HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900327v1 183/5/3383    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 Krönke, G. Articles by Schett, G. PubMed PubMed Citation Articles by Krönke, G. Articles by Schett, G.

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

Gerhard Krönke^1,*, Julia Katzenbeisser^1,*, Stefan Uderhardt^*, Mario M. Zaiss^*, Carina Scholtysek^*, Gernot Schabbauer, Alexander Zarbock, Marije I. Koenders, Roland Axmann^*, Jochen Zwerina^*, Hans W. Baenckler^*, Wim van den Berg, Reinhard E. Voll^*, Hartmut Kühn^||, Leo A. B. Joosten^,¶ and Georg Schett^2,*

^* Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany; Department for Vascular Biology, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, Vienna, Austria; Department of Anesthesiology and Intensive Care Medicine, University of Münster, Münster, Germany; Department of Rheumatology and ^¶ Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and ^|| Institute of Biochemistry, Humboldt University, Berlin, Germany

Eicosanoids are essential mediators of the inflammatory response and contribute both to the initiation and the resolution of inflammation. Leukocyte-type 12/15-lipoxygenase (12/15-LO) represents a major enzyme involved in the generation of a subclass of eicosanoids, including the anti-inflammatory lipoxin A₄ (LXA₄). Nevertheless, the impact of 12/15-LO on chronic inflammatory diseases such as arthritis has remained elusive. By using two experimental models of arthritis, the K/BxN serum-transfer and a TNF transgenic mouse model, we show that deletion of 12/15-LO leads to uncontrolled inflammation and tissue damage. Consistent with these findings, 12/15-LO-deficient mice showed enhanced inflammatory gene expression and decreased levels of LXA₄ within their inflamed synovia. In isolated macrophages, the addition of 12/15-LO-derived eicosanoids blocked both phosphorylation of p38MAPK and expression of a subset of proinflammatory genes. Conversely, 12/15-LO-deficient macrophages displayed significantly reduced levels of LXA₄, which correlated with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-. Taken together, these results support an anti-inflammatory and tissue-protective role of 12/15-LO and its products during chronic inflammatory disorders such as arthritis.

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 G.K. and J.K. contributed equally to the manuscript.

² Address correspondence and reprint requests to Dr. Georg Schett, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen, Krankenhausstrasse 12, Erlangen, Germany. E-mail address: georg.schett{at}uk-erlangen.de

³ Abbreviations used in this paper: COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; LO, lipoxygenase; LXA₄, lipoxin A₄; RA, rheumatoid arthritis; tg, transgenic; WT, wild type; KC, keratinocyte chemoattractant.