation, and IL-6 mRNA expression. Moreover, LTB4-induced ROS-formation and IL-6 mRNA expression was abolished by NAD(P)H-oxidase inhibition using diphenyleneiodonium chloride (DPI 10 muM). In conclusion, the present study demonstrates that ANG II enhances LTB4-formation in an 5-LOX dependent manner. LTB4 activates the vascular type NAD(P)H-oxidase, leading to an increase in IL-6 transcripts. (C) 2003 Elsevier Inc. All rights reserved.