Mediation of aldose reductase in lipopolysaccharide-induced inflammatory signals in mouse peritoneal macrophages

• Published in: Cytokine (Philadelphia, Pa.) Vol. 36; no. 3; pp. 115 - 122
• Main Authors: Ramana, Kota V., Srivastava, Satish K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2006
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - metabolism; Aldose reductase; Animals; Benzothiazoles - pharmacology; Chemokine CCL2 - metabolism; Cyclooxygenase 2 - metabolism; Dinoprostone - metabolism; Enzyme Inhibitors - pharmacology; I-kappa B Kinase - metabolism; Imidazolidines - pharmacology; Inflammation; Inflammation Mediators - metabolism; Interferon-gamma - metabolism; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Lipopolysaccharide; Lipopolysaccharides - pharmacology; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred BALB C; Naphthalenes - pharmacology; NF-kappa B - metabolism; NF-κB; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Phosphorylation - drug effects; Phthalazines - pharmacology; Protein Kinase C - metabolism; Reactive Oxygen Species - metabolism; Sepsis; Tumor Necrosis Factor-alpha - metabolism; Lipopolysaccharide; NF-κB; Sepsis; Inflammation; Aldose reductase
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2006.11.003

Aldose reductase (AR; AKR1B1) a member of aldo-keto reductase super family, that we had shown earlier mediates cytotoxic signals induced by high glucose, cytokines and growth factors, also mediates the inflammatory signals induced by Gram-negative bacterial endotoxin, lipopolysaccharide (LPS). Inhibition of AR by three distinct AR inhibitors sorbinil, tolrestat or zopolrestat suppressed the LPS-induced production of inflammatory cytokines such as TNF-α, IL-6, IL-1β, IFN-γ, and chemokine MCP-1 in murine peritoneal macrophages. Inhibition of AR also prevented the production of nitric oxide, and prostaglandin E2 and expression of iNOS and Cox-2 proteins. The LPS-induced DNA binding activity of NF-κB and AP1 were significantly inhibited by AR inhibitors, and this effect was mediated through the inhibition of phosphorylation of IκB-α, IKK α/β and PKC. These results suggest the therapeutic use of AR inhibitors as anti-inflammatory drugs.