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Department of Allergic Diseases, Novartis Research Institute, Vienna, Austria
Allergic inflammatory conditions such as asthma are characterized
by an accumulation of eosinophils at sites of inflammation.
Eotaxin-3/CCL26 is a member of the family of CC chemokines,
which are known to be potent chemoattractants for eosinophils. This
chemokine was shown to be up-regulated by IL-4 and IL-13 in endothelial
cells. This study demonstrates that eotaxin-3 transcription and
eotaxin-3 protein expression are stimulated by IL-4 and IL-13 in a
time- and dose-dependent fashion in human dermal fibroblasts. In
contrast to eotaxin-1/CCL11, TNF-
could not act as inducer on its
own nor did it synergize with IL-4. The activities of eotaxin-3
promoter luciferase constructs were significantly increased by IL-4 and
IL-13 in human dermal fibroblasts. This effect was mediated by a
binding site for the transcription factor STAT6 in the eotaxin-3
promoter sequence. Mutations in the STAT6 binding site abrogated
up-regulation of eotaxin-3 promoter activity. In STAT6-defective human
embryonic kidney 293 cells, the wild-type luciferase construct, but not
the STAT6 binding mutant, was inducible by IL-4 only upon
cotransfection of STAT6 expression vector. In addition, eotaxin-3
protein was detectable in the supernatants of STAT6-transfected human
embryonic kidney 293 cells upon IL-4 or IL-13 stimulation. In the same
experiments, TNF- induced activation of the monocyte chemoattractant
protein-1/CCL2 gene was independent of STAT6 transfection. These
results indicate that IL-4 and IL-13 activate eotaxin-3 gene expression
in a STAT6-dependent fashion. Although both eotaxin-1 and -3 are
regulated by this transcription factor, the response of the eotaxin-3
gene to TNF- stimulation appears to be
different.
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