title: Hyaluronan regulates chemical allergen-induced IL-18 production in human keratinocytes.
abstract: Interleukin-18 (IL-18) has been shown to play a key proximal role in the induction of allergic contact dermatitis. Low molecular weight hyaluronan (LMWHA), an endogenous molecule and a member of the so-called damage associated molecular patterns (DAMPs), has been suggested to elicit immune-stimulatory effects. The purpose of this study was to examine the role of hyaluronan (HA) degradation in IL-18 production in human keratinocytes following stimulation with the contact sensitizers 2,4-dinitrochlorobenzene (DNCB) and PPD. IL-18 production in the human keratinocyte cell line NCTC2544 was measured by ELISA, whereas changes in HA metabolism were determined by Real-time PCR and immunofluorescence. Both contact allergens were able to enhance hyaluronidase (HYAL) 1 and 2 expression inducing HA degradation. Modulation of HA production, by HYAL or aristolochic acid pre-treatment, resulted in a significant reduction of contact allergen-induced IL-18 production. Oxidative stress appears to be the initial step in KC activation, as all the sequels of events can be blocked using antioxidants. This is the first indication that LMWHA can act as a DAMP in keratinocytes. In conclusion LMWHA fragments are important mediators in the process of contact sensitisation leading to IL-18 dependent responses.
authors.affiliation: Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece. Electronic address: dnikitovic@med.uoc.gr.
authors.forename: Dragana
authors.initials: D
authors.lastname: Nikitovic
authors.affiliation: Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Berdiaki
authors.affiliation: Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Galbiati
authors.affiliation: Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Rafaela-Maria
authors.initials: RM
authors.lastname: Kavasi
authors.affiliation: Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Papale
authors.affiliation: Department of Forensic Sciences and Toxicology, University of Crete, Heraklion, Greece.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Tsatsakis
authors.affiliation: Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: George N
authors.initials: GN
authors.lastname: Tzanakakis
authors.affiliation: Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Corsini
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D034341:Aristolochic Acids / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D017449:Dermatitis, Allergic Contact / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D004137:Dinitrochlorobenzene / Q000633:toxicity*; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000276:immunology / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010655:Phenylenediamines / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D034341:Aristolochic Acids; C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; D004137:Dinitrochlorobenzene; D058851:GPI-Linked Proteins; D018960:Hyaluronan Receptors; D020382:Interleukin-18; D010655:Phenylenediamines; D017382:Reactive Oxygen Species; D006820:Hyaluronic Acid; C000228:aristolochic acid I; C473096:Hyal2 protein, human; D006821:Hyaluronoglucosaminidase; C029728:4-phenylenediamine
keywords: Hyaluronan; Interleukin 18; Keratinocytes; Low molecular weight hyaluronan; Reactive oxygen species