Tumor necrosis factor-α acutely up-regulates urea synthesis in vivo in rats – a hepatic component of inflammatory catabolism?

Abstract

Background. Catabolism is a serious problem in patients with active inflammation. The tissue nitrogen (N) depletion is related to increased hepatic capacity for elimination of N via conversion of amino-N into urea-N. This is caused by the inflammatory process, but the mediators responsible are unknown. Tumor necrosis factor-α (TNF-α) plays a key role in inflammation, and we hypothesized that TNF-α up-regulates urea synthesis. Methods. We examined the in vivo capacity of urea-N synthesis (CUNS) and mRNA levels of urea cycle enzyme genes 3 h after TNF-α injection in rats. Circulating concentrations of glucagon, corticosterone, insulin, glucose, cytokines and acute phase proteins and their liver tissue gene expressions were measured. Results. TNF-α increased CUNS by 40% (p=0.03) despite decreased urea-cycle enzyme gene expression. TNF-α increased interleukin 6 (IL-6) (p < 0.001); circulating acute phase proteins were unchanged. Conclusion. TNF-α in rats caused an acute up-regulation of the in vivo capacity of urea synthesis which may promote loss of nitrogen from the body and catabolism. The results indicate that TNF-α has a post-transcriptional effect on regulation of urea synthesis that is independent of the acute phase protein synthesis. Effects of IL-6 may be involved.

Key Words::

• Cytokines
• inflammation
• metabolism
• rats
• RNA
• messenger
• urea

Acknowledgements

This study was generously supported by grants from The Aarhus University Research Foundation and Clinical Institute, Aarhus University, Denmark. We are indebted to Rikke Andersen, Birgitte Nielsen, Joan Hansen, Kirsten Nyborg and Kirsten Priisholm for skilled technical assistance.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.