Interaction of apoptotic cells with macrophages upregulates COX-2/PGE2 and HGF expression via a positive feedback loop.

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.

Prenatal increased asymmetric dimethylarginine is associated with placental heat-shock protein 70 and lectin-like oxidized low-density lipoprotein receptor-1 expression.

BACKGROUND: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction by reversibly blocking NO production from L-arginine. To elucidate the association of prenatal status of ADMA with placental heat-shock protein 70 (HSP70) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in normal full-term pregnancies, we evaluated the expression of placental HSP70 and LOX-1. METHODS: Tissue samples of placentas obtained from 60 normal-term pregnancies were categorized into 30 cases with a lower level of prenatal ADMA (0.28 +/- 0.07 microM) and 30 cases with a higher level of prenatal ADMA (1.31 +/- 0.44 microM). We evaluated the placental expression of HSP70 and LOX-1 with Western blot analysis and immunohistochemistry and determined the correlation between HSP70 and LOX-1. RESULTS: We found that prenatal increased ADMA is associated with increased placental HSP70 and LOX-1 expression. CONCLUSIONS: We postulate that higher ADMA levels are associated with excessive levels of oxidative damage and stress markers (HSP, LOX-1) in placental tissues.