title: The Expression and Regulation of Interleukin-33 in Human Epidermal Keratinocytes: A New Mediator of Atopic Dermatitis and Its Possible Signaling Pathway.
abstract: Interleukin (IL)-33 is a novel member of the IL-1 superfamily of cytokines that has recently become a focal point for research into the pathogenesis of atopic dermatitis (AD). However, the expression and regulation of IL-33 in human epidermal keratinocytes have not well been delineated. The aim of this study was to evaluate IL-33 and its receptor ST2L expression in skin lesions of AD patients and explored the signal transduction mechanisms leading to the IL-33 expression and of the IL-33's pharmacological action in keratinocytes from AD patients (ADKs) and those from healthy controls (NHEKs). We performed immunocytochemistry, reverse transcription-polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay to investigate ADKs compared with NHEKs. We found that IL-33/ST2L were positively expressed in the skin lesions of AD patients and a high expression of IL-33 was induced in keratinocytes by IL-4 plus interferon [IFN]-γ or IFN-γ alone at the mRNA and protein levels. Meanwhile, IFN-γ induced IL-33 expression through extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR), and Janus kinase/signal transducer and activator of transcription. The expression of ST2L was increased in a time- and dose-dependent manner in both types of cells incubated with IL-33, and was especially increased in ADKs compared with NHEKs. We examined the cytokine IL-6 and the chemokines CXCL-8/IL-8, CCL-20, CCL-17, CCL-5, and CCL-2 in keratinocytes, which showed increased expression in a time- and dose-dependent manner in ADKs when induced by IL-33. Furthermore, 4 signaling pathways (ERK, p38 MAPK, c-Jun N-terminal kinase, and nuclear factor-κB) were involved in the IL-33-mediated induction in both cells. In conclusion, IL-33 is closely interlinked in AD skins and keratinocytes. IL-33 plays an important role in the pathogenesis of immune inflammatory responses in AD, which might be a possible therapeutic target in the treatment of AD.
authors.affiliation: 1 Department of Dermatology, The Air Force General Hospital of PLA , Beijing, China .|2 Department of Dermatology in the First Affiliated Hospital of Liaoning Medical University , Jinzhou, Liaoning, China .
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Du
authors.affiliation: 2 Department of Dermatology in the First Affiliated Hospital of Liaoning Medical University , Jinzhou, Liaoning, China .
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Fu
authors.affiliation: 2 Department of Dermatology in the First Affiliated Hospital of Liaoning Medical University , Jinzhou, Liaoning, China .
authors.forename: Dong-Ning
authors.initials: DN
authors.lastname: Li
authors.affiliation: 1 Department of Dermatology, The Air Force General Hospital of PLA , Beijing, China .
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: 1 Department of Dermatology, The Air Force General Hospital of PLA , Beijing, China .
authors.forename: Qiao-Wei
authors.initials: QW
authors.lastname: Wang
authors.affiliation: 1 Department of Dermatology, The Air Force General Hospital of PLA , Beijing, China .
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics / Q000378:metabolism; D000067596:Interleukin-33 / Q000235:genetics* / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018925:Chemokines; D016207:Cytokines; C079241:IL1RL1 protein, human; D018836:Inflammation Mediators; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D016328:NF-kappa B; D012333:RNA, Messenger; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases