Regulation of urea synthesis during the acute phase response in rats.

Catabolism is a serious clinical problem in patients with active inflammation. Under such stressful conditions, the catabolism and loss of tissue nitrogen (N) result from proteolysis and are augmented by an up-regulation of the hepatic capacity to eliminate amino-N via urea-N. Our earlier studies suggest that this is part of the acute phase response to inflammation despite the increased need for amino-N for incorporation into acute phase proteins synthesised by the liver. It is, therefore, patho-physiologically and potentially therapeutically important to identify regulators of urea synthesis which, in this way, aggravate the inflammatory loss of body N; this study aimed at identifying such mediators, quantifying their effects, and unravelling their mode of action. The cytokines tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) play key roles in inflammation, and they both induce protein breakdown and catabolism. Therefore, they are both potential mediators of the up-regulation of urea synthesis. Our first experiments showed that TNF-α administration in rats acutely, i.e. after 3 h, up-regulated the in vivo capacity of urea-N synthesis (CUNS) by 30%, whereas IL-6 was observed not to acutely change CUNS. Furthermore, our experiments aimed at characterising the regulation of hepatic N elimination via urea during different phases of the TNF-α-induced acute phase response and to identify the steps between gene expression and physiological function that might be involved. We did so by using four different methods 1, 3, 24, and 72 h after TNF-α injection in rats: examination of urea cycle enzyme mRNA levels in liver tissue, the hepatocyte urea cycle enzyme proteins, CUNS, and known hormonal regulators of CUNS. The major serum acute phase proteins and their liver mRNA levels were also measured. Despite a progressive down-regulation of the urea cycle genes and a fully established acute phase response 24 h after TNF-α administration, no change in the in vivo capacity for the disposal of amino-N by urea synthesis was observed 1, 24, and 72 h after TNF-α injection. Moreover, TNF-α actually up-regulated urea synthesis 3 h after administration (cf. above). The dissociation of the effects of TNF-α on the urea genes and on physiological functions remains unexplained. The lack of down-regulation of whole body urea synthesis may promote the loss of N from the body and contribute towards inflammatory catabolism. This indicates the presence of an independent hepatic component of the inflammation response that is of primary importance for the stress-catabolic state.