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
Ej. Shannon et al., 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, Immunopharmacology, 36(1), 1997, pp. 9-15
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.