Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

Abstract

The rhizome of ginger (Zingiber officinale) is employed in Asian traditional medicine to treat mild forms of rheumatoid arthritis and fever. We have profiled ginger constituents for robust effects on proinflammatory signaling and cytokine expression in a validated assay using human whole blood. Independent of the stimulus used (LPS, PMA, anti-CD28 Ab, anti-CD3 Ab, and thapsigargin), ginger constituents potently and specifically inhibited IL-1β expression in monocytes/macrophages. Both the calcium-independent phospholipase A2 (iPLA2)-triggered maturation and the cytosolic phospholipase A2 (cPLA2)-dependent secretion of IL-1β from isolated human monocytes were inhibited. In a fluorescence-coupled PLA2 assay, most major ginger phenylpropanoids directly inhibited i/cPLA2 from U937 macrophages, but not hog pancreas secretory phospholipase A2. The effects of the ginger constituents were additive and the potency comparable to the mechanism-based inhibitor bromoenol lactone for iPLA2 and methyl arachidonyl fluorophosphonate for cPLA2, with 10-gingerol/-shogaol being most effective. Furthermore, a ginger extract (2 μg/ml) and 10-shogaol (2 μM) potently inhibited the release of PGE2 and thromboxane B2 (>50%) and partially also leukotriene B4 in LPS-stimulated macrophages. Intriguingly, the total cellular arachidonic acid was increased 2- to 3-fold in U937 cells under all experimental conditions. Our data show that the concurrent inhibition of iPLA2 and prostanoid production causes an accumulation of free intracellular arachidonic acid by disrupting the phospholipid deacylation-reacylation cycle. The inhibition of i/cPLA2, the resulting attenuation of IL-1β secretion, and the simultaneous inhibition of prostanoid production by common ginger phenylpropanoids uncover a new anti-inflammatory molecular mechanism of dietary ginger that may be exploited therapeutically.

Multitargeted Effects of Hangeshashinto for Treatment of Chemotherapy-Induced Oral Mucositis on Inducible Prostaglandin E2 Production in Human Oral Keratinocytes

“…According to the literature, ginger-derived phenylpropanoids, including shogaols and gingerols suppress cPLA2 enzymatic activity. 15 These lines show that HST is quite different from NSAIDs and COX-2 selective inhibitors. It should be noted that shogaols and gingerols are hardly detected in human plasma in their respective unchanged forms after they are administered orally because they are easily metabolized by β-glucuronidase and sulfatase in the small intestine and liver.…”

“…[10][11][12] It has been reported that some ingredients of HST inhibit PGE2 production and/or COX-2 expression. [13][14][15][16][17][18][19][20][21][22] Phenylpropanoids like [6]-shogaol (6SG) and [6]-gingerol (6GG), flavonoids like wogonin (WGN), baicalein (BCN), and baicalin (BC), and isoquinoline alkaloids like berberine (BBR) are well established to have anti-PGE2 activity via their particular mechanisms. However, these studies demonstrated the effects and features of each as only a single compound, but not HST as a multicomponent agent.…”

Ginger (Zingiber officinale Roscoe) prevents the development of morphine analgesic tolerance and physical dependence in rats

“…Nievergelt et al (2011) reported that 10-gingerol/-shogaol from the rhizome of ginger potently inhibit phospholipase A2.…”

The effect of mefenamic acid and ginger on pain relief in primary dysmenorrhea: a randomized clinical trial

“…Nitrous oxide improves pelvic circulation by expanding vessels, and may prevent prostaglandin aggregation. As another probable mechanism, the pungent components of ginger strongly and specifically inhibit interleukin-1beta in macrophages [41]. Furthermore, researchers point out that salicylate in fresh ginger root has relieving and anti-inflammatory effects, and can be used for treating smooth muscles disorders [25].…”