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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900521v1 183/7/4755    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Wang, H. Articles by Simmet, T. PubMed PubMed Citation Articles by Wang, H. Articles by Simmet, T.

Targeting NF-B with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis¹

Honglin Wang^*,, Tatiana Syrovets, Daniel Kess, Berthold Büchele, Heidi Hainzl, Oleg Lunov, Johannes M. Weiss, Karin Scharffetter-Kochanek^2, and Thomas Simmet^2,3,

^* Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University Medical School, Shanghai, China; and Department of Dermatology and Allergic Diseases and Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany

Psoriasis vulgaris is a common chronic inflammatory skin disease involving cytokines and an activated cellular immune system. At variance to skin from patients with atopic dermatitis or from healthy subjects, human psoriatic skin lesions exhibit strong activation of transcription factor NF-B that is mainly confined to dermal macrophages, whereas only a few dendritic cells but no CD3⁺ lymphocytes show activated NF-B. Since NF-B signaling is required for the induction and/or function of many cytokines and aberrant cytokine expression has been proposed as an underlying cause of psoriasis, we investigated whether NF-B targeting would affect the course of the disease in the CD18 hypomorphic (CD18^hypo) mouse model of psoriasis. When mice with severe psoriasiform lesions were treated systemically or locally with the IB kinase inhibitor acetyl-11-keto-β-boswellic acid (AKβBA), NF-B signaling and the subsequent NF-B-dependent cytokine production as shown by the TNF- production of macrophages were profoundly suppressed. Additionally, application of the compound counteracted the intradermal MCP-1, IL-12, and IL-23 expression in previously lesional skin areas, led to resolution of the abundant immune cell infiltrates, and significantly reduced the increased proliferation of the keratinocytes. Overall, the AKβBA treatment was accompanied by a profound improvement of the psoriasis disease activity score in the CD18^hypo mice with reconstitution of a nearly normal phenotype within the chosen observation period. Our data demonstrate that NF-B signaling is pivotal for the pathogenesis in the CD18^hypo mouse model of psoriasis. Therefore, targeting NF-B might provide an effective strategy for the treatment of psoriasis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the German Research Foundation (DFG) within the SFB 497 (C7), as well as by individual research grants to K.S.-K. and Th.S.

² K.S.-K. and Th.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Thomas Simmet, Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Helmholtzstrasse 20, D-89081 Ulm, Germany. E-mail address: thomas.simmet{at}uni-ulm.de

⁴ Abbreviations used in this paper: IKK, IB kinase; AKβBA, acetyl-11-keto-β-boswellic acid; CD18^hypo, CD18 hypomorphic mutation; -CD, -cyclodextrin; K14, keratin 14; PASI, psoriasis activity and severity index; wt, wild type.

⁵ The online version of this article contains supplemental material.