title: BK Induces cPLA2 Expression via an Autocrine Loop Involving COX-2-Derived PGE2 in Rat Brain Astrocytes.
abstract: Bradykinin (BK) is a proinflammatory mediator and elevated in several brain injury and inflammatory diseases. The deleterious effects of BK on brain astrocytes may aggravate brain inflammation mediated through the upregulation of cytosolic phospholipase A2 (cPLA2)/cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) production. However, the signaling mechanisms underlying BK-induced cPLA2 expression in brain astrocytes remain unclear. Herein, we investigated the effects of activation of cPLA2/COX-2 system on BK-induced cPLA2 upregulation in rat brain astrocytes (RBA-1). The data obtained with Western blotting, RT-PCR, and immunofluorescent staining analyses showed that BK-induced de novo cPLA2 expression was mediated through activation of cPLA2/COX-2 system. Upregulation of native cPLA2/COX-2 system by BK through activation of PKCδ, c-Src, MAPKs (ERK1/2 and JNK1/2) cascades led to PGE2 biosynthesis and release. Subsequently, the released PGE2 induced cPLA2 expression via the same signaling pathways (PKCδ, c-Src, ERK1/2, and JNK1/2) and then activated the cyclic AMP response element-binding protein (CREB) via B2 BK receptor-mediated cPLA2/COX-2 system-derived PGE2/EP-dependent manner. Finally, upregulation of cPLA2 by BK may promote more PGE2 production. These results demonstrated that in RBA-1, activation of CREB by PGE2/EP-mediated PKCδ/c-Src/MAPK cascades is essential for BK-induced de novo cPLA2 protein. More importantly, upregulation of cPLA2 by BK through native cPLA2/COX-2 system may be a positive feedback mechanism that enhances prolonged brain inflammatory responses. Understanding the mechanisms of cPLA2/COX-2 system upregulated by BK on brain astrocytes may provide rational therapeutic interventions for brain injury and inflammatory diseases.
authors.affiliation: Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Hsi-Lung
authors.initials: HL
authors.lastname: Hsieh
authors.forename: Shiau-Wen
authors.initials: SW
authors.lastname: Liu
authors.forename: Hui-Ching
authors.initials: HC
authors.lastname: Tseng
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D054510:Phospholipases A2, Cytosolic / Q000096:biosynthesis*; D051381:Rats
chemical_list: D051546:Cyclooxygenase 2; D054510:Phospholipases A2, Cytosolic; D015232:Dinoprostone; D001920:Bradykinin