Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds.
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 Ca2+ flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca2+ 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.
['Schepetkin|Igor A|IA|', 'Kirpotina|Liliya N|LN|', 'Khlebnikov|Andrei I|AI|0000-0002-3022-4510', 'Balasubramanian|Narayanaganesh|N|', 'Quinn|Mark T|MT|0000-0001-8114-5073']
D000498:Allyl Compounds D000975:Antioxidants D004220:Disulfides D005737:Garlic D018922:HL-60 Cells D006571:Heterocyclic Compounds D006801:Humans D007155:Immunologic Factors D020928:Mitogen-Activated Protein Kinases D009504:Neutrophils D009930:Organic Chemicals D019869:Phosphatidylinositol 3-Kinases D000081082:Phosphoinositide-3 Kinase Inhibitors D010766:Phosphorylation D011810:Quinoxalines D017382:Reactive Oxygen Species D013440:Sulfides D013457:Sulfur Compounds D045162:Thiazolidinediones
neutrophil organosulfur compounds 1,3-dithiane reactive oxygen species phosphatidylinositol-3 kinase immunomodulation