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INFLAMMATION AND IMMUNOPHARMACOLOGY

Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs

Celgene Corporation, Warren, New Jersey (P.H.S., A.K.G., M.A.L., R.S.C., H.-W.M., S.G., L.G.C., F.P., G.W.M., D.I.S.); and Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Alberta, Canada (P.P.M.S., G.W.)

CC-4047 (Actimid) and CC-5013 (Revimid) belong to a class of thalidomide analogs collectively known as the immunomodulatory drugs (IMiDs), which are currently being assessed in the treatment of patients with multiple myeloma and other cancers. IMiDs potently enhance T cell and natural killer cell responses and inhibit tumor necrosis factor-, interleukin (IL)-1, and IL-12 production from LPS-stimulated peripheral blood mononuclear cells. However, the molecular mechanism of action for these compounds is unknown. Herein, we report on the ability of the IMiDs to up-regulate production of IL-2 from activated human CD4⁺ and CD8⁺ peripheral blood T cells, production of IL-2 and IFN- from T helper (Th)1-type cells, and production of IL-5 and IL-10 from Th2-type cells. Elevation of IL-2 production from Jurkat T cells was observed as early as 6 h poststimulation and correlated with an increase in IL-2 promoter activity that was dependent upon the proximal but not the distal AP-1 binding site. The IMiDs enhanced AP-1-driven transcriptional activity 2- to 4-fold after 6 h of T cell stimulation, and their relative potencies for AP-1 activation correlated with their potencies for increased IL-2 production in Jurkat T cells and in CD4⁺ or CD8⁺ human peripheral blood T cells. The most potent of these IMiDs, CC-4047, had no effect on nuclear factor of activated T cells transcriptional activity, calcium signaling, or phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH₂-terminal kinase 1/2, p38 mitogen-activated protein kinase, or c-Jun/Jun D in Jurkat T cells. These data suggest that IMiDs increase T cell cytokine production by potentiating AP-1 transcriptional activity.

Address correspondence to: Dr. Peter H. Schafer, Celgene Corporation, 7 Powder Horn Dr., Warren, NJ 07059. E-mail: pschafer{at}celgene.com

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