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Sumoylation of Peroxisome Proliferator-Activated Receptor by Apoptotic Cells Prevents Lipopolysaccharide-Induced NCoR Removal from B Binding Sites Mediating Transrepression of Proinflammatory Cytokines¹

Carla Jennewein^*, Anne-Marie Kuhn^*, Martina Victoria Schmidt^*, Virginie Meilladec-Jullig^*, Andreas von Knethen^*, Frank J. Gonzalez and Bernhard Brüne^2,*

^* Institute of Biochemistry I/Zentrum für Arzneimittelforschung, -Entwicklung und -Sicherheit (ZAFES), Faculty of Medicine, Goethe-University Frankfurt am Main, Frankfurt, Germany; and Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892

Efficient clearance of apoptotic cells (AC) by professional phagocytes is crucial for tissue homeostasis and resolution of inflammation. Macrophages respond to AC with an increase in antiinflammatory cytokine production but a diminished release of proinflammatory mediators. Mechanisms to explain attenuated proinflammatory cytokine formation remain elusive. We provide evidence that peroxisome proliferator-activated receptor (PPAR) coordinates antiinflammatory responses following its activation by AC. Exposing murine RAW264.7 macrophages to AC before LPS stimulation reduced NF-B transactivation and lowered target gene expression of, that is, TNF- and IL-6 compared with controls. In macrophages overexpressing a dominant negative mutant of PPAR, NF-B transactivation in response to LPS was restored, while macrophages from myeloid lineage-specific conditional PPAR knockout mice proved that PPAR transmitted an antiinflammatory response, which was delivered by AC. Expressing a PPAR-aa32–250 deletion mutant, we observed no inhibition of NF-B. Analyzing the PPAR domain structures within aa 32–250, we anticipated PPAR sumoylation in mediating the antiinflammatory effect in response to AC. Interfering with sumoylation of PPAR by mutating the predicted sumoylation site (K77R), or knockdown of the small ubiquitin-like modifier (SUMO) E3 ligase PIAS1 (protein inhibitor of activated STAT1), eliminated the ability of AC to suppress NF-B. Chromatin immunoprecipitation analysis demonstrated that AC prevented the LPS-induced removal of nuclear receptor corepressor (NCoR) from the B site within the TNF- promoter. We conclude that AC induce PPAR sumoylation to attenuate the removal of NCoR, thereby blocking transactivation of NF-B. This contributes to an antiinflammatory phenotype shift in macrophages responding to AC by lowering proinflammatory cytokine production.

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 grants from Deutsche Forschungsgemeinschaft (Br 999, FOG 784, Excellence Cluster Cardiopulmonary System), Deutsche Krebshilfe, Sander Foundation, LiFF, and European Community (PROLIGEN).

² Address correspondence and reprint requests to Dr. Bernhard Brüne, Goethe-University Frankfurt am Main, Faculty of Medicine, Institute of Biochemistry I/Zentrum für Arzneimittelforschung, -Entwicklung und –Sicherheit (ZAFES), Pathobiochemistry, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail address: bruene{at}zbc.kgu.de

³ Abbreviations used in this paper: AC, apoptotic cells; ChIP, chromatin immunoprecipitation; d/n, dominant negative; HDAC, histone deacetylase; iNOS, inducible NO synthase; NCoR, nuclear receptor corepressor; PIAS1, protein inhibitor of activated STAT1; PPAR, peroxisome proliferator-activated receptor ; siRNA, small interfering RNA; TBL1, transducin β-like protein-1; TSA, trichostatin A.

⁴ The online version of this article contains supplemental material.

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