The indirubin derivative 6-bromoindirubin-3′-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference
Czapka A, König S, Pergola C, Grune C, Vougogiannopoulou K, Skaltsounis AL, Fischer D, Werz O (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 180
Article Number: 114170
DOI: 10.1016/j.bcp.2020.114170
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 with CRIS profile
Involved external institutions
National and Kapodistrian University of Athens
Greece (GR)
Friedrich-Schiller-Universität Jena
Germany (DE)
Greece (GR)
Friedrich-Schiller-Universität Jena
Germany (DE)
How to cite
APA:
Czapka, A., König, S., Pergola, C., Grune, C., Vougogiannopoulou, K., Skaltsounis, A.L.,... Werz, O. (2020). The indirubin derivative 6-bromoindirubin-3′-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference. Biochemical Pharmacology, 180. https://doi.org/10.1016/j.bcp.2020.114170
MLA:
Czapka, Anna, et al. "The indirubin derivative 6-bromoindirubin-3′-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference." Biochemical Pharmacology 180 (2020).
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