e3 ligases Little information is available regarding the

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
Results
Discussion In this study we report that PGE2 is a potent suppressor of LPS-stimulated TNF-α production in human monocytic e3 ligases 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.
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Acknowledgements
Introduction Myocardial infarction (MI) causes cardiac remodeling, a complex process involving both hypertrophy of cardiac myocytes and fibrosis. Fibrosis results from cardiac fibroblast proliferation and increased collagen deposition. The increased interstitial fibrosis results in decreased compliance [1] and increases the oxygen diffusion distance between capillaries and myocytes, which negatively impacts ventricular function [2]. Thus, an understanding of the factors that regulate cardiac fibroblast growth is of vital importance to our knowledge of cardiac pathophysiology. Prostaglandins are well-known regulators of cell growth. Previous studies from our laboratory show that prostaglandin E2 (PGE2) is released in micromolar quantities following induction of COX-2 and causes hypertrophy of neonatal ventricular myocytes in vitro, an effect mediated by its EP4 receptor and activation of p42/44 MAP kinase [3]. Additionally, we have previously reported that the selective COX-2 inhibitor NS398 decreases interstitial collagen fraction in a mouse model of myocardial infarction [4]. Others have reported that COX-2 products influence vascular smooth muscle cell proliferation. Using vascular smooth muscle cells isolated from the thoracic aorta, Ohnaka et al. [5] demonstrated that angiotensin-induced increases in thymidine incorporation into DNA could be reduced with a selective COX-2 inhibitor. Likewise, Young et al. [6] showed that both angiotensin II and tumor necrosis factor-induced cell proliferation required COX-2. Cell proliferation requires entry into the cell cycle from the quiescent G0 state, progression through the G1/S checkpoint, at which stage the cell is committed to divide, and further progression through a second growth phase (G2) followed by mitosis (M). The cell cycle is regulated by proteins called cyclins, and their regulatory partners, the cyclin-dependent kinases (cdks). In each phase of the cell cycle, a specific cyclin binds to and activates a partner cdk which leads to progression through the cycle. Additionally, another group of proteins termed cyclin-dependent kinase inhibitors (cdki), negatively regulate cell cycle progression by inhibiting cyclin–cdk complexes, resulting in cell cycle arrest. Therefore, expression of cyclin D is a crucial component to facilitate G1 to S phase transition and subsequently increase cell proliferation. There are 3 members of the cyclin D family (D1, D2, D3), all of which play a role in G1 progression [7].