Ginger phenylpropanoids inhibit IL-1beta and prostanoid secretion and disrupt arachidonate-phospholipid remodeling by targeting phospholipases A2.

Andreas Nievergelt,Karl-Heinz Altmann,Jürg Gertsch,Roland Schoop,Janine Marazzi

doi:10.4049/jimmunol.1100880

Andreas Nievergelt, Karl-Heinz Altmann + Show 3 more

Open Access

https://doi.org/10.4049/jimmunol.1100880

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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 A(2) (iPLA(2))-triggered maturation and the cytosolic phospholipase A(2) (cPLA(2))-dependent secretion of IL-1β from isolated human monocytes were inhibited. In a fluorescence-coupled PLA(2) assay, most major ginger phenylpropanoids directly inhibited i/cPLA(2) from U937 macrophages, but not hog pancreas secretory phospholipase A(2). The effects of the ginger constituents were additive and the potency comparable to the mechanism-based inhibitor bromoenol lactone for iPLA(2) and methyl arachidonyl fluorophosphonate for cPLA(2), with 10-gingerol/-shogaol being most effective. Furthermore, a ginger extract (2 μg/ml) and 10-shogaol (2 μM) potently inhibited the release of PGE(2) and thromboxane B2 (>50%) and partially also leukotriene B(4) 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 iPLA(2) and prostanoid production causes an accumulation of free intracellular arachidonic acid by disrupting the phospholipid deacylation-reacylation cycle. The inhibition of i/cPLA(2), 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.

Highlights

A ginger extract (2 mg/ml) and 10-shogaol (2 mM) potently inhibited the release of PGE2 and thromboxane B2 (>50%) and partially leukotriene B4 in LPS-stimulated macrophages
We provide evidence that the inhibition of i/cytosolic phospholipase A2 (cPLA2) by phenylpropanoids is directly linked to the global inhibition of IL-1b secretion by ginger extracts in vitro
Because the ginger extract and 10-shogaol inhibit both independent phospholipase A2 (iPLA2) and COX, we speculated that this double effect may lead to an increase of free arachidonic acid (AA) from the pool that constitutively feeds COX catalyzing prostanoid synthesis

Summary

Introduction

A ginger extract (2 mg/ml) and 10-shogaol (2 mM) potently inhibited the release of PGE2 and thromboxane B2 (>50%) and partially leukotriene B4 in LPS-stimulated macrophages. For IL-1b detection with CBA, the isolated monocytes, in 96-well plates at a density of 2 3 106 cells/ml and 100 ml/ well, were stimulated in fresh RPMI 1640 for 4 h under different priming conditions (vehicle, 100 ng/ml LPS and/or 10 mg/ml ginger Hot Flavor extract).

Results

Conclusion