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Differential Inhibition of Inducible T Cell Cytokine Secretion by Potent Iron Chelators

Berlex Biosciences, Richmond, CA

April Holbrook

Berlex Biosciences, Richmond, CA

Beverly King

Berlex Biosciences, Richmond, CA

Hong-Tao Lu

Berlex Biosciences, Richmond, CA

Vincent Evans

Berlex Biosciences, Richmond, CA

Neil Miyamoto

Berlex Biosciences, Richmond, CA

Cornell Mallari

Berlex Biosciences, Richmond, CA

Susan Harvey

Berlex Biosciences, Richmond, CA

Dave Davey

Berlex Biosciences, Richmond, CA

Elena Ho

Berlex Biosciences, Richmond, CA

Wei-Wei Li

Berlex Biosciences, Richmond, CA

John Parkinson

Berlex Biosciences, Richmond, CA

Richard Horuk

Berlex Biosciences, Richmond, CA

Stefan Jaroch

Schering AG, Berlin, Germany

Markus Berger

Schering AG, Berlin, Germany

Werner Skuballa

Schering AG, Berlin, Germany

Christopher West

Berlex Biosciences, Richmond, CA

Rebecca Pulk

Berlex Biosciences, Richmond, CA

Gary Phillips

Berlex Biosciences, Richmond, CA

Judi Bryant

Berlex Biosciences, Richmond, CA

Babu Subramanyam

Berlex Biosciences, Richmond, CA

Caralee Schaefer

Berlex Biosciences, Richmond, CA

Hugh Salamon

Berlex Biosciences, Richmond, CA

Eric Lyons

Berlex Biosciences, Richmond, CA

Daniela Schilling

Schering AG, Berlin, Germany

Henrik Seidel

Schering AG, Berlin, Germany

Joern Kraetzschmar

Schering AG, Berlin, Germany

Michael Snider

Berlex Biosciences, Richmond, CA

Daniel Perez

Berlex Biosciences, Richmond, CA

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-). 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- 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- 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- 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

Key Words: Th1 response • iron chelators • T helper cells • cytokines

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