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  • br Conclusions br Acknowledgement br Introduction The macrop


    Introduction The macrophage is an important cell species that plays key roles in innate immune responses and inflammatory reactions through phagocytosis of foreign bodies and secretion of inflammatory mediators such as interleukin (IL)-1, tumor necrosis factor (TNF)-α, and prostaglandin E2 (PGE2) [1], [2]. Among these inflammatory mediators, PGE2 plays a role in triggering early inflammatory responses. A large amount of PGE2 is synthesized by macrophages during the inflammatory process [3], [4]. PGE2 is a lipid mediator that regulates a number of biological functions such as renal blood flow, platelet reactivity, vascular tone, and neurotransmitter release under GYKI 52466 dihydrochloride normal conditions [1], [2], [3], [5], [6]. However, upon inflammatory stimuli, synthesis of PGE2 is dramatically elevated and early inflammatory reactions such as red flare, heat, swelling, and pain are evoked [7], [8], [9], [10]. Synthesis of PGE2 is mainly mediated by two cyclooxygenase (COX) isoforms, COX-1 and COX-2, and three prostaglandin E synthase (PGES) isoforms, cytosolic PGES (cPGES), microsomal PGES-1 (mPGES-1), and mPGES-2. Among these enzymes, COX-2 and mPGES-1 are responsible for the inflammatory reaction. Their expression levels are elevated in response to inflammatory stimuli, which increases the amount of PGE2 leading to the inflammatory reaction [1], [4]. Therefore, chemical compounds that inhibit COX-2 and/or mPGES-1 may be useful as anti-inflammatory drugs. In fact, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit COXs are widely used to inhibit the synthesis of PGE2 and thereby suppress inflammatory reactions [11]. Glycogen synthase kinase-3 (GSK-3) was first identified as a cytoplasmic serine/threonine protein kinase that phosphorylates glycogen synthase to inhibit its activity [12]. However, today, GSK-3 is known to be involved in a variety of biological processes such as embryonic development, GYKI 52466 dihydrochloride control, cell differentiation, cell motility, microtubule function, apoptosis, and cell adhesion [13], [14]. GSK-3 has also been shown to be involved in inflammatory responses, suggesting that GSK-3 inhibitors could be useful as anti-inflammatory drugs [15], [16], [17], [18]. However, to our knowledge, there is only one report that investigated the role of GSK-3 in PGE2 production during inflammatory responses, in which a primary culture of rat microglia was used [19]. In the present study, therefore, we investigated the role of GSK-3 in inflammatory PGE2 production using pharmacological and genetic inhibitions of GSK-3 in macrophage-like cells differentiated from THP-1 cells (TPA-treated THP-1 cells), murine peritoneal macrophages, and inflammatory air pouches made under the skin of living mice.
    Materials and methods
    Discussion In the present study, we showed the involvement of GSK-3 in inflammatory PGE2 production in vitro and in vivo. We demonstrated that pharmacological inhibition of GSK-3 suppressed PGE2 production through suppression of COX-2 and mPGES-1 expression in TPA-treated THP-1 cells. Moreover, we demonstrated that pharmacological and genetic inhibition of GSK-3 suppressed PGE2 production using mouse peritoneal macrophages and the subcutaneous air pouch inflammation model mice. Exploring the mechanisms by which GSK-3 inhibitors reduced COX-2 and mPGES-1, we found that the inhibition of Egr-1 expression could be one of the mechanisms. The Egr-1 gene, which belongs to a group of early response genes, is rapidly induced by a variety of environmental stimuli including growth factors and hormones and mediates various biological functions by regulating the expression of diverse genes [28]. Egr-1 is also induced by LPS and mediates inflammatory responses. Particularly, Egr-1 has been reported to regulate LPS-mediated induction of COX-2 and mPGES-1 in mouse macrophage cell line RAW 264.7 [7]. Therefore, it is possible that the decrease in Egr-1 expression by GSK-3 inhibitors suppresses LPS-mediated induction of COX-2 and mPGES-1 in TPA-treated THP-1 cells, resulting in the suppression of PGE2 production. However, we could not identify the mechanisms by which GSK-3 inhibitors suppressed Egr-1 expression in the present study. A recent report showed that the inhibition of GSK-3 decreased the expression levels of TLR4 mRNA and its protein in mouse liver [29]. This could be one possible mechanism by which GSK-3 inhibitors suppressed Egr-1 expression.