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

ESDR354 - Heat Shock Protein 90 Inhibitor Attenuates Inflammation Induced by 12-O-tetradecanoylphorbol-13-acetate in Primary Human Keratinocytes and Mice

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.