Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds
Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, <i>Ferula</i> EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (<i>Allium sativum</i>) is used to boost the immune system; however, the mechanisms involved in t...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-05-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/24/9/1809 |
| _version_ | 1818487922844762112 |
|---|---|
| author | Igor A. Schepetkin Liliya N. Kirpotina Andrei I. Khlebnikov Narayanaganesh Balasubramanian Mark T. Quinn |
| author_facet | Igor A. Schepetkin Liliya N. Kirpotina Andrei I. Khlebnikov Narayanaganesh Balasubramanian Mark T. Quinn |
| author_sort | Igor A. Schepetkin |
| collection | DOAJ |
| description | Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, <i>Ferula</i> EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (<i>Allium sativum</i>) 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<sup>2+</sup> flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca<sup>2+</sup> 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. |
| first_indexed | 2024-12-10T16:44:36Z |
| format | Article |
| id | doaj.art-bb39f163b6a443cead0a65f87a3cca88 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-10T16:44:36Z |
| publishDate | 2019-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-bb39f163b6a443cead0a65f87a3cca882022-12-22T01:41:07ZengMDPI AGMolecules1420-30492019-05-01249180910.3390/molecules24091809molecules24091809Neutrophil Immunomodulatory Activity of Natural Organosulfur CompoundsIgor A. Schepetkin0Liliya N. Kirpotina1Andrei I. Khlebnikov2Narayanaganesh Balasubramanian3Mark T. Quinn4Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USADepartment of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USAKizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, RussiaDepartment of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USADepartment of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USAOrganosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, <i>Ferula</i> EOs, asafoetida, and other plant and food extracts. Traditionally, garlic (<i>Allium sativum</i>) 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<sup>2+</sup> flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca<sup>2+</sup> 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.https://www.mdpi.com/1420-3049/24/9/1809organosulfur compoundsphosphatidylinositol-3 kinasereactive oxygen species1,3-dithianeneutrophilimmunomodulation |
| spellingShingle | Igor A. Schepetkin Liliya N. Kirpotina Andrei I. Khlebnikov Narayanaganesh Balasubramanian Mark T. Quinn Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds Molecules organosulfur compounds phosphatidylinositol-3 kinase reactive oxygen species 1,3-dithiane neutrophil immunomodulation |
| title | Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds |
| title_full | Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds |
| title_fullStr | Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds |
| title_full_unstemmed | Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds |
| title_short | Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds |
| title_sort | neutrophil immunomodulatory activity of natural organosulfur compounds |
| topic | organosulfur compounds phosphatidylinositol-3 kinase reactive oxygen species 1,3-dithiane neutrophil immunomodulation |
| url | https://www.mdpi.com/1420-3049/24/9/1809 |
| work_keys_str_mv | AT igoraschepetkin neutrophilimmunomodulatoryactivityofnaturalorganosulfurcompounds AT liliyankirpotina neutrophilimmunomodulatoryactivityofnaturalorganosulfurcompounds AT andreiikhlebnikov neutrophilimmunomodulatoryactivityofnaturalorganosulfurcompounds AT narayanaganeshbalasubramanian neutrophilimmunomodulatoryactivityofnaturalorganosulfurcompounds AT marktquinn neutrophilimmunomodulatoryactivityofnaturalorganosulfurcompounds |