Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF- , IL-1 , and LPS-stimulated human PBMC in a partially IL-10-dependent manner

Immunomodulatory drugs (IMiDs) are potent inhibitors of TNFand IL-1 and elevators of IL-10 production in LPS-stimulated human PBMC. They are currently in clinical trials for various diseases, including multiple myeloma, myelodysplastic syndrome, and melanoma. In the present study, we have investigated the eVects of thalidomide, CC-5013 and CC-4047 on the expression of COX-2 by stimulated PBMC. Our results show that thalidomide and IMiDs inhibited the expression of COX-2 but not the COX-1 protein in LPS-TNFand IL-1 stimulated PBMC and shortened the half-life of COX-2 mRNA in a dose-dependent manner. They also inhibited the synthesis of prostaglandin E2 from LPS-stimulated PBMC. While anti-TNFor IL-1 neutralizing antibodies had no eVect on COX-2 expression, anti-IL-10 neutralizing antibody elevated the expression of COX-2 mRNA, and protein from treated PBMC. These data suggest that the anti-inXammatory and anti-tumor eVects of IMiDs may be due in part to elevation of IL10 production and its subsequent inhibition of COX-2 expression.  2004 Elsevier Inc. All rights reserved.