KdPT, a Tripeptide Derivative of α-Melanocyte–Stimulating Hormone, Suppresses IL-1β–Mediated Cytokine Expression and Signaling in Human Sebocytes

Acne is the most common inflammatory skin disease in which IL-1 plays a central role. Although α-melanocyte–stimulating hormone has immunomodulatory effects, its usefulness as an anti-inflammatory agent in acne is hampered owing to its lipid- and pigment-inducing effects via activation of melanocortin receptors (MC-Rs). We used the immortalized human sebocyte line SZ95 as an in vitro model to investigate the anti-inflammatory potential of KdPT, a tripeptide derivative of the C-terminal end of α-melanocyte–stimulating hormone. KdPT potently suppressed IL-1β–induced IL-6 and IL-8 expression. Mechanistically, KdPT decreased IL-1β–mediated IκBα degradation, reduced nuclear accumulation of p65, and attenuated DNA binding of NF-κB. Moreover, KdPT reduced IL-1β–mediated generation of intracellular reactive oxygen species, which contributed to IL-1β–mediated cytokine induction. KdPT also reduced cell surface binding of fluorochrome-labeled IL-1β in SZ95 sebocytes. Analysis of the crystal structure of the complex between IL-1β/IL-1R type I (IL-1RI), followed by computer modeling of KdPT and subsequent modeling of the peptide receptor complex with the crystal structure of IL-1RI via manual docking, further predicted that the tripeptide, through several H-bonds and one hydrophobic bond, interacts with the IL-1RI. Importantly, KdPT did not bind to MC-1Rs, as demonstrated by blocking experiments with a peptide analog of Agouti signaling protein and by binding assays using MC-1R–expressing B16 melanoma cells. Accordingly, KdPT failed to induce melanogenesis. Our data demonstrate a promising anti-inflammatory potential of KdPT and point toward novel future directions in the treatment of acne—as well as of various other IL-1–mediated inflammatory diseases—with this small molecule.