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  • Introduction PGE is a major


    Introduction PGE2 is a major mediator present at sites of inflammation [1]. It is well established that PGE2 contributes to the localized and systemic symptoms of inflammation. A key study by Portanova et al. [2] demonstrated that anti-PGE2 TPEN were able to reverse the swelling and pain in localized inflammation. This directly connects PGE2 to the development of inflammatory symptoms. The major pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), which are produced in response to inflammatory stimuli such as lipopolysaccharide, sequentially induce PGE2 biosynthesis from macrophages in a concentration-dependent manner [3]. However, other early studies also showed that exogenous PGE2 potently suppressed the production of TNF-α from monocytic cells (at the transcriptional level) and the suppression of endogenous PGE2 production (using cyclooxygenase inhibitors) enhanced TNF-α synthesis clearly indicated that the downstream release of PGE2 is a negative-feedback loop [4,5]. It is now recognised that prostaglandins in general, and PGE2 in particular, play a cytoprotective and controlling role in limiting immune and inflammatory activation and consequent pathology [6]. Thus, the suppressive action of PGE2 on TNF-α production is an important axis in limiting the extent of an inflammatory response. The actions of PGE2 are mediated via at least 4 membrane receptors termed EP1–EP4, each with its particular signalling system some of which overlap [6]. Suppression of TNF-α production in monocytic cells can occur via EP2 receptors on the basis of a variety of agonists and antagonists of the respective receptors [1]. In the study of Brown et al. [1] it was also shown that the inhibition of TNF-α production by PGE2 could be reversed to an extent by an EP4 receptor antagonist. However, it is very clear that these compounds have greatly overlapping activities with relatively poor selectivity between EP receptor subtypes, particularly to distinguish clearly between EP2 and EP4 receptors. Thus, an alternative approach is required to attempt to delineate which precise EP receptors are involved in controlling monocyte-derived cytokine production, particularly TNF-α. Little information is available regarding the expression of the different EP receptor subtypes on human monocytic cells, particularly those that are involved in downregulating cytokine production. The receptors are controlled by the respective genes for each receptor i.e. PTGER1–PTGER4 for EP1–EP4 receptors respectively. This study attempts to correlate the functional characteristics of suppressing LPS-induced TNF-α production in monocytes by various PGE2 analogues (agonists) to the expression of PTGER genes particularly PTGER2 and PTGER4. This study reports that PGE2 can control the expression of EP2 and EP4 receptors and that EP4-selective agonists mimic this response whereas EP2 agonists are unable to do so. Coupled with the observation that overexpression of EP4 receptors enhances PGE2 suppression of TNF-α production and siRNA silencing of EP4 receptor expression elevates TNF-α and IL-1β production but not the production of the anti-inflammatory cytokine IL-10, this implies that the regulation of EP receptor expression in monocytes occurs primarily via EP4 receptors and that they may be important controllers of inflammatory responses. In addition, it also indicates that gene expression of the receptors has direct functional consequences indicating a complex dynamic control during inflammatory responses.
    Materials and methods
    Discussion In this study we report that PGE2 is a potent suppressor of LPS-stimulated TNF-α production in human monocytic cells and that expression of the genes (PTGER1–4) for the various PGE2 receptors (EP1–EP4) is important in the suppressive response to PGE2 particularly the EP4 receptor.
    Conflict of interest
    Transparency document