Submitted on February 22, 2008
Accepted on June 4, 2008
Interleukin-1
but not interleukin-6 enhances renal and systemic endothelin production in vivo
Erika I Boesen1, Jennifer M Sasser2, Mohamed A Saleh2, William A Potter1, Mandy Woods3, Timothy D Warner4, Jennifer S Pollock5, and David M. Pollock1*
1 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
2 Pharmacology, Medical College of Georgia, Augusta, Georgia, United States
3 William Harvey Research Institute, London, United Kingdom
4 William Harvey Research Institute. London, United Kingdom; William Harvey Research Institute, London, United Kingdom
5 Pharmacology, Medical College of Georgia, Augusta, Georgia, United States; Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
* To whom correspondence should be addressed. E-mail: dpollock{at}mcg.edu.
The inflammatory cytokines IL-1
and IL-6 have been shown to stimulate production of 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-1 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 at days 7 and 14 of 14-day s.c. infusion of IL-1 (10 ng/h), IL-6 (16 ng/h) or vehicle. By day 14, plasma ET-1 was significantly increased by IL-1 infusion (1.7 ± 0.1 pg/ml versus 0.8 ± 0.1 pg/ml for vehicle, P < 0.001). Compared to vehicle infusion, IL-1 infusion induced significant increases in urinary ET-1 excretion rate and urine flow, but did not affect conscious mean arterial pressure (telemetry). IL-1 infusion significantly increased renal cortical and medullary IL-1 content (ELISA) and prepro-ET-1 mRNA expression (quantitative real-time PCR). In contrast, 14-day IL-6 infusion had no significant effect on plasma ET-1 or urinary ET-1 excretion rate. To determine whether IL-1 stimulates ET-1 release via activation of NF-
B, IMCD-3 cells were incubated for 24 h with IL-1, and ET-1 release and NF-B activation measured (ELISA). IL-1 activated NF-B and increased ET-1 release in concentration-dependent manners. The effect of IL-1 on ET-1 release could be partially inhibited by pre-treatment of IMCD-3 cells with an inhibitor of NF-B activation (BAY 11-7082). These results indicate that IL-1 stimulates renal and systemic ET-1 production in vivo, providing further evidence that ET-1 participates in inflammatory responses.
