The Garlic Compound Z-Ajoene, S-Thiolates COX2 and STAT3 and Dampens the Inflammatory Response in RAW264.7 Macrophages.

Abstract

SCOPE:

Garlic (Allium sativum) has been used for centuries as a prophylactic and therapeutic medicinal agent to control inflammation-associated pathologies. To investigate the underlying mechanisms, an in vitro inflammatory model is established using RAW264.7 murine macrophages exposed to low-doses of lipopolysaccharide (LPS) in the presence of garlic compounds allicin and Z-ajoene (ZA), mimicking regular garlic consumption.

METHODS AND RESULTS:

Both allicin and Z-ajoene dampen both transcript and protein expression of the pro-inflammatory cytokines IL1β, IL6, and IL12β, and upregulate the expression of the anti-inflammatory cytokine IL10. Protein arrays of selected secreted inflammatory mediators confirm that Z-ajoene has a pronounced down-regulatory effect on LPS-induced inflammatory cytokines and chemokines. Many of these proteins are known targets of the transcription factor signal transducer and activator of transcription 3 (STAT3); and indeed, Z-ajoene or its analogue dansyl-ajoene is found to decrease phosphorylation and nuclear translocation of STAT3, and to covalently modify the protein by S-thiolation at Cys108, Cys367, and Cys687. Z-Ajoene dose-dependently and non-competitively inhibit the activity of cyclooxygenase 2 (COX2), possibly attributed to S-thiolation at Cys9 and Cys299.

CONCLUSION:

The characterization of Z-ajoene's activity of targeting and covalently modifying STAT3 and COX2, both important regulators of inflammation, may contribute to the health benefits of regular dietary garlic consumption.

• Authors: Jessica K Hitchcock, Nonkululeko Mkwanazi, Christopher Barnett, Lisa M Graham, Arieh A Katz, Roger Hunter, Georgia Schäfer, Catherine H Kaschula
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 65 Issue 3 Pg. e2000854 (02 2021) ISSN: 1613-4133 [Electronic] Germany
• PMID: 33274836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley-VCH GmbH.

Chemical References

• Cyclooxygenase 2 Inhibitors
• Cytokines
• Disulfides
• Lipopolysaccharides
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Sulfhydryl Compounds
• Sulfinic Acids
• Sulfoxides
• allicin
• ajoene
• Ptgs2 protein, mouse
• Cyclooxygenase 2

Topics

• Animals
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Cytokines (genetics, metabolism)
• Disulfides (pharmacology)
• Garlic (chemistry)
• Inflammation (drug therapy, metabolism, pathology)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism)
• Mice
• RAW 264.7 Cells
• STAT3 Transcription Factor (metabolism)
• Sulfhydryl Compounds (metabolism)
• Sulfinic Acids (pharmacology)
• Sulfoxides (pharmacology)