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ORIGINAL RESEARCH ARTICLE

Selenium Attenuates Lipopolysaccharide-Induced Oxidative Stress Responses Through Modulation of p38 MAPK and NF-B Signaling Pathways

Sang Hyun Kim^*,2, Victor J. Johnson^*,3, Tae-Yong Shin and Raghubir P. Sharma^*,1

^* Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602; and College of Pharmacy, Woosuk University, Chonju, Chonbuk, 565-701, Korea

To whom requests for reprints should be addressed at ¹ Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602–7389. E-mail: rpsharma{at}vet.uga.edu

Lipopolysaccharide (LPS) produces reactive oxygen species (ROS) and nitric oxide (NO) in macrophages. These molecules are involved in inflammation associated with endotoxic shock. Selenium (Se), a biologically essential trace element, modulates the functions of many regulatory proteins involved in signal transduction and affects a variety of cellular activities, including cell growth and survival. We demonstrate that Se attenuated LPS-induced ROS and NO production in murine macrophage cultures in vitro. This Se-decreased production of NO was demonstrated by decreases in both mRNA and protein expression for inducible NO synthase (iNOS). The preventive effects of Se on iNOS were p38 mitogen-activated protein kinase– and nuclear factor–B–dependent. Se specifically blocked the LPS-induced activation of p38 but not that of c-jun–N-terminal kinase and extracellular signal–regulated kinase; the p38-specific pathway was confirmed using p38 inhibitor SB 203580. These results suggest that the mechanism by which Se may act as an anti-inflammatory agent and that Se may be considered as a possible preventive intervention for endotoxemia, particularly in Se-deficient locations. However, the efficacy and safety of Se need to be further investigated, because long-term intake >0.4 mg Se/day in adults can produce adverse effects.

Key Words: selenium • glutathione • iNOS • lipopolysaccharide • mitogen-activated protein kinases • nitric oxide • nuclear factor-B • reactive oxygen species

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