Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages.
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-kappaB-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-alpha, interleukin 1beta, interleukin-6, macrophage-chemoattractant protein-1, and cyclooxygenase-2 and prostaglandin E(2) 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-kappaB, and phosphorylation and proteolytic degradation of IkappaBalpha 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 (GS-DHN) activated NF-kappaB and PLC/PKC. Pharmacological inhibition or antisense ablation of AR that catalyzes the reduction of GS-HNE to GS-DHN prevented PLC, PKC, IKKalpha/beta, and NF-kappaB 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.
Ramana
Kota V
KV
Department of Biochemistry, University of Texas Medical Branch, Galveston, Texas 77555, USA. kvramana@utmb.edu
Fadl
Amin A
AA
Tammali
Ravinder
R
Reddy
Aramati B M
AB
Chopra
Ashok K
AK
Srivastava
Satish K
SK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000447:Aldehydes; D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000449:Aldehyde Reductase; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D005978:Glutathione; D015232:Dinoprostone