Activation of Eotaxin-3/CCL26 Gene Expression in Human Dermal Fibroblasts Is Mediated by STAT6

摘要

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-3 in a time- and dose-dependent fashion in human dermal fibroblasts.In contrast to eotaxin-1/CCL11,TNF-#alpha# could not 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-#alpha# 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-#alpha# stimulation appears to be different.