Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively.

Abstract

Leukotrienes generated by 5-lipoxygenase (5-LOX)-catalyzed reaction are key regulators of inflammation. In ionophore-stimulated (A23187; 1-2.5 μM) human blood neutrophils or differentiated HL-60 cells, vitamin E forms differentially inhibited leukotriene B(4) (LTB(4)) with an IC(50) of 5-20 μM for γ-tocopherol, δ-tocopherol (δT), and γ-tocotrienol, but a much higher IC(50) for α-tocopherol. 13'-Carboxychromanol, a long-chain metabolite of δT, suppressed neutrophil- and HL-60 cell-generated LTB(4) with an IC(50) of 4-7 μM and potently inhibited human recombinant 5-LOX activity with an IC(50) of 0.5-1 μM. In contrast, vitamin E forms had no effect on human 5-LOX activity but impaired ionophore-induced intracellular calcium increase and calcium influx as well as the subsequent signaling including ERK1/2 phosphorylation and 5-LOX translocation from cytosol to the nucleus, a key event for 5-LOX activation. Further investigation showed that δT suppressed cytosolic Ca(2+) increase and/or LTB(4) formation triggered by ionophores, sphingosine 1-phosphate, and lysophosphatidic acid but not by fMLP or thapsigargin, whereas 13'-carboxychromanol decreased cellular production of LTB(4) regardless of different stimuli, consistent with its strong inhibition of the 5-LOX activity. These observations suggest that δT does not likely affect fMLP receptor-mediated signaling or store depletion-induced calcium entry. Instead, we found that δT prevented ionophore-caused cytoplasmic membrane disruption, which may account for its blocking of calcium influx. These activities by vitamin E forms and long-chain carboxychromanol provide potential molecular bases for the differential anti-inflammatory effects of vitamin E forms in vivo.

• Authors: Ziying Jiang, Xinmin Yin, Qing Jiang
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 186 Issue 2 Pg. 1173-9 (Jan 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21169551 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Calcium Channel Blockers
• Chromans
• Leukotriene Antagonists
• Lipoxygenase Inhibitors
• Vitamin E
• Leukotriene B4
• Calcimycin
• Calcium

Topics

• Calcimycin (pharmacology)
• Calcium (antagonists & inhibitors, metabolism)
• Calcium Channel Blockers (pharmacology)
• Catalysis (drug effects)
• Cell Line, Transformed
• Cell Line, Tumor
• Chromans (metabolism, pharmacology)
• Clone Cells
• Down-Regulation (drug effects, immunology)
• HL-60 Cells
• Humans
• Leukotriene Antagonists (metabolism, pharmacology)
• Leukotriene B4 (antagonists & inhibitors, blood)
• Lipoxygenase Inhibitors (pharmacology)
• Neutrophil Activation (drug effects, immunology)
• Neutrophils (drug effects, enzymology, metabolism)
• Vitamin E (metabolism, pharmacology)