Abstract
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.
Footnotes
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This work was supported by Celgene Corporation.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.048496.
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ABBREVIATIONS: IMiD, immunomodulatory drug; TNF-α, tumor necrosis factor-α; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cell; IL, interleukin; MM, multiple myeloma; NK, natural killer; SEE, staphylococcal enterotoxin E; PMA, phorbol 12-myristate 13-acetate; NFAT, nuclear factor of activated T cells; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; JAK2, Janus kinase 2; DMSO, dimethyl sulfoxide; Th, T helper; PKC, protein kinase C; PKA, protein kinase A; rhIL, recombinant human interleukin; ELISA, enzyme-linked immunosorbent assay; MEK1, mitogen-activated protein kinase/ERK kinase 1; MEKK1, mitogen-activated protein kinase kinase kinase 1; TBST, Tris-buffered saline-Tween 20; PDE4, phosphodiesterase type 4; PD98059, 2′-amino-3′-methoxyflavone; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole; H-89, N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide HC1; AG-490, N-benzyl-3,4-dihydroxybenzylidenecyanoacetamide; RWJ-60475 (AM3), 2-(4-bromophenoxy)-5-nitrophenylhydroxymethylphosphonic acid Tris acetoxymethyl ester.
- Received December 23, 2002.
- Accepted March 7, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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