Tumor necrosis factor-alpha acutely up-regulates urea synthesis in vivo in rats--a hepatic component of inflammatory catabolism?
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-alpha (TNF-alpha) plays a key role in inflammation, and we hypothesized that TNF-alpha 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-alpha 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-alpha increased CUNS by 40% (p=0.03) despite decreased urea-cycle enzyme gene expression. TNF-alpha increased interleukin 6 (IL-6) (p < 0.001); circulating acute phase proteins were unchanged.


CONCLUSIONS
TNF-alpha 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-alpha 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.
Department of Medicine V (Hepatology & Gastroenterology), Aarhus University Hospital, Aarhus C, Denmark. karethom@rm.dk
Karen L
KL
Thomsen
Susanne S
SS
Nielsen
Niels K
NK
Aagaard
Thomas D
TD
Sandahl
Henning
H
Grønbaek
Jan
J
Frystyk
Allan
A
Flyvbjerg
Hendrik
H
Vilstrup
D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood; D007249:Inflammation / Q000097:blood / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007378:Interleukins / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013002:Somatomedins / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D014508:Urea / Q000378:metabolism*
D000209:Acute-Phase Proteins; D001786:Blood Glucose; D007328:Insulin; D007378:Interleukins; D012333:RNA, Messenger; D013002:Somatomedins; D014409:Tumor Necrosis Factor-alpha; D014508:Urea; D005934:Glucagon; D003345:Corticosterone