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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Peter H. Schafer, Anita K. Gandhi, Michelle A. Loveland, Roger S. Chen, Hon-Wah Man, Paul P. M. Schnetkamp, Gregor Wolbring, Sowmya Govinda, Laura G. Corral, Faribourz Payvandi, George W. Muller and David I. Stirling
Journal of Pharmacology and Experimental Therapeutics June 2003, 305 (3) 1222-1232; DOI: https://doi.org/10.1124/jpet.102.048496
Peter H. Schafer
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Anita K. Gandhi
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Michelle A. Loveland
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Roger S. Chen
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Hon-Wah Man
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Paul P. M. Schnetkamp
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Gregor Wolbring
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Sowmya Govinda
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Laura G. Corral
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Faribourz Payvandi
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George W. Muller
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David I. Stirling
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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

  • This work was supported by Celgene Corporation.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.102.048496.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 305 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 3
1 Jun 2003
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Peter H. Schafer, Anita K. Gandhi, Michelle A. Loveland, Roger S. Chen, Hon-Wah Man, Paul P. M. Schnetkamp, Gregor Wolbring, Sowmya Govinda, Laura G. Corral, Faribourz Payvandi, George W. Muller and David I. Stirling
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 1222-1232; DOI: https://doi.org/10.1124/jpet.102.048496

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Peter H. Schafer, Anita K. Gandhi, Michelle A. Loveland, Roger S. Chen, Hon-Wah Man, Paul P. M. Schnetkamp, Gregor Wolbring, Sowmya Govinda, Laura G. Corral, Faribourz Payvandi, George W. Muller and David I. Stirling
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 1222-1232; DOI: https://doi.org/10.1124/jpet.102.048496
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