Differential inhibition of inducible T cell cytokine secretion by potent iron chelators.
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.
Leung
Stewart
S
Berlex Biosciences, Richmond, CA 84804, USA. Stewart_Leung@berlex.com
Holbrook
April
A
King
Beverly
B
Lu
Hong-Tao
HT
Evans
Vincent
V
Miyamoto
Neil
N
Mallari
Cornell
C
Harvey
Susan
S
Davey
Dave
D
Ho
Elena
E
Li
Wei-Wei
WW
Parkinson
John
J
Horuk
Richard
R
Jaroch
Stefan
S
Berger
Markus
M
Skuballa
Werner
W
West
Christopher
C
Pulk
Rebecca
R
Phillips
Gary
G
Bryant
Judi
J
Subramanyam
Babu
B
Schaefer
Caralee
C
Salamon
Hugh
H
Lyons
Eric
E
Schilling
Daniela
D
Seidel
Henrik
H
Kraetzschmar
Joern
J
Snider
Michael
M
Perez
Daniel
D
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
D016207:Cytokines; D007477:Ions; D007502:Iron Chelating Agents; D016328:NF-kappa B