Selenoorganic compound, ebselen, inhibits nitric oxide and tumor necrosis factor-? production by the modulation of Jun-N-terminal kinase and the NF-?b signaling pathway in rat Kupffer cells

Abstract

In response to the bacterial endotoxin, LPS, Kupffer cells are induced to express NO and TNF-alpha. These compounds are involved in hepatic inflammation/injury, especially that associated with endotoxic shock. In this study, we demonstrate that ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one), a selenoorganic compound, blocks LPS-induced NO and TNF-alpha production by cultured rat liver Kupffer cells. LPS can activate both the NF-kappaB signaling pathway and MAPK signal transduction pathways such as JNK and p38 MAPK. We find that ebselen inhibits LPS-induced NF-kappaB nuclear translocalization, and also suppresses the LPS-induced phosphorylation of JNK, but not the phosphorylation of p38 MAPK. This inhibition of signal transduction leads to a decrease in the transcription of TNF-alpha and the inducible isoform of NO. Furthermore, ebselen inhibits LPS-induced COX-2 expression, which is responsible for proinflammatory prostaglandin production, without affecting constitutive COX-1 expression. These data suggest the mechanism by which ebselen acts as an antiinflammatory agent, and also suggest that ebselen may be potent in preventing hepatic injury such as endotoxic shock, in which Kupffer cell activation has been implicated.

An Inducible Nitric Oxide Synthase-Luciferase Reporter System for In Vivo Testing of Anti-inflammatory Compounds in Transgenic Mice

“…EGCG, the major polyphenol present in green tea, has been reported to inhibit the induction of iNOS expression in the RAW264.7 murine macrophage cell line (32). Ebselen, an organic selenium compound, can inhibit LPS-induced NO production in rat liver Kupffer cells (33). Ebselen and dexamethasone reportedly protect mice from galactosamine and Salmonella-LPS-induced hepatitis (34).…”

“…Ebselen and dexamethasone reportedly protect mice from galactosamine and Salmonella-LPS-induced hepatitis (34). Dexamethasone, EGCG, and ebselen may reduce iNOS gene expression through NF-B signaling, either by up-regulating I-B␣ or inhibiting NF-B (32,33,35,36).…”

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

“…It is difficult to determine whether this reflects in vivo mechanisms by which increases in dietary Se affect macrophage activation. Experiments using the selenoorganic compound, ebselen, showed that this compound inhibited NO, Cox-2, and TNF-a in rat Kupfer cells, which are the resident macrophages of the liver (229). This suggests that small-molecular-weight selenocompounds influence redox status in these in vitro experiments, but the role of these compounds versus selenoproteins in vivo needs to be considered.…”

“…One example is the inhibition histone deacetylase (HDAC) activity in diffuse large B-cell lymphoma cell lines by methylseleninic acid and the toxic effects this may exert in chemoprevention (125). In addition, some studies have used the selenoorganic compound, ebselen, to show that macrophage and dendritic cell functions are affected by this smallmolecular-weight selenocompound (156,229). However, there are very few studies that investigate the effects of selenocompounds on inflammation or immunity, and most of the data regarding the biological activity of Se is related to its incorporation into selenoproteins.…”

Activation of Retinoic X Receptor and Peroxisome Proliferator-Activated Receptor–γ Inhibits Nitric Oxide and Tumor Necrosis Factor–α Production in Rat Kupffer Cells

“…22 Semiquantitative RT-PCR assay was basically performed as described. [22][23][24] The PCR primers were constructed based on the published nucleotide sequences of the rat TNF-␣ gene 25 (GenBank accession number, L00981) [5Ј-CCC AGA CCC TCA CAC TCA GA-3Ј (sense); 5Ј-GCC ACT ACT TCA GCA TCT CG-3Ј (antisense)]; the rat iNOS gene 26 (GenBank accession number, U03699) [5Ј-TGG GCA CCG AGA TTG GAG TC-3Ј (sense); 5Ј-AAA TAC CGC ATA CCT GAA GG-3Ј (antisense)]; and the rat glycerol aldehyde 3-phosphate dehydrogenase (GAPDH) gene 27 (GenBank accession number, M17701) [5Ј-GGC AAG TTC AAT GGC ACA GT-3Ј (sense); 5Ј-AAG GTG GAG GAA TGG GAG TT-3Ј (antisense)]. In the competitive PCR of TNF-␣, iNOS, or GAPDH, the TNF-␣ cDNA sequence with a 74-base pair (bp) deletion, the iNOS cDNA sequence with an 82-bp deletion, or the GAPDH cDNA sequence with a 146-bp deletion, respectively, was used as the competitor DNA sequence.…”