Interleukin‐4 up‐regulation of epidermal interleukin‐19 expression in keratinocytes involves the binding of signal transducer and activator of transcription 6 (Stat6) to the imperfect Stat6 sites

• Published in: Immunology Vol. 143; no. 4; pp. 601 - 608
• Main Authors: Bao, Lei, Alexander, Jaime B., Shi, Vivian Y., Mohan, Girish C., Chan, Lawrence S.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-12-2014; BlackWell Publishing Ltd
• Subjects: Animals; Asthma; atopic dermatitis; Cell Line, Transformed; Cytokines; Dermatitis, Atopic - genetics; Dermatitis, Atopic - metabolism; Disease Models, Animal; Gene Expression; Gene Expression Regulation - drug effects; Genes, Reporter; Humans; Interleukin-4 - genetics; Interleukin-4 - metabolism; Interleukin-4 - pharmacology; Interleukins - genetics; interleukin‐19; interleukin‐4; Janus Kinases - metabolism; keratinocyte; Keratinocytes - drug effects; Keratinocytes - metabolism; Medical research; Mice, Transgenic; Mutation; Original; Promoter Regions, Genetic; Response Elements; Rodents; signal transducer and activator of transcription 6; signal transducer and activator of transcription 6 response elements; Signal Transduction - drug effects; STAT6 Transcription Factor - metabolism; interleukin-4; signal transducer and activator of transcription 6 response elements; atopic dermatitis; interleukin-19; keratinocyte; signal transducer and activator of transcription 6
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12339

Summary
Interleukin‐19 (IL‐19) plays an important role in asthma by stimulating T helper type 2 (Th2) cytokine production. Interestingly, IL‐4, a key Th2 cytokine, in turn up‐regulates IL‐19 expression in bronchial epithelial cells, so forming a positive feedback loop. In atopic dermatitis (AD), another Th2 disease closely related to asthma, IL‐19 is up‐regulated in the skin. We propose to use IL‐4 transgenic (Tg) mice and human keratinocyte culture to delineate the molecular mechanisms involved in the up‐regulation of IL‐19 in AD. IL‐19 is similarly up‐regulated in the skin of IL‐4 Tg mice as in human AD. Next we show that IL‐4 up‐regulates IL‐19 expression in keratinocytes. Interestingly, the up‐regulation was suppressed by a pan‐Janus kinase (Jak) inhibitor, suggesting that the Jak–signal transducer and activator of transcription (Jak‐STAT) pathway may be involved. Dominant negative studies further indicate that STAT6, but not other STATs, mediates the up‐regulation. Serial 5′ deletion of the IL‐19 promoter and mutagenesis studies demonstrate that IL‐4 up‐regulation of IL‐19 in keratinocytes involves two imperfect STAT6 response elements. Finally, chromatin immunoprecipitation assay studies indicate that IL‐4 increases the binding of STAT6 to its response elements in the IL‐19 promoter. Taken together, we delineate the detailed molecular pathway for IL‐4 up‐regulation of IL‐19 in keratinocytes, which may play an important role in AD pathogenesis.