CCL23 expression is induced by IL-4 in a STAT6-dependent fashion.
The chemokine CCL23 is primarily expressed in cells of the myeloid lineage but little information about its regulation is available. In this study, it is demonstrated that IL-4 and IL-13 induced CCL23 expression in human peripheral blood monocytes. GM-CSF had no effect on its own but synergized with IL-4, but not IL-13. CCL23 promoter reporter gene constructs were sensitive to IL-4 stimulation in the presence of the transcription factor STAT6. A canonical STAT6 binding site in the promoter region of the CCL23 gene was critical for the IL-4-inducible phenotype because reporter plasmids with a defective STAT6 binding site were unable to respond to IL-4 stimulation. In addition, two tandem copies of the STAT6 site conferred cytokine responsiveness to a heterologous minimal promoter. Furthermore, IL-4 inducibility of the CCL23 promoter was dependent on the absence of a negatively acting cis-element downstream of the STAT6 binding site. The negative function of this element was operative also on heterologous IL-4-inducible promoters. CCL23 was also expressed in skin from patients suffering from atopic dermatitis at higher levels than in normal individuals. However, no correlation between CCL23 expression in the serum and IgE levels as a diagnostic marker for atopy was found. Collectively, these data suggest a link between the inducible phenotype of CCL23 expression in monocytes by the prototype Th2 molecule pair IL-4/STAT6 and the increased number of CCL23-expressing cells in skin of atopic dermatitis patients.
Novak
Hermann
H
Department of Autoimmunity and Transplantation, Novartis Institutes for Biomedical Research, Brunnerstrasse, Vienna, Austria.
Müller
Anke
A
Harrer
Nathalie
N
Günther
Claudia
C
Carballido
Jose M
JM
Woisetschläger
Maximilian
M
D001665:Binding Sites; D019742:Chemokines, CC / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000276:immunology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D012867:Skin / Q000737:chemistry / Q000276:immunology
C105504:CCL23 protein, human; D019742:Chemokines, CC; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor