Interleukin-1beta, but not interleukin-6, enhances renal and systemic endothelin production in vivo.
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.
Boesen
Erika I
EI
Department of Pharmacology and Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, USA.
Sasser
Jennifer M
JM
Saleh
Mohamed A
MA
Potter
William A
WA
Woods
Mandy
M
Warner
Timothy D
TD
Pollock
Jennifer S
JS
Pollock
David M
DM
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D007679:Kidney Medulla / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D019332:Endothelin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones