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Toxicol Lett. 2015 Jan 5;232(1):89-97. doi: 10.1016/j.toxlet.2014.09.026. Epub 2014 Oct 1.

Hyaluronan regulates chemical allergen-induced IL-18 production in human keratinocytes.

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Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece. Electronic address:
Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece.
Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Italy.
Department of Forensic Sciences and Toxicology, University of Crete, Heraklion, Greece.


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.


Hyaluronan; Interleukin 18; Keratinocytes; Low molecular weight hyaluronan; Reactive oxygen species

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