HYDROLYSIS OF THALIDOMIDE ABROGATES ITS ABILITY TO ENHANCE MONONUCLEAR CELL SYNTHESIS OF IL-2 AS WELL AS ITS ABILITY TO SUPPRESS THE SYNTHESIS OF TNF-ALPHA

Thalidomide is effective in the treatment of inflammatory conditions l ike erythema nodosum leprosum in leprosy patients, and aphthous ulcers in AIDS patients. Its mechanism of action is uncertain and reports of its effect on the synthesis of inflammatory cytokines such as IL-2 an d TNF-alpha are contradictory. As thalidomide is labile to spontaneous hydrolysis at pH 7.4, studies were carried out to explore the effects of deliberate hydrolysis on the ability of thalidomide to modulated c ytokine production by human mononuclear cells stimulated in vitro with Staphylococcal enterotoxin A (SEA)(IL-2) or lipopolysaccharide from S almonella minnesota (LPS)(TNF-alpha). Unhydrolyzed thalidomide at 4.0 mu g/ml consistently enhanced the synthesis of IL-2 in SEA-stimulated cells, and suppressed the synthesis of TNF-alpha in LPS-stimulated cel ls; whereas, hydrolyzed thalidomide had no enhancing effect on SEA sti mulated-cell synthesis of IL-2 or suppressive effect on LPS stimulated -cell synthesis of TNF-alpha. These findings demonstrate that thalidom ide's ability in vitro to enhance IL-2 and to suppress TNF-alpha in st imulated cells is dependent on the intact molecule and underscore the necessity to employ thalidomide under appropriate physicochemical cond itions.