Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages

Kota Ramana, Amin A. Fadl, Ravinder Tammali, Aramati B M Reddy, Ashok Chopra, Satish Srivastava

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Abnormal production of inflammatory cytokines and chemokines is a key feature of bacterial endotoxin, lipopolysaccharide (LPS)-induced inflammation, and cytotoxicity; however, the mechanisms regulating production of inflammatory markers remain unclear. Herein, we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR; AKR1B3) modulates NF-κB-dependent activation of inflammatory cytokines and chemokines in mouse serum, liver, heart, and spleen. Pharmacological inhibition or small interfering RNA ablation of AR prevented the biosynthesis of tumor necrosis factor-α, interleukin 1β, interleukin-6, macrophage-chemoattractant protein-1, and cyclooxygenase-2 and prostaglandin E2 in LPS-activated RAW264.7 murine macrophages. The AR inhibition or ablation significantly attenuated LPS-induced activation of protein kinase C (PKC) and phospholipase C (PLC), nuclear translocation of NF-κB, and phosphorylation and proteolytic degradation of IκBα in macrophages. Furthermore, treatment of macrophages with 4-hydroxy-trans-2-nonenal (HNE), and cell-permeable esters of glutathionyl-4-hydroxynonanal (GS-HNE) and glutathionyl-1,4-dihydroxynonane (GSDHN) activated NF-κB and PLC/PKC. Pharmacological inhibition or antisense ablation of AR that catalyzes the reduction of GS-HNE to GS-DHN prevented PLC, PKC, IKKα/β, and NF-κB activation caused by HNE and GS-HNE, but not by GS-DHN, suggesting that reduced GS-lipid aldehydes catalyzed by AR propagate LPS-induced production of inflammatory markers. Collectively, these data provide evidence that inhibition of AR may be a significant therapeutic approach in preventing bacterial endotoxin-induced sepsis and tissue damage.

Original languageEnglish (US)
Pages (from-to)33019-33029
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number44
DOIs
StatePublished - Nov 3 2006

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Aldehyde Reductase
Macrophages
Lipopolysaccharides
Type C Phospholipases
Ablation
Protein Kinase C
Chemical activation
Chemokines
Aldehydes
Endotoxins
Pharmacology
Cytokines
Phosphorylation
Biosynthesis
Chemotactic Factors
Cyclooxygenase 2
Cytotoxicity
Interleukin-1
Dinoprostone
Liver

ASJC Scopus subject areas

  • Biochemistry

Cite this

Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages. / Ramana, Kota; Fadl, Amin A.; Tammali, Ravinder; Reddy, Aramati B M; Chopra, Ashok; Srivastava, Satish.

In: Journal of Biological Chemistry, Vol. 281, No. 44, 03.11.2006, p. 33019-33029.

Research output: Contribution to journalArticle

Ramana, Kota ; Fadl, Amin A. ; Tammali, Ravinder ; Reddy, Aramati B M ; Chopra, Ashok ; Srivastava, Satish. / Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 44. pp. 33019-33029.
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AB - Abnormal production of inflammatory cytokines and chemokines is a key feature of bacterial endotoxin, lipopolysaccharide (LPS)-induced inflammation, and cytotoxicity; however, the mechanisms regulating production of inflammatory markers remain unclear. Herein, we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR; AKR1B3) modulates NF-κB-dependent activation of inflammatory cytokines and chemokines in mouse serum, liver, heart, and spleen. Pharmacological inhibition or small interfering RNA ablation of AR prevented the biosynthesis of tumor necrosis factor-α, interleukin 1β, interleukin-6, macrophage-chemoattractant protein-1, and cyclooxygenase-2 and prostaglandin E2 in LPS-activated RAW264.7 murine macrophages. The AR inhibition or ablation significantly attenuated LPS-induced activation of protein kinase C (PKC) and phospholipase C (PLC), nuclear translocation of NF-κB, and phosphorylation and proteolytic degradation of IκBα in macrophages. Furthermore, treatment of macrophages with 4-hydroxy-trans-2-nonenal (HNE), and cell-permeable esters of glutathionyl-4-hydroxynonanal (GS-HNE) and glutathionyl-1,4-dihydroxynonane (GSDHN) activated NF-κB and PLC/PKC. Pharmacological inhibition or antisense ablation of AR that catalyzes the reduction of GS-HNE to GS-DHN prevented PLC, PKC, IKKα/β, and NF-κB activation caused by HNE and GS-HNE, but not by GS-DHN, suggesting that reduced GS-lipid aldehydes catalyzed by AR propagate LPS-induced production of inflammatory markers. Collectively, these data provide evidence that inhibition of AR may be a significant therapeutic approach in preventing bacterial endotoxin-induced sepsis and tissue damage.

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