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Regulation of prostaglandin E 2 synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2
Author(s) -
de Oliveira Antonio Carlos Pinheiro,
CandelarioJalil Eduardo,
Bhatia Harsharan S.,
Lieb Klaus,
Hüll Michael,
Fiebich Bernd L.
Publication year - 2008
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20658
Subject(s) - ly294002 , biology , phosphatidylinositol , signal transduction , microbiology and biotechnology , prostaglandin e2 , prostaglandin e , protein kinase c , protein kinase b , microglia , pi3k/akt/mtor pathway , downregulation and upregulation , kinase , tumor necrosis factor alpha , eicosanoid , prostaglandin , prostaglandin h2 , cytosol , endocrinology , inflammation , biochemistry , immunology , enzyme , cyclooxygenase , arachidonic acid , gene
Abstract Prostaglandin E 2 (PGE 2 ) is among the most important mediators involved in neuroinflammatory processes. The final step of its synthesis is regulated by enzymes termed prostaglandin E 2 synthases (PGES). Three PGES are known, cytosolic (c)PGES, membrane‐associated (m)PGES‐1 and mPGES‐2. The expression of mPGES‐1 is induced by inflammatory stimuli such as lipopolysaccharide (LPS), interleukin (IL)‐1β, and tumor necrosis factor (TNF)‐α. Although some roles of mPGES‐1 have already been suggested, its function in the CNS and the signaling pathways involved in its upregulation are poorly understood. In this study, we examined the regulation of mPGES‐1 in primary rat microglia and the signaling pathways involved in its expression. Whereas the expression of cPGES and mPGES‐2 was not stimulated by LPS, low doses of LPS (0.1–1 ng/mL) sufficiently stimulated mPGES‐1 mRNA expression. A corresponding protein synthesis, however, was obtained only with higher doses (10–100 ng/mL). The LPS‐induced increase of mPGES‐1 was inhibited by different signaling pathway inhibitors, such as SP600125, LY294002, GF109203X, and SC‐514, suggesting the involvement of c‐Jun N‐terminal kinase (JNK), phosphatidylinositol 3‐kinase (PI‐3K)/Akt, protein kinase C (PKC) pathways, and the nuclear factor (NF)‐κB, respectively. In contrast to other reports, LPS‐induced mPGES‐1 synthesis was not invariably coupled to the synthesis of COX‐2, since inhibition of PI‐3K with LY294002 decreased mPGES‐1 but increased COX‐2 levels. This detailed view of the intracellular signaling pathways involved in mPGES‐1 expression in activated microglia opens a new avenue in the search for novel potential therapeutic targets to reduce neuroinflammation, and demonstrates that mPGES‐1 expression is not strictly coupled to the expression of COX‐2. © 2008 Wiley‐Liss, Inc.