KdPT, a tripeptide derivative of alpha-melanocyte-stimulating hormone, suppresses IL-1 beta-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 alpha-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 alpha-melanocyte-stimulating hormone. KdPT potently suppressed IL-1beta-induced IL-6 and IL-8 expression. Mechanistically, KdPT decreased IL-1beta-mediated IkappaBalpha degradation, reduced nuclear accumulation of p65, and attenuated DNA binding of NF-kappaB. Moreover, KdPT reduced IL-1beta-mediated generation of intracellular reactive oxygen species, which contributed to IL-1beta-mediated cytokine induction. KdPT also reduced cell surface binding of fluorochrome-labeled IL-1beta in SZ95 sebocytes. Analysis of the crystal structure of the complex between IL-1beta/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.
Mastrofrancesco
Arianna
A
Department of Dermatology, University of Münster, Münster, Germany.
Kokot
Agatha
A
Eberle
Alex
A
Gibbons
Nicholas C J
NC
Schallreuter
Karin U
KU
Strozyk
Elwira
E
Picardo
Mauro
M
Zouboulis
Christos C
CC
Luger
Thomas A
TA
Böhm
Markus
M
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors; D008546:Melanoma, Experimental; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D010446:Peptide Fragments / Q000502:physiology*; D012627:Sebaceous Glands / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D000521:alpha-MSH / Q000502:physiology*; D000093242:Interleukin-6 Inhibitors
D016207:Cytokines; D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D016209:Interleukin-8; D000072000:NF-KappaB Inhibitor alpha; D010446:Peptide Fragments; D000521:alpha-MSH; D000093242:Interleukin-6 Inhibitors; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C056932:interleukin 1beta (193-195)