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to Mediate IL-4 Gene Expression in Response to CD28 Costimulation in T Cells1
Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
The secretion of IL-4, which displays many important
immunoregulatory functions, is restricted to cells of the Th2 subtype.
In this study, we investigated the early signaling events leading to
the activation of IL-4 transcription. Vav, the protein kinase C (PKC)
isoform 
, and the adaptor protein SLP76 (SH2-domain-containing
leukocyte protein of 76 kDa), induced transcription from the IL-4
promoter. Vav and PKC synergistically activated human IL-4 promoter
transcription and IL-4 mRNA production and were found to be
constitutively associated in vivo. CD3/CD28-induced IL-4 transcription
was inhibited upon coexpression of dominant negative forms of Vav, the
adaptor proteins LAT (linker for activation of T cells) and SLP76,
PKC, and components of the pathways leading to the activation of
c-Jun N-terminal kinase (mitogen-activated protein kinase kinase 7
(MKK7), mixed lineage kinase 3 (MLK3)) and NF-
B (IB kinase 
and IB kinase ß). The Vav/PKC-mediated synergistic activation
of IL-4 transcription was not inhibited by cyclosporin A. Three
independent experimental approaches revealed that Vav/PKC-derived
signals selectively target the P1 and positive regulatory element
(PRE)-I elements contained within the human IL-4 promoter. Vav/PKC
strongly activated a luciferase reporter construct controlled by
trimerized P1 or PRE-I elements and furthermore stimulated DNA binding
of nuclear proteins to the P1 and PRE-I elements. Vav/PKC-induced
transcription from the IL-4 promoter was almost completely abrogated by
mutation of either the P1 or the PRE-I element within the entire IL-4
promoter.
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