We previously reported on the impact of the melanocortin peptide alpha-melanocyte-stimulating hormone (alpha-MSH) on fibroblast function including skin fibrosis. Truncated peptides from the C-terminal domain of alpha-MSH as well as some derivatives have persevered immunomodulating effects but do not bind to the melanocortin-1 receptor (MC-1R). Thus, they do not elicit MC-1R-mediated pigmentation as an obligatory adverse effect of MC1R agonistic peptides. Among the melanocortin tripeptide derivatives is Lys-Pro-d-Thr (KdPT) which not only suppressed interleukin-IL-1beta-mediated expression of proinflammatory cytokines but also exhibited beneficial effects in animal models of inflammatory bowel disease as well as in patients with Crohn's disease. Here we investigated whether KdPT and another more stable derivative, WOL074-029 are capable of suppressing fibroblast activation induced by transforming growth factor-beta1 (TGF-beta1). Both KdPT and WOL074-029 suppressed mRNA expression of collagen I, fibronectin I, connective tissue growth factor and alpha-smooth muscle actin in human dermal fibroblasts (HDF) compared with TGF-beta1 alone as shown by real-time RT-PCR analysis. These effects were dose-independent and detectable at subnanomolar levels of both peptides. In accordance, secretion of collagen I was significantly suppressed by KdPT and WOL074-029. The peptides did not interfere with smad2/3 signalling as shown by Western immunoblotting and immunofluorescence analysis. Interestingly, expression of PepT2 but not PepT1 was present in HDF raising the possibility that KdPT and WOL074-029 elicit the observed effects by these tripeptide transporters. Future studies are in progress to further define the mode of action of KdPT and WOL074-029 in fibroblasts and the in vivo relevance of these findings.

ESDR623 - Fibroblast function in vitro modulated by the melanocortin tripeptide derivatives KdPT and WOL074-029

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.