PMID- 25280773 OWN - NLM STAT- MEDLINE DCOM- 20170207 LR - 20201209 IS - 1879-3169 (Electronic) IS - 0378-4274 (Linking) VI - 232 IP - 1 DP - 2015 Jan 5 TI - Hyaluronan regulates chemical allergen-induced IL-18 production in human keratinocytes. PG - 89-97 LID - S0378-4274(14)01360-5 [pii] LID - 10.1016/j.toxlet.2014.09.026 [doi] AB - 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. CI - Copyright (c) 2014 Elsevier Ireland Ltd. All rights reserved. FAU - Nikitovic, Dragana AU - Nikitovic D AD - Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece. Electronic address: dnikitovic@med.uoc.gr. FAU - Berdiaki, Aikaterini AU - Berdiaki A AD - Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece. FAU - Galbiati, Valentina AU - Galbiati V AD - Laboratory of Toxicology, DiSFeB, Universita degli Studi di Milano, Italy. FAU - Kavasi, Rafaela-Maria AU - Kavasi RM AD - Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece. FAU - Papale, Angela AU - Papale A AD - Laboratory of Toxicology, DiSFeB, Universita degli Studi di Milano, Italy. FAU - Tsatsakis, Aristidis AU - Tsatsakis A AD - Department of Forensic Sciences and Toxicology, University of Crete, Heraklion, Greece. FAU - Tzanakakis, George N AU - Tzanakakis GN AD - Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece. FAU - Corsini, Emanuela AU - Corsini E AD - Laboratory of Toxicology, DiSFeB, Universita degli Studi di Milano, Italy. LA - eng PT - Journal Article DEP - 20141001 PL - Netherlands TA - Toxicol Lett JT - Toxicology letters JID - 7709027 RN - 0 (Antioxidants) RN - 0 (Aristolochic Acids) RN - 0 (CD44 protein, human) RN - 0 (Cell Adhesion Molecules) RN - 0 (Dinitrochlorobenzene) RN - 0 (GPI-Linked Proteins) RN - 0 (Hyaluronan Receptors) RN - 0 (Interleukin-18) RN - 0 (Phenylenediamines) RN - 0 (Reactive Oxygen Species) RN - 9004-61-9 (Hyaluronic Acid) RN - 94218WFP5T (aristolochic acid I) RN - EC 3.2.1.25 (Hyal2 protein, human) RN - EC 3.2.1.35 (Hyaluronoglucosaminidase) RN - U770QIT64J (4-phenylenediamine) SB - IM MH - Antioxidants/pharmacology MH - Aristolochic Acids/pharmacology MH - Cell Adhesion Molecules/metabolism MH - Cell Line MH - Dermatitis, Allergic Contact/*etiology/immunology/metabolism MH - Dinitrochlorobenzene/*toxicity MH - GPI-Linked Proteins/metabolism MH - Humans MH - Hyaluronan Receptors/metabolism MH - Hyaluronic Acid/immunology/*metabolism MH - Hyaluronoglucosaminidase/metabolism MH - Interleukin-18/immunology/*metabolism MH - Keratinocytes/*drug effects/immunology/metabolism MH - Oxidative Stress/drug effects MH - Phenylenediamines/*toxicity MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/drug effects MH - Up-Regulation OTO - NOTNLM OT - Hyaluronan OT - Interleukin 18 OT - Keratinocytes OT - Low molecular weight hyaluronan OT - Reactive oxygen species EDAT- 2014/10/05 06:00 MHDA- 2017/02/09 06:00 CRDT- 2014/10/05 06:00 PHST- 2014/07/31 00:00 [received] PHST- 2014/09/26 00:00 [revised] PHST- 2014/09/29 00:00 [accepted] PHST- 2014/10/05 06:00 [entrez] PHST- 2014/10/05 06:00 [pubmed] PHST- 2017/02/09 06:00 [medline] AID - S0378-4274(14)01360-5 [pii] AID - 10.1016/j.toxlet.2014.09.026 [doi] PST - ppublish SO - Toxicol Lett. 2015 Jan 5;232(1):89-97. doi: 10.1016/j.toxlet.2014.09.026. Epub 2014 Oct 1.