PT  - JOURNAL ARTICLE
AU  - Schafer, Peter H.
AU  - Gandhi, Anita K.
AU  - Loveland, Michelle A.
AU  - Chen, Roger S.
AU  - Man, Hon-Wah
AU  - Schnetkamp, Paul P. M.
AU  - Wolbring, Gregor
AU  - Govinda, Sowmya
AU  - Corral, Laura G.
AU  - Payvandi, Faribourz
AU  - Muller, George W.
AU  - Stirling, David I.
TI  - Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs
AID  - 10.1124/jpet.102.048496
DP  - 2003 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1222--1232
VI  - 305
IP  - 3
4099  - http://jpet.aspetjournals.org/content/305/3/1222.short
4100  - http://jpet.aspetjournals.org/content/305/3/1222.full
SO  - J Pharmacol Exp Ther2003 Jun 01; 305
AB  - 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-α, interleukin (IL)-1β, 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-γ 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. The American Society for Pharmacology and Experimental Therapeutics