The inflammatory cytokines IL-1beta and IL-6 have been shown to stimulate production of endothelin-1 (ET-1) by several cell types in vitro, but their effects on renal ET-1 production in vivo are not known. To test whether IL-1beta and IL-6 stimulate renal ET-1 production and release in vivo, urine was collected from male C57BL/6 mice over 24-h periods at baseline and on days 7 and 14 of a 14-day subcutaneous infusion of IL-1beta (10 ng/h), IL-6 (16 ng/h), or vehicle. By day 14, plasma ET-1 was significantly increased by IL-1beta infusion (1.7 +/- 0.1 vs. 0.8 +/- 0.1 pg/ml for vehicle, P < 0.001). Compared with vehicle infusion, IL-1beta infusion induced significant increases in urinary ET-1 excretion rate and urine flow but did not affect conscious mean arterial pressure (telemetry). IL-1beta infusion significantly increased renal cortical and medullary IL-1beta content (ELISA) and prepro-ET-1 mRNA expression (quantitative real-time PCR). In contrast, 14 days of IL-6 infusion had no significant effect on plasma ET-1 or urinary ET-1 excretion rate. To determine whether IL-1beta stimulates ET-1 release via activation of NF-kappaB, inner medullary collecting duct (IMCD-3) cells were incubated for 24 h with IL-1beta, and ET-1 release and NF-kappaB activation were measured (ELISA). IL-1beta activated NF-kappaB and increased ET-1 release in a concentration-dependent manner. The effect of IL-1beta on ET-1 release could be partially inhibited by pretreatment of IMCD-3 cells with an inhibitor of NF-kappaB activation (BAY 11-7082). These results indicate that IL-1beta stimulates renal and systemic ET-1 production in vivo, providing further evidence that ET-1 participates in inflammatory responses.