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Regulation of peroxisome proliferator-activated receptor gamma in macrophages during inflammatory processes

By Carla Jennewein

Abstract

The peroxisome proliferator activated receptor gamma (PPARgamma) plays an eminent role during alternative activation of macrophages and resolution of inflammation. As an antiinflammatory signaling molecule, it seems likely that it is tightly regulated dependent on the state of the immune response. There is growing evidence that PPARgamma expression is reduced during inflammation, whereas molecular mechanisms are illdefined. Even though, its role in immunosuppression is getting more definite. Apoptotic cells (AC) provoke an active repression of pro-inflammatory responses inter alia by the inhibition of pro-inflammatory cytokine expression or attenuated generation of reactive oxygen species (ROS). The reduced formation of ROS was attributed to PPARgamma activation, while mechanisms behind the reduced cytokine expression remained unclear. Therefore, my Ph.D. thesis addressed the role of PPARgamma during inhibited cytokine synthesis in response to AC and the regulation of PPARgamma expression during an inflammatory response, which was initiated by lipopolysaccharide (LPS) exposure. In the first part of the thesis, I investigated the role of PPARgamma in coordinating the attenuation of pro-inflammatory cytokine expression in response to AC. Exposing murine RAW264.7 macrophages to AC prior to LPS-stimulation, reduced NFKB transactivation and lowered target gene expression of e.g. TNFalpha and IL-6 compared to controls. In macrophages over-expressing a dominant negative (d/n) mutant of PPARgamma, NFKB transactivation in response to LPS was restored, while using macrophages from myeloid lineage-specific conditional PPARgamma knock-out mice proved that PPARgamma transmitted the anti-inflammatory response delivered by AC. Domain analysis revealed that amino acids 32-250 are essential for inhibition of NFKB. Mutation of a SUMOylation (SUMO: small-ubiquitin related modifier) site in this region (K77R) and interfering SUMOylation by silencing the SUMO E3 ligase PIAS1 (protein inhibitor of activated Stat1) eliminated AC-provoked NFKB inhibition and concomitant TNFalpha expression. Chromatin-immunoprecipitation assays demonstrated that AC prevented the LPS-induced removal of nuclear receptor co-repressor (NCoR) from the KB response element within the TNFalpha promoter. I concluded that AC induce PPARgamma SUMOylation to attenuate the removal of NCoR, thereby blocking transactivation of NFKB. This contributes to an anti-inflammatory phenotype shift in macrophages in response to AC, by lowering pro-inflammatory cytokine production. The second part addressed molecular mechanisms responsible for reduced PPARgamma expression upon LPS exposure. PPARgamma gained considerable interest as a therapeutic target during chronic inflammatory diseases. Remarkably, the pathogenesis of diseases such as multiple sclerosis or Alzheimer’s disease is associated with impaired PPARgamma expression. Initiation of an inflammatory response by exposing primary human macrophages to LPS revealed a rapid decline of PPARgamma1 expression. PPARgamma1 mRNA decrease was prevented by inhibition of NFKB and also after pre-treatment with the PPARgamma agonist rosiglitazone, suggesting a NFKB-dependent pathway, because activated PPARgamma is known to inhibit NFKB transactivation. Since promoter activities were not affected by LPS, I focused on mRNA stability and noticed a decreased PPARgamma1 mRNA half-life. RNA stability is often regulated via 3’ untranslated regions (UTRs). Therefore, I analyzed the impact of the PPARgamma-3’UTR by luciferase assays. LPS significantly reduced luciferase activity of pGL3-PPARgamma-3’UTR, suggesting that PPARgamma1 mRNA is destabilized. Deletion of a potential miR-27a/b binding site within the 3’UTR completely restored luciferase activity. Moreover, inhibition of miR-27b, which was induced upon LPS-exposure, partially reversed PPARgamma1 mRNA decay, whereas the mature miR-27 mimicked the effect of LPS. MiR-27b was at least partially induced by NFKB, thus correlating with NFKB-dependent PPARgamma1 mRNA decrease. Since deletion of the miR-27 site also containing an AU-rich element (ARE) completely abrogated LPS-induced reduction but inhibition of miR-27b only partially restored PPARgamma1 mRNA expression, I suggested an additional implication of an ARE-binding protein. I provide evidence that LPS induces miR-27b, which in turn destabilizes PPARgamma1 mRNA. Understanding the molecular mechanism of