Guggulsterone protects against lipopolysaccharide-induced inflammation and lethal endotoxemia via heme oxygenase-1.

Abstract

Guggulsterone (GS) is a phytosterol used to treat inflammatory diseases. Although many studies have examined the anti-inflammatory activities of GS, the detailed mechanisms of GS in lipopolysaccharide (LPS)-induced inflammation and endotoxemia have not yet been examined. Therefore, we investigated the anti-inflammatory effects of GS on LPS-induced inflammation. In murine peritoneal macrophages, the anti-inflammatory activity of GS was primarily mediated by heme oxygenase-1 (HO-1) induction. HO-1 induction by GS was mediated by GSH depletion and reactive oxygen species (ROS) production. The ROS generated by GS caused the phosphorylation of GSK3β (ser9/21) and p38, leading to the translocation of nuclear factor erythroid-related factor 2 (Nrf2), which ultimately induced HO-1. In addition, GS pretreatment significantly inhibited inducible nitric oxide synthase (iNOS), iNOS-derived NO, and COX-2 protein and mRNA expression, and production of COX-derived prostaglandin PGE2, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). In a mouse model of endotoxemia, GS treatment prolonged survival and inhibited the expression of inflammatory mediators, including IL-1β, IL-6, and TNF-α. GS treatment also inhibited LPS-induced liver injury. These results suggest that GS-induced HO-1 could exert anti-inflammatory effects via ROS-dependent GSK (ser21/9)-p38 phosphorylation and nuclear translocation of Nrf2.

• Authors: Bitna Kweon, Dong-Uk Kim, Jin-Young Oh, Gi-Sang Bae, Sung-Joo Park
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 124 Issue Pt B Pg. 111073 (Nov 2023) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 37844468 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• Lipopolysaccharides
• pregna-4,17-diene-3,16-dione
• NF-kappa B
• Interleukin-6
• Tumor Necrosis Factor-alpha
• Heme Oxygenase-1
• NF-E2-Related Factor 2
• Reactive Oxygen Species
• Anti-Inflammatory Agents
• Nitric Oxide Synthase Type II

Topics

• Animals
• Mice
• Lipopolysaccharides (pharmacology)
• NF-kappa B (metabolism)
• Interleukin-6 (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Heme Oxygenase-1 (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Endotoxemia (chemically induced, drug therapy)
• Inflammation (drug therapy, metabolism)
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Nitric Oxide Synthase Type II (genetics, metabolism)