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J. Biol. Chem., Vol. 281, Issue 44, 33019-33029, November 3, 2006

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Aldose Reductase Mediates the Lipopolysaccharide-induced Release of Inflammatory Mediators in RAW264.7 Murine Macrophages^*

Kota V. Ramana¹, Amin A. Fadl², Ravinder Tammali, Aramati B. M. Reddy, Ashok K. Chopra, and Satish K. Srivastava

From the Departments of Biochemistry and Molecular Biology and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555

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-B-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-, interleukin 1, 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-B, and phosphorylation and proteolytic degradation of IB 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-B and PLC/PKC. Pharmacological inhibition or antisense ablation of AR that catalyzes the reduction of GS-HNE to GS-DHN prevented PLC, PKC, IKK/, and NF-B 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.

Received for publication, April 20, 2006 , and in revised form, August 15, 2006.

^* This work was supported in part by National Institutes of Health Grants GM71036 (to K. V. R.), DK36118 (to S. K. S.), AI064389, and AI041611 (to A. K. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Supported in part by a McLaughlin postdoctoral fellowship.

¹ To whom the correspondence should be addressed. Tel.: 409-772-3776; Fax: 409-772-9679; E-mail: kvramana{at}utmb.edu.

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