title: Interaction of apoptotic cells with macrophages upregulates COX-2/PGE2 and 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.
authors: Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea ; Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea.
authors: Ji Yeon
authors: JY
authors: Byun
authors: Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea ; Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea.
authors: Young-So
authors: YS
authors: Youn
authors: Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea ; Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea.
authors: Ye-Ji
authors: YJ
authors: Lee
authors: Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea ; Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea ; Global Top 5 Research Program, Ewha Womans University, Seoul 158-710, Republic of Korea.
authors: Youn-Hee
authors: YH
authors: Choi
authors: Department of Microbiology, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea.
authors: So-Yeon
authors: SY
authors: Woo
authors: Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea ; Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-gu, Seoul 158-710, Republic of Korea ; Global Top 5 Research Program, Ewha Womans University, Seoul 158-710, Republic of Korea.
authors: Jihee Lee
authors: JL
authors: Kang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001761:Bleomycin / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D019169:Jurkat Cells; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C066855:HGF protein, human; D001761:Bleomycin; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone