Thiazolidinediones, Agonisten des PPAR-γ-Rezeptors (peroxisomaler proliferatoraktivierter Rezeptor) reduzieren die peritoneale Makrophagenanzahl

Zusammenfassung

Fragestellung

Die Migration von Makrophagen in die Peritonealhöhle ist ein wesentlicher pathophysiologischer Faktor der Endometriose. Frühere Daten aus unserem Labor deuteten darauf hin, dass RANTES (Regulated on Activation, Normal T cell Expressed and Secreted) ein mögliches Ziel für Therapieformen ist, die die Infertilität und Schmerzen behandeln wollen. Wir charakterisieren die inflammatorische Antwort in einem In-vivo-Mausmodell der Peritonitis und beschreiben den anti-inflammatorischen Effekt von Ciglitazone, einem Thiazolidinedion (TZD) und PPAR-γ-Aktivator (peroxisomaler, proliferatoraktivierter Rezeptor γ).

Material und Methode

Die intraperitoneale Injektion von Thioglycollat-Medium in 7 Wochen alte, weibliche C57 BL/6-Mäuse wurde dazu benutzt, eine Rekrutierung von aktivierten Peritonealmakrophagen hervorzurufen. Die Peritonealflüssigkeit wurde gesammelt und die Peritonealzellen gezählt. Immunzytochemie wurde mit spezifischen PPAR-γ-Antikörpern durchgeführt. RNA wurde aus Peritoneal-Leukozyten isoliert und RT-PCR mit c-fms-spezifischen Primern angewendet.

Ergebnisse

Die intraperitoneale Injektion von Thioglycollat führte zu einer Rekrutierung von aktivierten Peritonealzellen. Die gleichzeitige, intraperitoneale Injektion von Ciglitazone reduzierte die peritoneale Leukozyteninfiltration signifikant. Spezifische, neutralisierende RANTES-Antikörper reduzierten ebenfalls die Makrophagenanzahl und dies deutet darauf hin, dass RANTES eine wesentliche Rolle bei der inflammatorischen Antwort spielt. Immunzytochemie demonstrierte, dass CD68-positive Makrophagen den PPAR-γ-Rezeptor enthalten. RT-PCR mit c-fms-spezifischen Primern bestätigte den monozytischen Phänotyp dieser Zellen.

Schlussfolgerung

Aktivatoren von PPAR-γ könnten für die Behandlung der endometrioseassoziierten Inflammation und Infertilität erprobt werden.

Abstract

Purpose

Migration of macrophages into the peritoneal cavity is an important pathophysiological feature of endometriosis. Prior data from our laboratory suggest that RANTES (Regulated on Activation, Normal T cell Expressed and Secreted) is a potential target for therapies designed to mitigate the inflammatory response associated with infertility and pain in this condition. We characterized the inflammatory response in an in vivo murine model of peritonitis and assessed the anti-inflammatory effect of ciglitazone, a thiazolidinedione (TZD) and PPAR-γ activator (peroxisome proliferator activated receptor γ).

Materials and Methods

Intraperitoneal injection of thioglycollate solution into 7-week-old female C57 BL/6 mice was used to elicit the recruitment of activated peritoneal leukocytes. Pelvic fluid was collected and peritoneal cells were counted. Immunocytochemistry with specific PPAR-γ-antibodies were afforded. RNA from peritoneal leukocytes was isolated and RT-PCR was performed with c-fms-specific primers.

Results

Intraperitoneal injection of thioglycollate elicited the recruitment of activated peritoneal cells. Concomitant peritoneal injection of ciglitazone reduced peritoneal leukocyte infiltration significantly. Specific neutralizing anti-RANTES antibodies also reduced the number of macrophages, indicating that RANTES played a major role in the inflammatory response. Immunocytochemistry demonstrated that CD68 positive macrophages contained the PPAR-γ receptor. RT-PCR with c-fms-specific primers confirmed the monocytic phenotype of these cells.

Conclusions

Activators of PPAR-γ could be developed for the treatment of inflammation and infertility associated with endometriosis.

Schlüsselwörter

Endometriose - Peritonealmakrophagen - PPAR-γ - Thiazolidinedione

Key words

Endometriosis - Peritoneal macrophages - PPAR-γ - Thiazolidinedione

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