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Inhibition of GSK-3 reduces prostaglandin E2 production by decreasing the expression levels of COX-2 and mPGES-1 in monocyte/macrophage lineage cells.
Biochem Pharmacol. 2016 09 15; 116:120-9.BP

Abstract

Inflammatory stimuli induce prostaglandin E2 (PGE2) synthesis by upregulating cycloxgenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1). Glycogen synthase kinase-3 (GSK-3) reportedly plays an important role in inflammatory reactions, whereas the role of this enzyme in inflammatory PGE2 production remains unclear. In the present study, therefore, we examined whether inhibition of GSK-3 can reduce inflammatory PGE2 production in vitro and in vivo. When macrophage-like cells differentiated from THP-1 were stimulated with lipopolysaccharide (LPS), PGE2 production and the expression levels of COX-2 and mPGES-1 were markedly elevated. GSK-3 inhibitors LiCl and SB216763 strongly suppressed their protein levels through inhibition of mRNA expressions. Subsequently, we examined the effect of GSK-3 inhibitors on nuclear factor κB (NF-κB) and early growth response-1 (Egr-1). The GSK-3 inhibitors had no significant effect on the NF-κB pathway, whereas they significantly decreased the expression level of Egr-1. Pharmacological and genetic inhibitions of GSK-3 also strongly suppressed PGE2 production in cultured peritoneal macrophages and in inflammatory air pouches made under the skin of living mice. These results suggested that GSK-3 plays a key role in PGE2 production by increasing COX-2 and mPGES-1 probably through Egr-1-mediated transcription and GSK-3 inhibitors may be potential as novel anti-inflammatory drugs.

Authors+Show Affiliations

Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Oral-Maxillofacial Surgery, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan.Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: yanaga@clipharm.med.kyushu-u.ac.jp.Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.Department of Oral-Maxillofacial Surgery, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan.Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27453433

Citation

Noma, Toshihiro, et al. "Inhibition of GSK-3 Reduces Prostaglandin E2 Production By Decreasing the Expression Levels of COX-2 and mPGES-1 in Monocyte/macrophage Lineage Cells." Biochemical Pharmacology, vol. 116, 2016, pp. 120-9.
Noma T, Takahashi-Yanaga F, Arioka M, et al. Inhibition of GSK-3 reduces prostaglandin E2 production by decreasing the expression levels of COX-2 and mPGES-1 in monocyte/macrophage lineage cells. Biochem Pharmacol. 2016;116:120-9.
Noma, T., Takahashi-Yanaga, F., Arioka, M., Mori, Y., & Sasaguri, T. (2016). Inhibition of GSK-3 reduces prostaglandin E2 production by decreasing the expression levels of COX-2 and mPGES-1 in monocyte/macrophage lineage cells. Biochemical Pharmacology, 116, 120-9. https://doi.org/10.1016/j.bcp.2016.07.014
Noma T, et al. Inhibition of GSK-3 Reduces Prostaglandin E2 Production By Decreasing the Expression Levels of COX-2 and mPGES-1 in Monocyte/macrophage Lineage Cells. Biochem Pharmacol. 2016 09 15;116:120-9. PubMed PMID: 27453433.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of GSK-3 reduces prostaglandin E2 production by decreasing the expression levels of COX-2 and mPGES-1 in monocyte/macrophage lineage cells. AU - Noma,Toshihiro, AU - Takahashi-Yanaga,Fumi, AU - Arioka,Masaki, AU - Mori,Yoshihide, AU - Sasaguri,Toshiyuki, Y1 - 2016/07/21/ PY - 2016/06/03/received PY - 2016/07/19/accepted PY - 2016/7/26/entrez PY - 2016/7/28/pubmed PY - 2017/5/10/medline KW - Anti-inflammatory drug KW - COX-2 KW - GSK-3 KW - PGE(2) KW - mPGES-1 SP - 120 EP - 9 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 116 N2 - Inflammatory stimuli induce prostaglandin E2 (PGE2) synthesis by upregulating cycloxgenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1). Glycogen synthase kinase-3 (GSK-3) reportedly plays an important role in inflammatory reactions, whereas the role of this enzyme in inflammatory PGE2 production remains unclear. In the present study, therefore, we examined whether inhibition of GSK-3 can reduce inflammatory PGE2 production in vitro and in vivo. When macrophage-like cells differentiated from THP-1 were stimulated with lipopolysaccharide (LPS), PGE2 production and the expression levels of COX-2 and mPGES-1 were markedly elevated. GSK-3 inhibitors LiCl and SB216763 strongly suppressed their protein levels through inhibition of mRNA expressions. Subsequently, we examined the effect of GSK-3 inhibitors on nuclear factor κB (NF-κB) and early growth response-1 (Egr-1). The GSK-3 inhibitors had no significant effect on the NF-κB pathway, whereas they significantly decreased the expression level of Egr-1. Pharmacological and genetic inhibitions of GSK-3 also strongly suppressed PGE2 production in cultured peritoneal macrophages and in inflammatory air pouches made under the skin of living mice. These results suggested that GSK-3 plays a key role in PGE2 production by increasing COX-2 and mPGES-1 probably through Egr-1-mediated transcription and GSK-3 inhibitors may be potential as novel anti-inflammatory drugs. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/27453433/Inhibition_of_GSK_3_reduces_prostaglandin_E2_production_by_decreasing_the_expression_levels_of_COX_2_and_mPGES_1_in_monocyte/macrophage_lineage_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(16)30190-3 DB - PRIME DP - Unbound Medicine ER -