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.
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