Τίτλος:
The indirubin derivative 6-bromoindirubin-3′-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2020 Elsevier Inc.
Συγγραφείς:
Czapka, A.
König, S.
Pergola, C.
Grune, C.
Vougogiannopoulou, K.
Skaltsounis, A.-L.
Fischer, D.
Werz, O.
Περιοδικό:
Biochemical Pharmacology
Εκδότης:
ELSEVIER SCIENCE INC 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
Λέξεις-κλειδιά:
2 (2,4 dichlorophenyl) 3 (1 methyl 3 indolyl)maleimide; 6 bromoindirubin 3' glycerol oxime; beta catenin; cyclooxygenase 2; glycogen synthase kinase 3; indirubin; interleukin 10; interleukin 1beta; lipopolysaccharide; prostaglandin; unclassified drug; 6-bromoindirubin-3'-oxime; autacoid; cytokine; glycogen synthase kinase 3; indirubin; indole derivative; oxime; prostaglandin; prostaglandin receptor blocking agent, adult; aged; Article; egg; enzyme activity; enzyme inhibition; hen; human; human cell; IC50; monocyte; nonhuman; normal human; priority journal; prostaglandin release; tandem mass spectrometry; ultra performance liquid chromatography; adolescent; animal; chicken; dose response; drug effect; female; male; metabolism; middle aged; monocyte; young adult, Adolescent; Adult; Aged; Animals; Chickens; Cytokines; Dose-Response Relationship, Drug; Female; Glycogen Synthase Kinase 3; Humans; Indoles; Inflammation Mediators; Male; Middle Aged; Monocytes; Oximes; Prostaglandin Antagonists; Prostaglandins; Young Adult
DOI:
10.1016/j.bcp.2020.114170
