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

• Published in: SLAS discovery Vol. 10; no. 2; pp. 157 - 167
• Main 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
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.03.2005
• Subjects: cytokines; iron chelators; T helper cells; Th1 response; iron chelators; T helper cells; Th1 response; cytokines
• ISSN: 2472-5552; 2472-5560
• DOI: 10.1177/1087057104272295

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. (Journal of Biomolecular Screening 2005:157-167)