Identification of P2Y receptors involved in oleamide-suppressing inflammatory responses in murine microglia and human dendritic cells

Abstract

Microglia, a type of immune cell in the central nervous system, are involved in inflammation leading to neurodegenerative diseases. We previously identified oleamide from fermented dairy products as a neuroprotective compound suppressing microglial inflammation. Oleamide is an endocannabinoid and displays anti-inflammatory activity via the cannabinoid-2 (CB2) receptor; however, the mechanism underlying this anti-inflammatory activity has not been fully elucidated. Here, we found that the suppressive effect of oleamide on microglial tumor necrosis factor-α (TNF-α) production was canceled by inhibitors of G-protein-coupled receptor (GPCR) downstream signaling but not by a CB2 antagonist, suggesting that GPCRs other than CB2 are involved in the anti-inflammatory effects of oleamide. An extensive screen for GPCRs using a transforming growth factor-α shedding assay system identified P2Y1, P2Y4, P2Y6, P2Y10, and P2Y11 as candidates for the oleamide target. P2Y1 and P2Y10 agonists suppressed microglial TNF-α production, while a pan P2 receptor antagonist canceled the suppressive effect. Furthermore, we observed a relationship between the P2Y1 agonistic activities and the suppressive activities of oleamide and its analogs. Taken together, our results suggest that, in addition to CB2, P2Y type receptors are the potential targets of oleamide, and P2Y1 plays a role in the suppression of microglial inflammatory responses by oleamide. (200/200 words)

Anti-inflammatory and detoxification activities of some Ipomoea species determined by ion channel inhibition and their phytochemical constituents

“…However, the experiment on oleamide activity merits further study given its use for treatments of Alzheimer's disease, stress, deep sleep, and appetite induction [10]. Recently, the anti-inflammatory effect of oleamide has been shown [11][12][13]. Additionally, phytol was present at 21.58% in I. batatas, 13.35% in I. carnea, and 11.76% in I. pes-caprae; but the amount was not high enough to functionally support the bioactivities of the plants.…”

Oleamide in Ipomoea and Dillenia Species and Inflammatory Activity Investigated through Ion Channel Inhibition

“…Supported by one more study, D. ovata was investigated to have no toxicity in normal human both at the cell and DNA levels [7]. The soft capsule may be used for Alzheimer's treatment due to its oleamide component [6], in addition with its anti-inflammatory activity [9,10]. Moreover, the other chemicals in the extract may be beneficial for human body as functional foods or nutraceuticals.…”

“…Recently, one of its functions was related to anti-inflammatory activities following disclosing. Oleamide shows an anti-inflammatory effect through inhibition of nuclear factor-kappa B activation in lipopolysaccharide-stimulated BV2 microglia [8]; has been used for the prevention and treatment of athero-sclerosis, thrombosis, arthritis, and cancer through its metabolic conversion into pros-taglandins, thromboxanes, and leukotrienes, can be used as a single ingredient treatment for inflammatory diseases [9]; is an endocannabinoid and displays anti-inflammatory activity via the cannabinoid-2 receptor [10].…”

Current Knowledge on the Biology of Lysophosphatidylserine as an Emerging Bioactive Lipid

“…Several immune-related functions of LPS 2 in these cell types have been revealed in recent years. Kita et al demonstrated that LysoPS and LPS 2 -selective LysoPS analog suppress LPS-induced TNF-α production in murine DCs and microglia in vitro [7]. Hwang et al reported LPS 2 functions in human eosinophils [5].…”

“…Recent analyses of mutant mice of these LysoPS receptors revealed immunomodulatory functions of LysoPS (Fig. 1) [4][5][6][7][8][9][10][11]. Moreover, LysoPSmetabolizing enzymes, including producing enzymes and degrading enzymes, have been identified in platelets and the CNS, leading to a better understanding of the links between LysoPS and diseases such as neurodegenerative disorders and autoimmune diseases [12][13][14][15][16][17][18][19].…”