Alloxan attenuates glucosamine-induced NF-κB activation and proinflammatory gene expression under normoglycemic conditions

Glucosamine (GlcN), a critical substrate in the hexosamine biosynthetic pathway, is known to modulate inflammatory responses in macrophages depending on extracellular glucose concentration. In hyperglycemic conditions (25 mM glucose), GlcN suppresses the production of nitric oxide (NO) and decreases...

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Veröffentlicht in:BMB reports Jg. 58; H. 11; S. 467
Hauptverfasser: Kim, Sang-Min, Lee, Chanhaeng, Kim, Dong Yeol, Han, Inn-Oc
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Korea (South) 01.11.2025
Schlagworte:
Alloxan - pharmacology
Animals
Cyclooxygenase 2 - metabolism
Glucosamine - metabolism
Glucosamine - pharmacology
Inflammation - genetics
Inflammation - metabolism
Interleukin-6 - metabolism
Lipopolysaccharides - pharmacology
Macrophages - drug effects
Macrophages - metabolism
Mice
NF-kappa B - metabolism
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - genetics
Nitric Oxide Synthase Type II - metabolism
RAW 264.7 Cells
Tumor Necrosis Factor-alpha - metabolism
ISSN:1976-670X, 1976-670X
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Zusammenfassung:Glucosamine (GlcN), a critical substrate in the hexosamine biosynthetic pathway, is known to modulate inflammatory responses in macrophages depending on extracellular glucose concentration. In hyperglycemic conditions (25 mM glucose), GlcN suppresses the production of nitric oxide (NO) and decreases the expression of inducible nitric oxide synthase (iNOS). Conversely, under normoglycemic conditions (5 mM glucose), GlcN paradoxically enhances lipopolysaccharide (LPS)-induced iNOS expression, NO production, and the upregulation of additional proinflammatory mediators. In this study, we examined the effect of alloxan, a known O-GlcNAc transferase (OGT) inhibitor, on GlcN- and/or LPS-mediated inflammatory responses in RAW264.7 macrophage cells. Under hyperglycemic conditions, alloxan exhibited little effect on the LPS-induced or LPS plus GlcN-induced expression of iNOS, cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In contrast, under normoglycemic conditions, alloxan significantly inhibited the induction of these inflammatory genes in response to LPS plus GlcN. At the mechanistic level, alloxan reduced NF-κB DNA-binding activity and prevented its recruitment to the iNOS promoter. In addition, alloxan attenuated GlcN-induced increase in OGlcNAcylation of the NF-κB subunit p65. Collectively, these results indicate that OGT-mediated O-GlcNAcylation of NF-κB is critical for GlcN-induced proinflammatory signaling under normoglycemia. Our work highlights the glucose dependency of O-GlcNAc cycling in macrophage responses and provides new perspectives on the metabolic regulation of innate immune responses. [BMB Reports 2025; 58(11): 467-474].
Bibliographie:content type line 23
SourceType-Scholarly Journals-1
ObjectType-News-1
ISSN:1976-670X
1976-670X
DOI:10.5483/bmbrep.2025-0118