Cyclosporine A inhibits TNF production without decreasing TNF mRNA

The role of cytokines in health and disease has received increasing attention and numerous investigations have explored the regulation of cytokine gene expression. Tumor necrosis factor-a (TNF) has received particular attention because of its central role in septic shock and more recent work has shown its participation in transplant immunology. We explored the mechanism of cyclosporine A (CsA) modulation of complete Freunds adjuvant macrophage (CFA-MO) TNF gene expression. From 0.001 to 1 ug/ml, CsA dose-dependently inhibited Iipopolysaccharide (LPS) induced secreted bioactivity; at doses above lOpg/ml CSA was directly toxic to CFA-MO. However, them was no suppression of TNF mRNA levels, and CsA also did not inhibit the accumulation of cell-associated TNF. Thus, CsA modulates TNF gene expression in a previously undescribed manner. Q 1989 Academic Press, Inc. TNF is a potent cytokine with diverse pathologic and physiologic effects. In vitro, this polypeptide mediator modulates a wide range of activities in multiple cell types (1). Although its original description was that of cytolytic activity against murine solid tumors (2), further investigations have shown TNF to play a major role in the pathophysiology of several disease states. TNF has been extensively studied in recent years because of the central role of thi