title: 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.
abstract: 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.
authors.affiliation: Department of Dermatology, University of Illinois, Chicago, IL, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Bao
authors.forename: Jaime B
authors.initials: JB
authors.lastname: Alexander
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Shi
authors.forename: Girish C
authors.initials: GC
authors.lastname: Mohan
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Chan
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics*; D053612:Janus Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D008822:Mice, Transgenic; D009154:Mutation; D011401:Promoter Regions, Genetic; D020218:Response Elements; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C421250:IL19 protein, human; D007378:Interleukins; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D053612:Janus Kinases
keywords: atopic dermatitis; interleukin-19; interleukin-4; keratinocyte; signal transducer and activator of transcription 6; signal transducer and activator of transcription 6 response elements