title: Distribution of IL-18 and IL-18 receptor in human skin: various forms of IL-18 are produced in keratinocytes.
abstract: Human interleukin-18 (IL-18) enhances IL-12-mediated IFN-gamma production by lymphocytes and Fas/perforin-mediated cytolysis by NK cells. IL-18 is synthesized as a 24 kDa proform, and the proform is processed in the cytoplasm into an 18 kDa mature form. Active and precursor forms of IL-18 have been detected in immunocompetent cells, and active IL-18 exerts its functions through its receptor. We sought to determine which human skin cells are responsible for production of IL-18 and which express its receptor. Monoclonal antibodies against human IL-18 and polyclonal antibody against IL-18 receptor were provided for this analysis. Formalin-embedded and frozen sections of human epidermis were analyzed by immunoperoxidase and immunofluorescence staining. IL-18 was detected in all living cell layers of the epidermis, hair follicles, arrectores pilorum, eccrine ducts and endothelial cells. IL-18 was localized in the cytoplasm of cells in living epidermal cell layers. In contrast, IL-18 receptor was mainly detected in keratinocytes and expressed in the cell periphery in living cell layers. Since keratinocytes were the main source of IL-18 and its receptor, cultured human keratinocytes were further analyzed by immunoblotting. IL-18 receptor was identified as an 80 kDa single band. The mature 18 kDa and precursor 24 kDa forms of IL-18 were detected by our monoclonal antibody (mAb) 21 and mAb 132, respectively, while only the 18 kDa form was detected by a commercial mAb, 125-2H. Cultured keratinocytes showed positive granular staining for IL-18 in the cytoplasm and positive staining for IL-18 receptor mainly in the cell periphery. Our findings indicate that mature IL-18, precursor IL-18 and IL-18 receptor are simultaneously expressed with different localizations by human epidermal keratinocytes. Keratinocytes might be activated by their own IL-18 in an autocrine or paracrine fashion.
authors.affiliation: Department of Dermatology, Hokkaido University School of Medicine, Sapporo, Japan. hiroko-koizumi@hokkaido.med.or.jp
authors.forename: H
authors.initials: H
authors.lastname: Koizumi
authors.forename: K C
authors.initials: KC
authors.lastname: Sato-Matsumura
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Shida
authors.forename: S
authors.initials: S
authors.lastname: Kikkawa
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Toyoshima
authors.forename: T
authors.initials: T
authors.lastname: Seya
mesh_terms: D000328:Adult; D000368:Aged; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D053724:Receptors, Interleukin-18; D012016:Reference Values; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C508572:IL18R1 protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D020033:Protein Isoforms; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18