title: Differential inhibition of inducible T cell cytokine secretion by potent iron chelators.
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.
authors.affiliation: Berlex Biosciences, Richmond, CA 84804, USA. Stewart_Leung@berlex.com
authors.forename: Stewart
authors.initials: S
authors.lastname: Leung
authors.forename: April
authors.initials: A
authors.lastname: Holbrook
authors.forename: Beverly
authors.initials: B
authors.lastname: King
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Lu
authors.forename: Vincent
authors.initials: V
authors.lastname: Evans
authors.forename: Neil
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Cornell
authors.initials: C
authors.lastname: Mallari
authors.forename: Susan
authors.initials: S
authors.lastname: Harvey
authors.forename: Dave
authors.initials: D
authors.lastname: Davey
authors.forename: Elena
authors.initials: E
authors.lastname: Ho
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Parkinson
authors.forename: Richard
authors.initials: R
authors.lastname: Horuk
authors.forename: Stefan
authors.initials: S
authors.lastname: Jaroch
authors.forename: Markus
authors.initials: M
authors.lastname: Berger
authors.forename: Werner
authors.initials: W
authors.lastname: Skuballa
authors.forename: Christopher
authors.initials: C
authors.lastname: West
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pulk
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
authors.forename: Judi
authors.initials: J
authors.lastname: Bryant
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Caralee
authors.initials: C
authors.lastname: Schaefer
authors.forename: Hugh
authors.initials: H
authors.lastname: Salamon
authors.forename: Eric
authors.initials: E
authors.lastname: Lyons
authors.forename: Daniela
authors.initials: D
authors.lastname: Schilling
authors.forename: Henrik
authors.initials: H
authors.lastname: Seidel
authors.forename: Joern
authors.initials: J
authors.lastname: Kraetzschmar
authors.forename: Michael
authors.initials: M
authors.lastname: Snider
authors.forename: Daniel
authors.initials: D
authors.lastname: Perez
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007477:Ions / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D013058:Mass Spectrometry; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016207:Cytokines; D007477:Ions; D007502:Iron Chelating Agents; D016328:NF-kappa B