Transient receptor potential ankyrin 1 activation enhances hapten sensitization in a T-helper type 2-driven fluorescein isothiocyanate-induced contact hypersensitivity mouse model.

Some chemicals contribute to the development of allergies by increasing the immunogenicity of other allergens. We have demonstrated that several phthalate esters, including dibutyl phthalate (DBP), enhance skin sensitization to fluorescein isothiocyanate (FITC) in a mouse contact hypersensitivity model, in which the T-helper type 2 (Th2) response is essential. On the other hand, some phthalate esters were found to activate transient receptor potential ankyrin 1 (TRPA1) cation channels on sensory neurons. We then found a positive correlation between the enhancing effects of several types of phthalate esters on skin sensitization to FITC and their ability to activate TRPA1. Here we examined the involvement of TRPA1 in sensitization to FITC by using TRPA1 agonists other than phthalate esters. During skin sensitization to FITC, the TRPA1 agonists (menthol, carvacrol, cinnamaldehyde and DBP) augmented the ear-swelling response as well as trafficking of FITC-presenting dendritic cells to draining lymph nodes. We confirmed that these TRPA1 agonists induced calcium influx into TRPA1-expressing Chinese hamster ovary (CHO) cells. We also found that TRPA1 antagonist HC-030031 inhibited DBP-induced calcium influx into TRPA1-expressing CHO cells. After pretreatment with this antagonist upon skin sensitization to FITC, the enhancing effect of DBP on sensitization was suppressed. These results suggest that TRPA1 activation will become a useful marker to find chemicals that facilitate sensitization in combination with other immunogenic haptens.

Phthalate esters reveal skin-sensitizing activity of phenethyl isothiocyanate in mice.

Phenethyl isothiocyanate (PEITC) is a constituent of edible cruciferous vegetables and has received attention due to its potential cancer chemopreventive activity. Although its protein-binding activity is known, PEITC has not been studied as a contact sensitizer. We previously demonstrated that phthalate esters, including dibutyl phthalate (DBP) and di-n-propyl phthalate (DPP), enhance skin sensitization in a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity mouse model. In this study, we examined whether DBP and DPP enhance skin sensitization to haptens other than FITC. During this study, we tested PEITC as a contact sensitizer. BALB/c mice were epicutaneously sensitized with a suboptimal dose of a hapten with or without a phthalate ester. Sensitization was evaluated as the ear swelling response after a challenge with the respective hapten. DBP and DPP did not enhance the sensitization to two T-helper 1-type (2,4-dinitrofluorobenzene and oxazolone) or three T-helper 2-type (trimellitic anhydride, methylenediphenyl 4,4'-diisocyanate, and tolulene 2,4-diisocyanate) haptens. In contrast, DBP and DPP enhanced the sensitization to two FITC analogues (eosin 5-isothiocyanate and rhodamine B isothiocyanate) as well as to PEITC. Adjuvant effects of DBP and DPP were observed in contact hypersensitivity to haptens other than FITC, including a food ingredient PEITC.