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Sebocytes Expression and Signaling in Human Mediated Cytokine KdPT, a Tripeptide Derivative of α -Melanocyte−Stimulating Hormone, Suppresses IL-1 β−Mediated Cytokine Expression and Signaling in Human This information is current as Sebocytes of September 25, 2021. Arianna Mastrofrancesco, Agatha Kokot, Alex Eberle, Nicholas C. J. Gibbons, Karin U. Schallreuter, Elwira Strozyk, Mauro Picardo, Christos C. Zouboulis, Thomas A. Luger and Markus Böhm Downloaded from J Immunol 2010; 185:1903-1911; Prepublished online 7 July 2010; doi: 10.4049/jimmunol.0902298 http://www.jimmunol.org/content/185/3/1903 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2010/07/06/jimmunol.090229 Material 8.DC1 References This article cites 44 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/185/3/1903.full#ref-list-1 by guest on September 25, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology KDPT, a Tripeptide Derivative of a-Melanocyte–Stimulating Hormone, Suppresses IL-1b–Mediated Cytokine Expression and Signaling in Human Sebocytes Arianna Mastrofrancesco,*,1 Agatha Kokot,* Alex Eberle,†,‡ Nicholas C. J. Gibbons,x Karin U. Schallreuter,x Elwira Strozyk,*,{ Mauro Picardo,‖ Christos C. Zouboulis,# Thomas A. Luger,* and Markus Bo¨hm*,1 Acne is the most common inflammatory skin disease in which IL-1 plays a central role. Although a-melanocyte–stimulating hormone has immunomodulatory effects, its usefulness as an anti-inflammatory agent in acne is hampered owing to its lipid- and pigment- Downloaded from 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 a-melanocyte– stimulating hormone. KDPT potently suppressed IL-1b–induced IL-6 and IL-8 expression. Mechanistically, KDPT decreased IL-1b–mediated IkBa degradation, reduced nuclear accumulation of p65, and attenuated DNA binding of NF-kB. Moreover, KDPT reduced IL-1b–mediated generation of intracellular reactive oxygen species, which contributed to IL-1b–mediated cytokine induction. KDPT also reduced cell surface binding of fluorochrome-labeled IL-1b in SZ95 sebocytes. Analysis of the http://www.jimmunol.org/ crystal structure of the complex between IL-1b/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 KDPTand 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. The Journal of Immunology, 2010, 185: 1903–1911. by guest on September 25, 2021 cne vulgaris is the most common inflammatory disease of bacterium acnes, resulting in perifollicular inflammation (2, 3). the pilosebaceous unit, affecting ∼93% of adolescents Among various mediators orchestrating the inflammatory response A with different degrees of severity (1). The pathogenesis of of the pilosebaceous unit in acne, several cytokines, including IL- this disease is complex, involving sebaceous gland hypertrophy, 1, IL-6, IL-8, and TNF-a, have been implicated (4–8). In particular, increased seborrhea with the presence of oxidized lipids, piloseba- IL-1 appears to play a key role in the pathogenesis of acne. IL-1a ceous duct hyperkeratinization, and colonization with Propioni- was shown to be present in open comedones, the very early lesions of this disease (4). IL-1a induces follicular hyperkeratinization in an ex vivo model (9), whereas sebocytes respond to IL-1b *Department of Dermatology, University of Mu¨nster, Mu¨nster; #Department of Dermatology, Dessau Medical Center, Dessau, Germany; †Department of Biomedi- with induction of proinflammatory cytokines. In light of these cine, Laboratory for Endocrinology, University Hospital Basel and ‡Children’s Hos- findings and in consideration of the role of IL-1 as a potent inducer pital Basel, Basel, Switzerland; xClinical and Experimental Dermatology/Department of Biomedical Sciences, School of Life Sciences, University of Bradford, United of both IL-6 and IL-8 (10, 11), blocking of IL-1–mediated responses Kingdom; {Department of Cancer Immunology, University of Medical Sciences at could offer a promising new immunomodulatory approach to com- ‖ Great Poland Cancer Center, Poznan, Poland; and S. Gallicano Dermatological In- bating acne. stitute, Rome, Italy 1 To date, there is compelling evidence that a-melanocyte– A.M. and M.B. contributed equally to this work. stimulating hormone (a-MSH), a tridecapeptide originally de- Received for publication July 16, 2010. Accepted for