GLUCOCORTICOID-DEPENDENT INDUCTION OF INTERLEUKIN-6 RECEPTOR EXPRESSION IN HUMAN HEPATOCYTES FACILITATES INTERLEUKIN-6 STIMULATION OF AMINO-ACID-TRANSPORT

Objective The authors studied the effects of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-LU) on glutamine and alanine transpor t in isolated human hepatocytes, They also evaluated the role of dexam ethasone in modulating this response and its effects on the expression of the plasma membrane high-affinity IL-6 receptor. Summary Backgroun d Data Animal studies indicate that cytokines are important mediators of the increased hepatic amino acid uptake that occurs during cancer a nd sepsis, but studies in human tissues are lacking. The control of tr ansport by cytokines and cytokine receptor expression in the liver may provide a mechanism by which hepatocytes can modulate amino acid avai lability during catabolic disease slates. Methods Human hepatocytes we re isolated from wedge biopsy specimens and plated in 24-well trays. I nterleukin-6 and TNf-alpha, in combination with the synthetic glucocor ticoid dexamethasone, were added to hepatocytes in culture, and the tr ansport of radiolabeled glutamine and alanine was measured. Fluorescen t-activated cell sorter (FACS) analysis was used to study the effects of dexamethasone on IL-6 receptor number in the well-differentiated hu man hepatoma HepG2. Results Both IL-6 and TNF-alpha exerted a small st imulatory effect on alanine and glutamine transport. Dexamethasone alo ne did not alter transport rates, but pretreatment of cells augmented the effects of both cytokines on carrier-mediated amino acid uptake. D examethasone pretreatment and a combination of IL-6 and TNF-alpha resu lted in a greater than twofold increase in transport activity. Fluores cent-activated cell sorter analysis demonstrated that dexamethasone in duced a threefold increase in the expression of high-affinity IL-6 rec eptors. Conclusions Interleukin-6 and TNF-alpha work coordinately with glucocorticoids to stimulate amino acid uptake in human hepatocytes. Dexamethasone exerts a permissive effect on cytokine-mediated increase s in transport by increasing IL-6 receptor expression on the cell surf ace. It is likely that this upregulation of IL-6 receptors ''primes'' human liver cells ?or subsequent stimulation by cytokines. The resulti ng increase in hepatic amino acid transport provides the liver with su bstrate to support key metabolic pathways during catabolic states.