IL-4 induces expression of TARC/CCL17 via two STAT6 binding sites.
A cardinal feature of allergic disorders and immune responses is enhanced leukocyte trafficking. This is largely orchestrated by chemokines. The CC chemokine thymus- and activation-regulated chemokine (TARC/CCL17) selectively attracts Th2 cells via the G protein-coupled chemokine receptor CCR4. We show here that TARC/CCL17 is expressed by human T cells upon stimulation with IL-4. Mapping of the transcriptional start site revealed the presence of two putative STAT6 binding motifs in proximity to the start position. EMSA and chromatin immunoprecipitation experiments demonstrated that STAT6 was able to bind to both motifs. A fragment of the TARC/CCL17 promoter containing both sites was tested in reporter gene assays for IL-4 inducibility. The promoter was inducible in a STAT6-deficient cell line only after introduction of functional STAT6. When mutations were inserted into one of the STAT6 motifs, IL-4-induced promoter activation was reduced. With both sites mutated, inducibility was completely abrogated. These data demonstrate collectively that T cells serve as a source of TARC/CCL17 when stimulated with IL-4 and that STAT6 is essential for this.
Wirnsberger
Gerald
G
Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
Hebenstreit
Daniel
D
Posselt
Gernot
G
Horejs-Hoeck
Jutta
J
Duschl
Albert
A
D000328:Adult; D001665:Binding Sites; D002478:Cells, Cultured; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D015847:Interleukin-4 / Q000502:physiology*; D011401:Promoter Regions, Genetic; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism
C106230:CCL17 protein, human; D054414:Chemokine CCL17; D019742:Chemokines, CC; C508598:IL4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4