title: Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene.
abstract: Interleukin-18 is a potent inducer of interferon-gamma by activated T cells, macrophages, and monocytes and is synthesized as an inactive precursor. Pro-interleukin-18 must be cleaved by interleukin-1-beta-converting enzyme for secretion of the biologically active form. We report that among selected non-bone marrow derived skin cells, interleukin-18 mRNA is constitutively expressed by human keratinocytes and not by dermal microvascular endothelial cells, dermal fibroblasts, or melanocytes. Interleukin-18 mRNA and intracellular protein levels are neither changed in human keratinocytes nor induced in human dermal microvascular endothelial cells, dermal fibroblasts, or melanocytes by exposure to pro-inflammatory stimuli. Exposure of human keratinocytes to phorbol 12-myrisate 13-acetate, lipopolysaccharides or the contact sensitizer DNCB results in the secretion of immunoprecipitable interleukin-18 protein. Human keratinocyte-secreted interleukin-18 is biologically active, in that conditioned media from phorbol 12-myrisate 13-acetate, lipopolysaccharide and DNCB-treated human keratinocytes induce interferon-gamma expression by peripheral blood mononuclear cells. This bioactivity is neutralized by anti-interleukin-18, but not anti-interleukin-12 antibodies. By immunohistochemistry, interleukin-18 protein is detected in basal keratinocytes of normal human skin, but its expression is markedly upregulated in suprabasal keratinocytes in psoriasis. These findings indicate that human keratinocytes are a source of biologically functional interleukin-18 and thus are capable of playing an initiating part in the local interferon-gamma-dependent inflammatory processes through expression, activation, and secretion of interleukin-18.
authors.affiliation: Emory Skin Diseases Research Core Center, Department of Dermatology University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Naik
authors.forename: G
authors.initials: G
authors.lastname: Cannon
authors.forename: G J
authors.initials: GJ
authors.lastname: Burbach
authors.forename: S R
authors.initials: SR
authors.lastname: Singh
authors.forename: R A
authors.initials: RA
authors.lastname: Swerlick
authors.forename: J N
authors.initials: JN
authors.lastname: Wilcox
authors.forename: J C
authors.initials: JC
authors.lastname: Ansel
authors.forename: S W
authors.initials: SW
authors.lastname: Caughman
mesh_terms: D004137:Dinitrochlorobenzene / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D011565:Psoriasis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000737:chemistry; D013601:T-Lymphocytes / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D004137:Dinitrochlorobenzene; D018836:Inflammation Mediators; D020382:Interleukin-18; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate