Expression of mRNAs for the diacylglycerol kinase family in immune cellsduring an inflammatory reaction

Abstract

Phosphoinositide metabolism is intimately involved in cellular signal transduction. In response to extracellular stimuli, it generates diacylglycerol (DG), which serves as a lipid second messenger molecule to activate various proteins in various organs under pathophysiological conditions. Diacylglycerol kinase (DGK) constitutes an enzyme family that catalyzes conversion of DG to phosphatidic acid. It is therefore regarded as a regulator of the DG signal. Previous studies have revealed the critical role of α and ζ types of DGK in T cell functions. Nevertheless, little is known about the expression patterns of the DGK family in immune cells of various kinds. After examination of the expression profile of DGK isozymes in immune cells that are isolated from human blood, we investigated whether their mRNA expression levels would be changed during an inflammatory reaction. Results showed that DGK isozyme mRNAs are widely expressed in immune cells, except for DGKβ and DGKι. During an inflammatory reaction, DGKε mRNA was increased transiently in the initial phase (20-40 min) of stimulation with both LPS and IL-2 in T cellderived HUT-102 cells and macrophage-derived RAW264 cells. At the organismal level, an intraperitoneal injection of LPS also induced upregulation of DGKε mRNA in the spleen in a similar, but not identical, manner. These results suggest that DGKε is involved in inflammatory processes of the cellular immune system. Phosphoinositide (PI) turnover is a key event of signal transduction in regulating cellular responses to widely various extracellular stimuli (6, 19). The PI-derived lipid second messengers are well recognized as carrying out specific tasks for widely various biological processes in eukaryotic cells (5). In this system, hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) by an action of phospholipase C (PLC) generates diacylglycerol (DG) (30, 31), which activates various effector proteins through the DGresponsive C1 domain, such as protein kinase C (PKC), protein kinase D, Munc-13, transient receptor potential (TRP) channel, and Ras guanyl nucleotide releasing protein (RasGRP) (38). Levels of DG should be tightly controlled to maintain cellular responsiveness within a physiological range because sustained activation of the DG signaling would induce a maladaptation of cellular homeostasis, which can promote tumorigenesis or cell death (26). DG metabolism is catalyzed by its phosphorylation by diacylglycerol kinase (DGK), which subsequently generates phosphatidic acid (PA). Recent evidence has revealed that PA, the product of DGK itself, is also linked to the regulation of signaling molecules, including a mammalian target of rapamycin (mTOR), phosphatidylinositol 4P 5-kinase (PI4P5K), Ras guanosine triphosphatase (RasGTPase)-activating pro-

Diacylglycerol kinase ε deficiency preserves glucose tolerance and modulates lipid metabolism in obese mice

“…Thus, DGK has a prominent role in enriching inositol phospholipids with unsaturated fatty acids (12). Because the functional overlap between DGK and other DGKs is predicted to be minimal, loss of DGK function gives rise to several disease states (15)(16)(17)(18)22). Here we explored the role of DGK in the regulation of glucose and energy homeostasis in relation to dietaryinduced insulin resistance and obesity.…”

“…In brain, DGK modulates neuronal signaling pathways linked to synaptic activity, neuronal plasticity, and epileptogenesis (15). In spleen, DGK mRNA is upregulated in T cells in response to inflammatory stimuli (16), implicating a role in immunology (16). In the heart, DGK overexpression prevents cardiac hypertrophy (17).…”

mRNA expression of diacylglycerol kinase isoforms in insulin-sensitive tissues: effects of obesity and insulin resistance

“…DGK ε is expressed in various immune cells, with increased levels observed in response to inflammatory stimuli (Yamamoto et al. ). In humans, DGK ε is highly expressed in brain and spleen, with lower, but comparable levels in liver, skeletal muscle and adipose tissue (Krupp et al.…”

“…), immune cells during an inflammatory reaction (Yamamoto et al. ), rat retina (Hozumi et al. ), lung (Katagiri et al.…”

“…DGK isoforms regulating wide variety of physiological processes including growth, metabolism, proliferation, immunological and neural development (Topham ; Krishna and Zhong ; Ishisaka and Hara ; Shirai and Saito ; Yamamoto et al. ). DGK δ expression is decreased in skeletal muscle from type 2 diabetic patients and haploinsufficiency (DGK δ +/− ) in mice leads to insulin resistance and late‐onset obesity (Chibalin et al.…”