Regulation of the Arachidonic Acid Cascade and PAF Metabolism in Reproductive Tissues
Murray D. Mitchell in Eicosanoids in Reproduction, 2020
Glycerophospholipid degradation in mammalian tissue is primarily catalyzed by the action of phospholipases, as illustrated in Figure 2. With the exception of phosphatidylinositol, most glycerophospholipids are degraded via phospholipase A enzymes. The phosphatidylinositol pathway employs phospholipase C; the products of this reaction are inositol phosphate(s) and diacylglycerol. The role of the inositol polyphosphates and diacylglycerol as second messengers and the relationship of Ca2+ to signal transduction and protein kinase C activity have recently been reviewed.31,32 More recently, a role for phospholipase D, which has been purified from mammalian tissues,33 has been implicated in the generation of phosphatidic acid, which may subsequently function as a second messenger.34
Pharmacological Control of Eosinophil Activation and Secretion
Gerald J. Gleich, A. Barry Kay in Eosinophils in Allergy and Inflammation, 2019
There is increasing evidence that phospholipase D (PLD) may play a role in signal transduction of inflammatory cells (62,63). PLD hydrolyzes predominantly phosphatidylcholine producing free choline and phosphatidic acid, which may then form diacylglycerol. Diacylglycerol can activate PKC, which in turn may activate PLD, providing a mechanism for perpetuation of responses. PLD may also be activated directly by certain receptors, including those that have intrinsic tyrosine kinase activity (64). In neutrophils PLD appears to be important in “priming” of the cells for increased responsiveness (65). PLD activity has also been demonstrated in human eosinophils (66) but does not appear to be important in oxidative burst responses to PAF or LTB4. PLD is activated by phorbol esters in guinea pig eosinophils, but not by PAF or LTB4 (Perkins R, Giembycz M, Barnes PJ, unpublished observations). In view of the potential importance of PLD in cell priming, it is important to investigate the effect of cytokines on PLD activation. Currently available PLD inhibitors such as wortmannin are nonspecific, and more selective inhibitors are needed; such drugs may have important therapeutic potential since they may reduce the priming of inflammatory cells and down-regulate inflammation.
Role of Vasoactive Intestinal Peptide in Myocardial Ischemia Reperfusion Injury
Sami I. Said in Proinflammatory and Antiinflammatory Peptides, 2020
Recently, phospholipase D has been found to be involved in the intracellular signaling in ischemic heart (71). Phospholipase D signaling, like the phenomenon of phospholipase C signaling, also occurs in the ischemic heart; but unlike phospholipase C signaling, phospholipase D signaling is actually beneficial to the ischemic heart. The results of this study also suggested that the activation of phospholipase D contributes significantly to the formation of DG, because phospholipase D-produced phosphatidic acid is dephosphorylated by phosphatidate phosphatase into DG (whereas phospholipase C activation produces DG directly). It seems likely that phosphatidic acid functions as a second messenger either indirectly, through generation of DG and subsequent protein kinase C activity, or directly, through an as yet unknown mechanism (as suggested also by recent studies in neutrophils and other cell types). If this is true (this possibility has never been explored), many unanswered questions may be resolved.
Expression and clinical significance of phospholipase D1 in de novo acute myeloid leukemia
Published in Hematology, 2020
Ying Lu, Jiasi Zhou, Renzhi Pei, Fenglin Li, Jie Jin, Lei Jiang
Phospholipase D (PLD) is a membrane protein that hydrolyzes phosphatidylcholine to phosphatidic acid and choline [3]. PLD1 and PLD2, two mammalian isoforms of PLD, have been proposed to play important roles in cancer. For instance, PLD1 is overexpressed in human breast cancer tissues and inhibition of either PLD1 or PLD2 enhances the sensitivity of breast cancer cells to radiotherapy [4,5]. Increased PLD expression or activity is also found in colorectal and prostate cancers, although the underlying mechanism remains unclear [6,7]. When wild-type melanoma and lung carcinoma cells are implanted in PLD1 deficiency mice, tumor growth, angiogenesis, and metastasis are impaired, indicating a critical role of PLD1 in tumor microenvironment [8]. However, a subset of chronic lymphocytic leukemia unresponsive to chemokine is characterized by defective activation of PLD1, suggesting that the function of PLD1 is not always pro-oncogenic [9,10].
PLD1 knockdown reduces metastasis and inflammation of fibroblast-like synoviocytes in rheumatoid arthritis by modulating NF-κB and Wnt/β-catenin pathways
Published in Autoimmunity, 2021
Zhengyu Zhang, Xi Chen, Bo Gao, Guomin Sun, Yan Wang, Junke Wang, Ting Zhang, Hao Qian, Yu Zhang, Jun Huang, Rurong Sun, Jiabiao Wu, Lei Zhou
Phospholipase D (PLD) is an enzyme that hydrolyses phosphodiester linkages in phosphatidylcholine (PC) [4]. PLD is divided into two subtypes, named PLD1 and PLD2 [6]. In mammals, PLD1 mainly acts in some signal transduction pathways, such as membrane transport, regulation of mitosis and cellular actin skeleton [7]. It is reported that PLD1 is able to regulate the proliferation, migration, and invasion of tumour cells [8,9]. Targeting PLD1 can ameliorate collagen-induced arthritis (CIA) by regulating the imbalance of Treg and Th17 cells, and thus inhibiting the development of osteoclasts [10]. In addition, PLD is associated with the activation of a variety of inflammatory mediators, which in turn affect the proliferation, division, and secretion of cell-specific protein kinases [4]. Therefore, the expression of PLD might be related with arthritis. However, the role of PLD1 in FLSs of RA remains unclear, which requires further investigations.
Different roles for the acyl chain and the amine leaving group in the substrate selectivity of N-Acylethanolamine acid amidase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Andrea Ghidini, Laura Scalvini, Francesca Palese, Alessio Lodola, Marco Mor, Daniele Piomelli
NAAA’s best known substrate, PEA4, is a member of the fatty acid ethanolamide (FAE) family of lipid messengers, which also includes anandamide (arachidonoylethanolamide) and oleoylethanolamide (OEA). Anandamide is an endogenous agonist for cannabinoid receptors, the target of Δ9-tetrahydrocannabinol in cannabis11, while PEA and OEA activate the ligand-operated transcription factor, peroxisome proliferator activated receptor-α (PPAR-α), to regulate energy balance12–14, pain15, and inflammation16,17. NAAA plays a key role in the control of the cellular levels of PEA. In healthy tissues, this lipid mediator is generated by the action of a structurally unique phospholipase D (N-acylphosphatidylethanolamine phospholipase D, NAPE-PLD) that cleaves the glycerophospholipid precursor, N-palmitoylphosphatidylethanolamine, to produce FAE and phosphatidic acid18–20. PEA formation contributes to tissue homeostasis by recruiting PPAR-α-dependent transcriptional programs that enhance host defence and curb inflammatory responses21,22. Suprathreshold inflammatory stimuli cause a rapid reduction in tissue PEA content, which may enable in turn the development of inflammation22. This decline in tissue PEA levels is due to a two-pronged process that involves the suppression of NAPE-PLD transcription23 and the enhancement of NAAA expression and activity24.
Related Knowledge Centers
- Cell Signaling
- Choline
- Enzyme
- Hydrolysis
- Phosphatidic Acid
- Phosphatidylcholine
- Phospholipase
- Protein Superfamily
- Substrate
- Substrate Presentation