Differential inhibition of inducible T cell cytokine secretion by potent iron chelators

Stewart Leung, April Holbrook, Beverly King, Hong Tao Lu, Vincent Evans, Neil Miyamoto, Cornell Mallari, Susan Harvey, Dave Davey, Elena Ho, Wei Wei Li, John Parkinson, Richard Horuk, Stefan Jaroch, Markus Berger, Werner Skuballa, Christopher West, Rebecca Pulk, Gary Phillips, Judi BryantBabu Subramanyam, Caralee Schaefer, Hugh Salamon, Eric Lyons, Daniela Schilling, Henrik Seidel, Joern Kraetzschmar, Michael Snider, Daniel Perez

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Effector functions and proliferation of T helper (Th) cells are influenced by cytokines in the environment. Th1 cells respond to a synergistic effect of interleukin-12 (IL-12) and interleukin-18 (IL-18) to secrete interferon-gamma (IFN-γ). In contrast, Th2 cells respond to interleukin-4 (IL-4) to secrete IL-4, interleukin-13 (IL-13), interleukin-5 (IL-5), and interleukin-10 (IL-10). The authors were interested in identifying nonpeptide inhibitors of the Th1 response selective for the IL-12/IL-18-mediated secretion of IFN-γ while leaving the IL-4-mediated Th2 cytokine secretion relatively intact. The authors established a screening protocol using human peripheral blood mononuclear cells (PBMCs) and identified the hydrazino anthranilate compound 1 as a potent inhibitor of IL-12/IL-18-mediated IFN-γ secretion from CD3′ cells with an IC50 around 200 nM. The inhibitor was specific because it had virtually no effect on IL-4-mediated IL-13 release from the same population of cells. Further work established that compound 1 was a potent intracellular iron chelator that inhibited both IL-12/IL-18- and IL-4-mediated T cell proliferation. Iron chelation affects multiple cellular pathways in T cells. Thus, the IL-12/IL-18-mediated proliferation and IFN-γ secretion are very sensitive to intracellular iron concentration. However, the IL-4-mediated IL-13 secretion does not correlate with proliferation and is partially resistant to potent iron chelation.

Original languageEnglish (US)
Pages (from-to)157-167
Number of pages11
JournalJournal of Biomolecular Screening
Volume10
Issue number2
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

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Keywords

  • Cytokines
  • Iron chelators
  • T helper cells
  • Th1 response

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biotechnology
  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Cite this

Leung, S., Holbrook, A., King, B., Lu, H. T., Evans, V., Miyamoto, N., Mallari, C., Harvey, S., Davey, D., Ho, E., Li, W. W., Parkinson, J., Horuk, R., Jaroch, S., Berger, M., Skuballa, W., West, C., Pulk, R., Phillips, G., ... Perez, D. (2005). Differential inhibition of inducible T cell cytokine secretion by potent iron chelators. Journal of Biomolecular Screening, 10(2), 157-167. https://doi.org/10.1177/1087057104272394