BINDING OF THALIDOMIDE TO ALPHA(1)-ACID GLYEOPROTEIN MAY BE INVOLVED IN ITS INHIBITION OF TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION

In addition to its well known sedative and teratogenic effects, thalid omide also possesses potent immunomodulatory and antiinflammatory acti vities, being most effective against leprosy and chronic graft-versus- host disease. The immunomodulatory activity of thalidomide has been as cribed to the selective inhibition of tumor necrosis factor alpha from monocytes. The molecular mechanism for the immunomodulatory effect of thalidomide remains unknown. To elucidate this mechanism, we synthesi zed an active photoaffinity label of thalidomide as a probe to identif y the molecular target of the drug, Using the probe, we specifically l abeled a pair of proteins of 43-45 kDa with high acidity from bovine t hymus extract. Purification of these proteins and partial peptide sequ ence determination revealed them to be alpha(1)-acid glycoprotein (AGP ). We show that the binding of thalidomide photoaffinity label to auth entic human AGP is competed with both thalidomide and the nonradioacti ve photoaffinity label at concentrations comparable to those required for inhibition of production of tumor necrosis factor alpha from human monocytes, suggesting that AGP may be involved in the immunomodulator y activity of thalidomide.