publication May 30, 2010. scribed as a neurohormone, has pleiotropic anti-inflammatory This work was supported by grants from the Deutsche Forschungsgemeinschaft (to effects (12), which have been demonstrated in various in vitro cell M.B.; MA-2247/3-1) and from the German Academic Exchange Service (to A.M., in the research laboratory of M.B.). culture models. Moreover, these effects have also been shown in Address correspondence and reprint requests to Prof. Markus Bo¨hm, Department of several animal models of, for example, contact dermatitis (13), Dermatology, University of Mu¨nster, Von-Esmarch-Strasse 58, D-48149 Mu¨nster, vasculitis (14), allergic asthma (15), and fibrosis (16), to mention Germany. E-mail address: [email protected] a few. The biologic actions of a-MSH are mediated via melano- The online version of this article contains supplemental material. cortin receptors (MC-Rs), which belong to the superfamily of G Abbreviations used in this paper: ASIP, Agouti signaling protein; CM-H2DCFDA, 5- protein-coupled receptors with seven transmembrane domains. (and 6-)chloromethyl-29,79-dichlorodihydrofluorescein diacetate acetyl ester; DAPI, Interestingly, receptors for a-MSH have not only been detected in 49,6-diamidino-2-phenylindole; IL-1RI, IL-1R type I; 5-LOX, 5-lipoxygenase; MC- R, melanocortin receptor; MnCpx3, Mn complex of 7-hydroxy-flavone; a-MSH, various cells of the immune system (17). They have also been iden- a-melanocyte–stimulating hormone; NDP-a–MSH, [Nle4, D-Phe7]-a-MSH; ROS, tified in sebocytes under in vitro conditions (18, 19). In fact, a-MSH reactive oxygen species. was shown to have weak inhibitory effects on IL-1b–induced Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 secretion of IL-8 in human sebocytes in vitro (19). However, www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902298 1904 KDPT SUPPRESSES CYTOKINE EXPRESSION/SIGNALING IN SEBOCYTES therapeutic exploitation of a-MSH as an anti-inflammatory agent in according to the manufacturer’s instructions. Real-time RT-PCR was per- patients with acne is problematic for several reasons because natural formed in a total volume of 20 ml with SYBR Green PCR Master Mix and synthetic melanocortin peptides such as [Nle4, D-Phe7]-a–MSH (Applied Biosystems, Foster City, CA), and a 200 nM concentration of each primer. The primer sequences for IL-6 were sense: 59-AGCCACTCAC- (NDP-a–MSH) or adrenocorticotropic hormone directly increase CTCTTCAGAACG-39; and antisense: 59-GGTTCAGGTTGTTTTCTGC- lipogenesis in primary human sebocytes (20). Moreover, the CAG-39; and for IL-8 were sense: 59-CTTGGCAGCCTTCCTGATTTC- melanotropic (pigment-inducing) activity of a-MSH analogs con- 39; and antisense: 59-TTCTGTGTTGGCGCAGTGTG-39. Reactions were taining the central pharmacophor may be a limiting factor for their carried out in duplicates in an ABI Prism 7000 sequence detector supplied with SDS 2.2 software (Applied Biosystems), using the following use, especially in Caucasian white-skinned patients. conditions: an initial activation step (2 min at 50˚C), a single denaturation KDPT (Lys-D-Pro-Thr) is a derivative of the C-terminal sequence step (15 min at 95˚C) followed by 40 cycles of 15 s at 95˚C and 60 s at 60˚C, of a-MSH in which the second amino acid, Pro, is replaced by its D- and a final cycle of 15 s at 95˚C, 30 s at 60˚C, and 15 s at 95˚C. Levels of gene -DDCT enantiomer and the third amino acid, Val, is exchanged for Thr. It is of expression in each sample were quantified applying the 2 method with glyceraldehyde-3-phosphate dehydrogenase as an endogenous control. interest that KPT, the L-enantiomer, is collinear with human IL- Glyceraldehyde-3-phosphate dehydrogenase primers were identical with 1b193–195. Originally, KDPT was reported to attenuate the IL-1b– those reported before (27). For the detection of IL-1RI mRNA, cDNA from mediated hyperalgesic response in a rat-paw pressure test (21, 22). SZ95 sebocytes was amplified by established primers (28), using a single KDPT, however, does not appear to act as a simple or uniform IL-1b denaturation step of 5 min at 94˚C followed by 35 cycles of 1 min at 94˚C, antagonist because the peptide did not have antipyretic activity 1 min of 60˚C, 1 min of 72˚C, and a final cycle of 5 min at 72˚C, yielding a 340-bp product.
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