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BK Induces cPLA2 Expression via an Autocrine Loop Involving COX-2-Derived PGE2 in Rat Brain Astrocytes

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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.

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Acknowledgments

This work was supported by the National Science Council, Taiwan; Grant numbers: NSC102-2321-B-182-011, NSC101-2320-B-182-039-MY3, NSC101-2314-B-182-182A-112, and NSC102-2320-B-255-005-MY3; the Chang Gung Medical Research Foundation, Grant numbers: CMRPD1C0102, CMRPD1B0383, CMRPD1C0562, CMRPG3B1093, CMRPG3C1302, CMRPD1B0331, CMRPG5C0061, CMRPF1C0191, and CMRPF1A0063; and the Ministry of Education, Taiwan; Grant numbers: EMRPD1D0231 and EMRPD1D0241.

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Authors and Affiliations

  1. Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan

    Chih-Chung Lin & Shiau-Wen Liu

  2. Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Kwei-San, Tao-Yuan, Taiwan

    Hsi-Lung Hsieh

  3. Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan

    Hui-Ching Tseng, Li-Der Hsiao & Chuen-Mao Yang

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  1. Chih-Chung Lin
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Correspondence to Chuen-Mao Yang.

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Chih-Chung Lin and Hsi-Lung Hsieh are equal contributors.

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Lin, CC., Hsieh, HL., Liu, SW. et al. BK Induces cPLA2 Expression via an Autocrine Loop Involving COX-2-Derived PGE2 in Rat Brain Astrocytes. Mol Neurobiol 51, 1103–1115 (2015). https://doi.org/10.1007/s12035-014-8777-7

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