Differential inhibition of inducible T cell cytokine secretion by potent iron chelators |
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Authors: | Leung Stewart Holbrook April King Beverly Lu Hong-Tao Evans Vincent Miyamoto Neil Mallari Cornell Harvey Susan Davey Dave Ho Elena Li Wei-Wei Parkinson John Horuk Richard Jaroch Stefan Berger Markus Skuballa Werner West Christopher Pulk Rebecca Phillips Gary Bryant Judi Subramanyam Babu Schaefer Caralee Salamon Hugh Lyons Eric Schilling Daniela Seidel Henrik Kraetzschmar Joern Snider Michael Perez Daniel |
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Institution: | Berlex Biosciences, Richmond, CA 84804, USA. Stewart_Leung@berlex.com |
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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-gamma). 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-gamma 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-gamma secretion from CD3(+) cells with an IC(50) 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-gamma 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. |
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