Tumor necrosis factor-alpha (TNF-alpha) has been proposed as an early proximal mediator of many metabolic and physiologic responses during septic shock. We have previously shown that direct addition to tissue (local effect) or intravenous administration (systemic effect) of lipopolysaccharide (LPS) reduces L-leucine absorption across rabbit jejunum. In the present study, we investigated whether the inhibitory effect of LPS on L-leucine intestinal absorption in rabbit is related to TNF-alpha. The results shown that the addition of TNF-alpha to tissue does not produce any effect on L-leucine uptake by the enterocyte. When TNF-alpha was inoculated by intravenous administration, a strong inhibition on the L-leucine uptake (about 40%), mediated by a secretagogue effect on water and Cl-ions was induced. We also found that the LPS intestinal effect induced by intravenous administration, was blocked by a TNF-alpha antagonist, indicating that TNF-alpha is a mediator of the LPS systemic effect on L-leucine intestinal uptake inhibition. The study of possible mediators involved in the TNF-alpha effect showed that nitric oxide and prostaglandins are implicated in the L-leucine intestinal uptake.