Downregulation of NO and PGE(2) in LPS-stimulated BV2 microglial cells by trans-isoferulic acid via suppression of PI3K/Akt-dependent NF-kappa B and activation of Nrf2-mediated HO-1

作者：Dilshara Matharage Gayani; Lee Kyoung Tae; Jayasooriya Rajapaksha Gedara Prasad Tharanga; Kang Chang Hee; Park Sang Rul; Choi Yung Hyun; Choi Il Whan; Hyun Jin Won; Chang Weon Young; Kim Yeon Su; Lee Hak Ju; Kim Gi Young^*

来源：International Immunopharmacology, 2014, 18(1): 203-211.

DOI：10.1016/j.intimp.2013.11.020

• Trans-isoferulic acid
• Nitric oxide
• Prostaglandin E-2
• Nuclear factor-kappa B
• Nuclear factor erythroid 2-related factor 2
• Heme oxgenase-1

Little is known about whether trans-isoferulic acid (TIA) regulates the production of lipopolysaccharide (LPS)-induced proinflammatory mediators. Therefore, we examined the effect of TIA isolated from Clematis mandshurica on LPS-induced nitric oxide (NO) and prostaglandin E-2 (PGE(2)) production in BV2 microglial cells. We found that TIA inhibited the production of LPS-induced NO and PGE(2) without accompanying cytotoxicity in BV2 microglial cells. TIA also downregulated the expression levels of specific regulatory genes such as inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) by suppressing LPS-induced NF-kappa B activity via dephosphorylation of PI3K/Akt. In addition, we demonstrated that a specific NF-kappa B inhibitor PDTC and a selective PI3K/Akt inhibitor, LY294002 effectively attenuated the expression of LPS-stimulated iNOS and COX-2 mRNA, while LY294002 suppressed LPS-induced NF-kappa B activity, suggesting that TIA attenuates the expression of these proinflammatory genes by suppressing PI3K/Akt-mediated NF-kappa B activity. Our results showed that TIA suppressed NO and PGE(2) production through the induction of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent heme oxygenase-1 (HO-1). Taken together, our data indicate that TIA suppresses the production of proinflammatory mediators such as NO and PGE(2), as well as their regulatory genes, in LPS-stimulated BV2 microglial cells, by inhibiting PI3K/Akt-dependent NF-kappa B activity and enhancing Nrf2-mediated HO-1 expression.

• 出版日期2014-1