The indirubin derivative 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference.

Abstract

Indirubin is a natural bis-indole alkaloid contained as active ingredient in the traditional Chinese remedy Danggui Longhui Wan. Indirubin and its 3'-oxime derivatives exhibit anti-cancer and anti-inflammatory properties and they inhibit glycogen synthase kinase (GSK)-3 in cell-free assays where 6-bromoindirubin-3'-oxime (6BIO) is among the most potent analogs. Here, we reveal 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE) as highly potent derivative able to inhibit pro-inflammatory cytokine, chemokine and prostaglandin (PG) release in human primary monocytes while increasing anti-inflammatory interleukin (IL)-10 levels. 6BIGOE suppressed lipopolysaccharide (LPS)-induced IL-1β and PGE2 release with IC50 of 0.008 and 0.02 µM, respectively, being ≥ 12-fold more potent than 6BIO. The effects of 6BIGOE are mediated via intracellular inhibition of GSK-3, where 6BIGOE again surpassed the effectiveness of 6BIO despite the higher potency of the latter in cell-free GSK-3 activity assays. Side-by-side comparison of 6BIGOE (0.1 µM) with the selective GSK-3 inhibitor SB216763 (5 µM) revealed congruent properties such as enrichment of β-catenin and suppression of cyclooxygenase (COX)-2 protein levels due to GSK-3 inhibition. Metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry showed that 6BIGOE selectively decreases pro-inflammatory COX-derived product formation without marked modulation of other lipid mediators. In summary, 6BIGOE is a highly potent indirubin derivative in the cellular context that favorably modulates pro- and anti-inflammatory cytokines as well as COX-2-derived PG via interference with GSK-3.

• Authors: Anna Czapka, Stefanie König, Carlo Pergola, Christian Grune, Konstantina Vougogiannopoulou, Alexios-Leandros Skaltsounis, Dagmar Fischer, Oliver Werz
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 180 Pg. 114170 (10 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32710971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• 6-bromoindirubin-3'-oxime
• Cytokines
• Indoles
• Inflammation Mediators
• Oximes
• Prostaglandin Antagonists
• Prostaglandins
• Glycogen Synthase Kinase 3
• indirubin

Topics

• Adolescent
• Adult
• Aged
• Animals
• Chickens
• Cytokines (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Female
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Humans
• Indoles (pharmacology)
• Inflammation Mediators (antagonists & inhibitors, metabolism)
• Male
• Middle Aged
• Monocytes (drug effects, metabolism)
• Oximes (pharmacology)
• Prostaglandin Antagonists (pharmacology)
• Prostaglandins (metabolism)
• Young Adult