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Two pathways can activate the interleukin-5 gene and induce binding to the
conserved lymphokine element 0
S Karlen, M D'Ercole and CJ Sanderson
TVW Telethon Institute for Child Health Research, Perth, Australia.
Eosinophilia is a uniquely specific phenomenon regulated by interleukin- 5
(IL-5), suggesting specific control for IL-5 gene expression. Using a
transient-transfection reporter assay and DNA mobility-shift experiments in
EL4 mouse lymphoma cells, reporter expression and binding of transcription
factors to the conserved lymphokine element 0 (CLE0) in the mouse (mIL-5)
promoter was investigated. Activation of the IL-5 promoter required
costimulation of T cells with phorbol ester (phorbol 12-myristate
13-acetate [PMA]) and cyclic adenosine 3',5'- monophosphate (cAMP), but was
blocked by the immunosuppressive drug, cyclosporin A (CsA). Binding to CLE0
was induced under conditions optimal for IL-5 transcription but was not
blocked by CsA. CD28-induced signals could partly substitute for cAMP.
However, the effects of cAMP, but not of CD28, were sensitive to the
cAMP-dependent protein kinase inhibitor, H89, suggesting that CD28 does not
involve a cAMP mechanism. It therefore appears that IL-5 expression can be
induced by at least two distinct stimulatory pathways. Although CLE0
contains sequences similar to AP-1 and NF-AT, only the AP-1 moiety of the
CLE0 element could be demonstrated to have inducible binding. Experiments
with antisera to the AP-1 family of transcription factors indicated that c-
fos and JunB bind to the IL-5 CLE0 in activated lymphoma cells. The role of
the NF-AT-like element was less clear. A constitutively expressed protein
showed a weak band that was inhibited by mIL-2 NF-AT competitor sequences.
However, this protein did not react with an anti- NF-ATp antiserum. On the
other hand, transcription was partially inhibited by an oligonucleotide
containing the intact NF-AT-like element from CLE0, suggesting that the
element is important for optimal transcription, but the nature of the
protein binding to it remains unknown. The fact that these factors are
induced in a subclone of EL4 that does not express IL-5 and bind to a
number of other cytokine gene promoters suggests that although binding to
CLE0 appears to be necessary for IL-5 transcription, other factors must
control the specific expression of the gene.
Volume 88,
Issue 1,
pp. 211-221,
07/01/1996
Copyright © 1996 by The American Society of Hematology
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