Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE₂and HGF Expression via a Positive Feedback Loop

Abstract

Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells via PGE2, PGD2, and HGF

“…We showed that PGE 2 and PGD 2 production in RAW 264.7 cells is enhanced by exposure to apoptotic cells, predominantly via inducing COX-2 expression ( Supplementary Fig. S4a,b ) 40 . Thus, we investigated whether COX-2-derived PGE 2 and PGD 2 , secreted from ApoJ-exposed macrophages, mediate anti-EMT effects in LA-4 cells.…”

Mesenchymal stem cells ameliorate myocardial fibrosis in diabetic cardiomyopathy via the secretion of prostaglandin E2

“…Moreover, it was observed that the concentration of PGE2 in MSC-treated supernatant was significantly higher than that in the non-treated group in vitro, which strengthened our determination to study the PGE2 pathway. PGE2 is synthesized through arachidonic acid metabolism with COX-2 being the key enzyme [32]. Thus, we used a COX-2 inhibitor to suppress the expression of PGE2.…”

Programming of macrophages by apoptotic cancer cells inhibits cancer progression through exosomal PTEN and PPARγ ligands

“…Cancer epithelial cell lines were exposed to ultraviolet irradiation at 254 nm for 10 min followed by incubation in RPMI-1640 with 10% FBS for 2 h at 37C and 5% CO2. Evaluation of nuclear morphology using light microscopy on Wright-Giemsa-stained samples indicated that the irradiated cells were approximately apoptotic (Byun et al, 2014). Lysed (necrotic) cancer cells were obtained by multiple freeze-thaw cycles (Fadok et al, 2001).…”

“…Lysed (necrotic) cancer cells were obtained by multiple freeze-thaw cycles (Fadok et al, 2001). Apoptosis and necrosis were confirmed by Annexin V-FITC/propidium iodide (BD Biosciences, San Jose, CA) staining followed by flow cytometric analysis on a FACSCalibur system (BD Biosciences) (Byun et al, 2014).…”