| KdPT, a tripeptide derivative of alpha-melanocyte-stimulating hormone, suppresses IL-1 beta-mediated cytokine expression and signaling in human sebocytes. | |
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MedLine Citation:
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PMID: 20610647 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Arianna Mastrofrancesco; Agatha Kokot; Alex Eberle; Nicholas C J Gibbons; Karin U Schallreuter; Elwira Strozyk; Mauro Picardo; Christos C Zouboulis; Thomas A Luger; Markus Böhm |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-07 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 185 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-07-27 Completed Date: 2010-09-08 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 1903-11 Citation Subset: AIM; IM |
Affiliation:
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Department of Dermatology, University of Münster, Münster, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cell Line, Transformed Cytokines / antagonists & inhibitors*, biosynthesis DNA-Binding Proteins / physiology Humans I-kappa B Kinase / antagonists & inhibitors, metabolism I-kappa B Proteins / antagonists & inhibitors, metabolism Immunosuppressive Agents / pharmacology* Interleukin-1beta / antagonists & inhibitors*, physiology Interleukin-6 / antagonists & inhibitors Interleukin-8 / antagonists & inhibitors Melanoma, Experimental Mice Peptide Fragments / physiology* Sebaceous Glands / cytology*, immunology*, metabolism Signal Transduction / immunology* alpha-MSH / physiology* |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/DNA-Binding Proteins; 0/I-kappa B Proteins; 0/Immunosuppressive Agents; 0/Interleukin-1beta; 0/Interleukin-6; 0/Interleukin-8; 0/Peptide Fragments; 117027-34-6/interleukin 1beta (193-195); 139874-52-5/NF-kappaB inhibitor alpha; 581-05-5/alpha-MSH; EC 2.7.11.10/I-kappa B Kinase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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