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J Biol Chem, Vol. 273, Issue 49, 32460-32466, December 4, 1998
From the Tumor Immunology Program, German Cancer Research Center,
D-69126 Heidelberg, Germany
CD28 serves as a costimulatory cell surface
molecule in T cell activation. CD28 signaling may also play a role in
balancing the inflammatory/humoral (Th1/Th2) responses during an immune reaction. CD28 costimulation has been shown to promote the production of Th2 cytokines including interleukin (IL)-4, a key cytokine essential
for Th2 differentiation and for the pathogenesis of allergic
inflammation. In this study, we show that IL-4 mRNA and activity of
the IL-4 promoter can be activated by the CD28 signal alone and are
further augmented by CD28 costimulation of 
-CD3- or
mitogen-activated Jurkat T cells. Two important IL-4 enhancer elements,
positive regulatory element (PRE)-I and P1, are found to respond to
CD28 stimulation-induced transactivation. In contrast to the Th1 IL-2
CD28RE, activity of the IL-4 PRE-I and P1 can be induced by the CD28
signal alone. In correlation with CD28-induced transcriptional
activation, AP-1 (c-Jun, JunD) and NF-
B/Rel (c-Rel, RelA) family
members are found to bind to the two regulatory elements PRE-I and P1
upon CD28 stimulation. The data provide the first mapping of the
CD28-responsive site in a Th2 cytokine gene, the IL-4 gene. They also
show that the CD28 signal can directly activate a gene
(e.g. IL-4) at the transcriptional level.
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