Geranylgeranylacetone (GGA) exerts cytoprotective activity against various toxic stressors via the
thioredoxin (TRX) redox system; however, its effect on skin
inflammation and molecular mechanism on inducing the TRX of GGA is still unknown. We investigated the effects of GGA in a murine
irritant contact dermatitis (ICD) model induced by
croton oil. Both a topical application and
oral administration of GGA induced TRX production and Nrf2 activation. GGA ameliorated ear swelling, neutrophil infiltration, and inhibited the expression of TNF-α, IL-1β,
GM-CSF, and 8-OHdG. GGA's cytoprotective effect was stronger orally than topically in mice. In vitro studies also showed that GGA suppressed the expression of NLRP3, TNF-α, IL-1β, and
GM-CSF and scavenged ROS in PAM212 cells after
phorbol myristate acetate stimulation. Moreover, GGA induced endogenous TRX production and Nrf2 nuclear translocation in PAM212 cells (dependent on the presence of ROS) and activated the PI3K-Akt signaling pathway. GGA significantly downregulated
thioredoxin-interacting
protein (TXNIP) levels in PAM212 cells treated with or without Nrf2
siRNA. After knocking down Nrf2 in PAM212 cells, the effect of GGA on TRX induction was significantly inhibited. This suggests that GGA suppress ICD by inducing endogenous TRX, which may be regulated by PI3K/Akt/Nrf2 mediation of the TRX redox system.