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In the development of inflammation, prostaglandins, especially prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>), are major players alongside with chemo- and cytokines, like tumor-necrosis-factor alpha (TNF\u03b1) and interleukin-1 beta (IL-1\u03b2). During inflammation, PGE<jats:sub>2<\/jats:sub> synthesis can be increased by the transcriptional induction of the two key enzymes: cyclooxygenase 2 (COX-2), which converts arachidonic acid to PGH<jats:sub>2<\/jats:sub>, and microsomal prostaglandin E2 synthase 1 (mPGES-1), which synthesizes PGE<jats:sub>2<\/jats:sub> from PGH<jats:sub>2<\/jats:sub>. Both COX-2 and mPGES-2 were induced by a dietary intervention where mice were fed a fatty acid-rich and, more importantly, cholesterol-rich diet, leading to the development of NASH. Since macrophages are the main source of PGE<jats:sub>2<\/jats:sub> synthesis and cholesterol is predominantly transported as LDL, the regulation of COX-2 and mPGES-1 expression by native LDL was analyzed in human macrophage cell lines. THP-1 and U937 monocytes were differentiated into macrophages, through which TNF\u03b1 and PGE-2 induced COX-2 and mPGES-1 expression by LDL could be analyzed on both mRNA and protein levels. In addition, the interaction of LDL- and EP receptor signal chains in COX-2\/mPGES-1 expression and PGE<jats:sub>2<\/jats:sub>-synthesis were analyzed in more detail using EP receptor specific agonists. Furthermore, the LDL-mediated signal transduction in THP-1 macrophages was analyzed by measuring ERK and Akt phosphorylation as well as transcriptional regulation of transcription factor Egr-1. COX-2 and mPGES-1 were induced in both THP-1 and U937 macrophages by the combination of TNF\u03b1 and PGE<jats:sub>2<\/jats:sub>. Surprisingly, LDL dose-dependently increased the expression of mPGES-1 but repressed the expression of COX-2 on mRNA and protein levels in both cell lines. The interaction of LDL and PGE<jats:sub>2<\/jats:sub> signal chains in mPGES-1 induction as well as PGE<jats:sub>2<\/jats:sub>-synthesis could be mimicked by through simultaneous stimulation with EP2 and EP4 agonists. In THP-1 macrophages, LDL induced Akt-phosphorylation, which could be blocked by a PI3 kinase inhibitor. Alongside blocking Akt-phosphorylation, the PI3K inhibitor inhibited LDL-mediated mPGES-1 induction; however, it did not attenuate the repression of COX-2 expression. LDL repressed basal ERK phosphorylation and expression of downstream transcription factor Egr-1, which might lead to inhibition of COX-2 expression. These findings suggest that simultaneous stimulation with a combination of TNF\u03b1, PGE<jats:sub>2<\/jats:sub>, and native LDL-activated signal chains in macrophage cell lines leads to maximal mPGES-1 activity, as well repression of COX-2 expression, by activating PI3K as well as repression of ERK\/Egr-1 signal chains.<\/jats:p>","DOI":"10.1007\/s10753-022-01778-y","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T05:03:13Z","timestamp":1672808593000},"page":"893-911","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["LDL-Dependent Regulation of TNF\u03b1\/PGE2 Induced COX-2\/mPGES-1 Expression in Human Macrophage Cell Lines"],"prefix":"10.1007","volume":"46","author":[{"given":"Frank","family":"Neusch\u00e4fer-Rube","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Sch\u00f6n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Kahnt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard Paul","family":"P\u00fcschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"1778_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0675-0","author":"D Furman","year":"2019","unstructured":"Furman, D., J. 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