Neutrophil immunomodulatory activity of natural organosulfur compounds

Igor A. Schepetkin, Liliya N. Kirpotina, Andrei I. Khlebnikov, Narayanaganesh Balasubramanian, Mark T. Quinn

Research output: Contribution to journalArticle

Abstract

Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, Ferula EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (Allium sativum) is used to boost the immune system; however, the mechanisms involved in the putative immunomodulatory effects of garlic are unknown. We investigated the effects of garlic EO and 22 organosulfur compounds on human neutrophil responses. Garlic EO, allyl propyl disulfide, dipropyl disulfide, diallyl disulfide, and allyl isothiocyanate (AITC) directly activated Ca 2+ flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca 2+ flux, this minor constituent of garlic EO stimulated neutrophil reactive oxygen species (ROS) production. In contrast, a close analog (1,4-dithiane) was unable to activate neutrophil ROS production. Although 1,3-dithiane-1-oxide also stimulated neutrophil ROS production, only traces of this oxidation product were generated after a 5 h treatment of HL60 cells with 1,3-dithiane. Evaluation of several phosphatidylinositol-3 kinase (PI3K) inhibitors with different subtype specificities (A-66, TGX 221, AS605240, and PI 3065) showed that the PI3K p110δ inhibitor PI 3065 was the most potent inhibitor of 1,3-dithiane-induced neutrophil ROS production. Furthermore, 1,3-dithiane enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3 α/β (GSK-3α/β), and cAMP response element binding (CREB) protein in differentiated neutrophil-like HL60 cells. Density functional theory (DFT) calculations confirmed the reactivity of 1,3-dithiane vs. 1,4-dithiane, based on the frontier molecular orbital analysis. Our results demonstrate that certain organosulfur compounds can activate neutrophil functional activity and may serve as biological response modifiers by augmenting phagocyte functions.

Original languageEnglish
Article number1809
JournalMolecules
Volume24
Issue number9
DOIs
Publication statusPublished - 1 Jan 2019

Fingerprint

neutrophils
Volatile Oils
Neutrophils
Reactive Oxygen Species
Phosphatidylinositol 3-Kinase
oils
Garlic
disulfides
Ferula
inhibitors
Fluxes
Glycogen Synthase Kinase 3
Cyclic AMP Response Element-Binding Protein
HL-60 Cells
Phosphorylation
oxygen
Mitogen-Activated Protein Kinase 3
Immune system
Immunologic Factors
Molecular orbitals

Keywords

  • 1,3-dithiane
  • Immunomodulation
  • Neutrophil
  • Organosulfur compounds
  • Phosphatidylinositol-3 kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Neutrophil immunomodulatory activity of natural organosulfur compounds. / Schepetkin, Igor A.; Kirpotina, Liliya N.; Khlebnikov, Andrei I.; Balasubramanian, Narayanaganesh; Quinn, Mark T.

In: Molecules, Vol. 24, No. 9, 1809, 01.01.2019.

Research output: Contribution to journalArticle

Schepetkin, Igor A. ; Kirpotina, Liliya N. ; Khlebnikov, Andrei I. ; Balasubramanian, Narayanaganesh ; Quinn, Mark T. / Neutrophil immunomodulatory activity of natural organosulfur compounds. In: Molecules. 2019 ; Vol. 24, No. 9.
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