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) (LTB(4)) formation, we postulated that LTB(4) is involved in the ANG II-dependent NAD(P)H-oxidase activation. Therefore, 5-LOX expression and LTB(4) formation following ANG II (100nM) 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 LTB(4) (0.6 microM) stimulation. 5-LOX mRNA and protein were detected in SMC. ANG II-induced LTB(4) formation at 2.5min and was followed by an increase in ROS-formation and IL-6 mRNA expression. Blockade of 5-LOX by MK886 (200nM) abrogated LTB(4)-formation, ROS-formation, and IL-6 mRNA expression. Moreover, LTB(4)-induced ROS-formation and IL-6 mRNA expression was abolished by NAD(P)H-oxidase inhibition using diphenyleneiodonium chloride (DPI 10 microM). In conclusion, the present study demonstrates that ANG II enhances LTB(4)-formation in an 5-LOX dependent manner. LTB(4) activates the vascular type NAD(P)H-oxidase, leading to an increase in IL-6 transcripts.