Phenylbutyrate suppresses distinct skin reactions that are enhanced by blockade of epidermal growth factor receptor signaling.

BACKGROUND

Epidermal growth factor receptor inhibitors (EGFRIs) cause skin inflammation, and understanding the factors that mediate this reaction is fundamental for designing therapies for EGFRI-related cutaneous side effects.

OBJECTIVE

We characterized EGFRI-enhanced skin reactions and evaluated the therapeutic efficacy of phenylbutyrate, a histone deacetylase inhibitor.

METHODS

PD168393, an EGFRI, was applied topically to the ear skin of mice with or without mast cell deficiency. The skin was then irritated once or pre-sensitized and repeatedly challenged with 2,4-dinitrofluorobenzene (DNFB). The reaction pattern, the type and number of infiltrating cells, changes in protein, cytokine (TNF-α) and chemokine (CCL2) expression, and the immune response were analyzed. Phenylbutyrate, formulated as a gel for topical treatment or dissolved in water for intraperitoneal administration, was tested as a treatment.

RESULTS

EGFRI rapidly upregulated the mast cell chemotactic factor, stem cell factor (SCF) and augmented DNFB-induced immediate contact dermatitis within hours of treatment in the presence of mast cells. Topical phenylbutyrate treatment suppressed EGFRI-induced SCF expression in the epithelium, inhibited DNFB-induced mast cell recruitment in the dermis, and ameliorated the EGFRI-enhanced acute skin reaction. EGFRI also enhanced the delayed-type DNFB-induced hypersensitive reaction that was mast-cell independent but was associated with T lymphocytes. Systemic phenylbutyrate administration suppressed EGFRI-enhanced delayed-type skin hypersensitivity by increasing the number and function of Foxp3(+) T regulatory suppressor cells, which inhibited T helper cell proliferation.

CONCLUSIONS

Our data suggest that phenylbutyrate has dual beneficial therapeutic effects on EGFRI-enhanced acute (local inflammatory) and late (systemic immune) skin reactions.