354 Heat Shock Protein 90 Inhibitor Attenuates Inflammation Induced by 12-O-tetradecanoylphorbol-13-acetate in Primary Human Keratinocytes and Mice

Heat shock protein 90 (HSP90) is a molecular chaperone that folds and promotes the activity of wide range client proteins, including key signaling proinflammatory molecules involved in aberrant inflammation. RGRN-305 novel HSP90 inhibitor has been reported to exhibit antiinflammatory properties autoimmune skin diseases. Here, effects were investigated vitro mouse model vivo. In primary human keratinocytes stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA; inducer inflammation), mRNA expression cytokines TNFα, IL-1β, IL-6 IL-8 significantly reduced by preincubation RGRN-305, when measured quantitative real-time PCR. Furthermore, Nanostring® nCounter gene assay showed led inhibition many related genes. To gain insights into intracellular mechanisms, further study demonstrated effect was mediated, at least partly, suppressing NF-κB c-Jun pathways. Topical application alleviated TPA-induced The ear thickness, as marker edema inflammation, 4 hours post-TPA application. Also, inhibitory associated (TNFα, IL-6, IL-17A) tissue. summary, mediates robust effect, providing potential therapeutic strategy for management