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

Immunomodulatory drugs (IMiDs) are potent inhibitors of TNF-alpha and IL-1beta 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 effects 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-TNF-alpha and IL-1beta 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-TNF-alpha or IL-1beta neutralizing antibodies had no effect 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-inflammatory and anti-tumor effects of IMiDs may be due in part to elevation of IL-10 production and its subsequent inhibition of COX-2 expression.