PPARgamma mRNA destabilization, might help to rationalize inflammatory diseases associated with impaired PPARgamma expression. Even though, further experiments are needed to clarify the potential involvement of ARE-binding proteins.Chronische Entzündungskrankheiten entstehen häufig in Folge einer unkontrollierten Entzündungsreaktion und damit verbundenen irreversiblen Schäden des umliegenden Gewebes. Die Ausbildung eines anti-inflammatorischen Makrophagen-Phänotyps ist ein wichtiger Bestandteil zur Beendigung von Entzündungen. Charakteristisch für diesen Phänotyp ist eine verminderte Synthese pro-inflammatorischer Zytokine, welche teilweise auf die Aktivierung des Transkriptionsfaktors PPARgamma (‚peroxisome proliferator activated receptor gamma‘) zurückzuführen ist. Daher ist die Regulation der Aktivierung als auch der Expression von PPARgamma entscheidend für die Immunantwort von Makrophagen. Es konnte bereits gezeigt werden, dass durch die Phagozytose apoptotischer Zellen (AZ) zum einen PPARgamma aktiviert und zum anderen die Zytokinexpression durch eine Hemmung von NFKB (‚nuclear factor KB‘) vermindert wird. Daher untersuchte ich im ersten Teil meiner Arbeit die Rolle von PPARgamma bei der Inhibition von NFKB nach Interaktion mit AZ. Die Stimulation von RAW264.7-Makrophagen mit AZ führte zu einer Hemmung der NFKB-Aktivität, welche durch Überexpression einer dominantnegativen Mutante von PPARgamma reduziert war. Weiterhin konnte in primären PPARgamma-knock-out Makrophagen keine Hemmung der TNFalpha-Expression, als klassisches NFKB-Zielgen, festgestellt werden. Analysen der PPARgamma-Protein Domänen zeigten, dass die Aminosäuren 32-250 essentiell für die NFKB-Inhibition sind. Mutation der in diesem Bereich liegenden SUMOylierungsstelle K77 (SUMO: „small-ubiquitin related modifier“) als auch das Ausschalten der essentiellen SUMO-E3-Ligase PIAS1 („protein inhibitor of activated Stat1“) verhinderte die Hemmung von NFKB und bestätigte die SUMOylierung von PPARgamma als zugrunde liegenden Mechanismus. Als verantwortlichen Repressor identifizierte ich NCoR („nuclear receptor co-repressor“), welcher im Ruhezustand konstitutiv an NFKB-Bindestellen verschiedener pro-inflammatorischer Promotoren gebunden ist. Nach TLR4-Aktivierung dissoziiert dieser von der Promotorregion und wird abgebaut. Durch Chromatin-Immunpräzipitationen konnte ich zeigen, dass vermutlich SUMOyliertes PPARgamma nach Interaktion mit AZ die Dissoziation von NCoR und damit die Zielgen-Expression verhindert. Die Aufklärung dieses Mechanismus trägt damit zum weiteren Verständnis bei, wie AZ einen anti-inflammatorischen Makrophagen-Phänotyp hervorrufen und damit zur Eindämmung einer Entzündungsreaktion beitragen. Bei verschiedenen Entzündungskrankheiten wie Alzheimer oder auch Multipler Sklerose konnte eine Verringerung der PPARgamma-Expression nachgewiesen werden. Da der Mechanismus dieser Reduktion jedoch weitgehend unbekannt ist, beschäftigte ich mich im zweiten Teil meiner Arbeit mit der Expressionsregulation von PPARgamma in Makrophagen. Die Stimulation von primären humanen Makrophagen mit LPS verringerte den PPARgamma1 mRNA-Gehalt. Diese mRNA-Reduktion konnte durch Hemmung von NFKB als auch durch Vorstimulation mit dem PPARgamma-Agonisten Rosiglitazone verhindert werden, was auf einen NFKB-abhängigen Mechanismus hinwies. Durch Promotor-Reporteranalysen konnte eine Reduktion der PPARgamma1 mRNA auf transkriptioneller Ebene ausgeschlossen werden. LPS führte vielmehr zu einer 3‘-UTR (‚untranslated region‘)-abhängigen Destabilisierung der PPARgamma1 mRNA. Aufgrund einer potentiellen Bindestelle für microRNA-27a/b (miR-27a/b), untersuchte ich deren Expression. LPS führte - zum Teil NFKB abhängig - zur Induktion von miR-27a und b. Eine Depletion der miR-27 Bindestelle innerhalb der PPARgamma-3’UTR verhinderte vollständig den destabilisierenden Effekt von LPS. Weiterhin führte die Inhibition von miR-27b, nicht aber von miR-27a, zur teilweisen Aufhebung der LPS-induzierten Reduktion. Die Destabilisierung von PPARgamma konnte außerdem durch Transfektion mit miR-27b simuliert werden, wobei die additive Zugabe von LPS den Effekt nur wenig verstärkte. Meine Daten beweisen, dass LPS-induzierte miR-27b zur Destabilisierung der PPARgamma1 mRNA führt. Die Aufklärung des vorliegenden molekularen Mechanismus könnte dazu beitragen, das Verständnis und damit verbundene Behandlungsmethoden von Entzündungskrankheiten, welche eine reduzierte PPARgamma-Expression zeigen, zu erweitern

Topics: ddc:610
Year: 2010
OAI identifier: oai:publikationen.ub.uni-frankfurt.de:7486

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