Anti-inflammatory Role of Microsomal Prostaglandin E Synthase-1 in a Model of Neuroinflammation

Abstract

A major immunological response during neuroinflammation is the activation of microglia, which subsequently release proinflammatory mediators such as prostaglandin E 2 (PGE 2 ). Besides its proinflammatory properties, cyclooxygenase-2 (COX-2)-derived PGE 2 has been shown to exhibit anti-inflammatory effects on innate immune responses. Here, we investigated the role of microsomal PGE 2 synthase-1 (mPGES-1), which is functionally coupled to COX-2, in immune responses using a model of lipopolysaccharide (LPS)-induced spinal neuroinflammation. Interestingly, we found that activation of Eprostanoid (EP)2 and EP4 receptors, but not EP1, EP3, PGI 2 receptor (IP), thromboxane A 2 receptor (TP), PGD 2 receptor (DP), and PGF 2 receptor (FP), efficiently blocked LPS-induced tumor necrosis factor ␣ (TNF␣) synthesis and COX-2 and mPGES-1 induction as well as prostaglandin synthesis in spinal cultures. In vivo, spinal EP2 receptors were up-regulated in microglia in response to intrathecally injected LPS. Accordingly, LPS priming reduced spinal synthesis of TNF␣, interleukin 1␤ (IL-1␤), and prostaglandins in response to a second intrathecal LPS injection. Importantly, this reduction was only seen in wild-type but not in mPGES-1-deficient mice. Furthermore, intrathecal application of EP2 and EP4 agonists as well as genetic deletion of EP2 significantly reduced spinal TNF␣ and IL-1␤ synthesis in mPGES-1 knock-out mice after LPS priming. These data suggest that initial inflammation prepares the spinal cord for a negative feedback regulation by mPGES-1-derived PGE 2 followed by EP2 activation, which limits the synthesis of inflammatory mediators during chronic inflammation. Thus, our data suggest a role of mPGES-1-derived PGE 2 in resolution of neuroinflammation.Neurodegenerative disorders, including Alzheimer and Parkinson disease, multiple sclerosis, and spinal cord or peripheral nerve injury, are associated with neuroinflammation (1, 2). Its initiation, maintenance and resolution are regulated by various cell types, including resident microglia, astroglia, and oligodendrocytes as well as invading blood leukocytes. Lipopolysaccharide (LPS) has traditionally been used to simulate innate immune responses in the central nervous system (CNS) by activating toll-like receptor-4 of microglia (3). Upon activation, microglia release inflammatory mediators such as cytokines, chemokines, free radicals, nitric oxide, or prostaglandins (4). One of the earliest events during LPS-induced neuroinflammation is the synthesis and release of the proinflammatory cytokine TNF␣ by microglia, which reaches maximum concentrations 2-8 h after the initial inflammatory stimulus (5). In effector cells, TNF␣ induces the expression of multiple proteins that further enhance the inflammatory response, including cyclooxygenase-2 (COX-2) and the functionally coupled microsomal PGE 2 synthase-1 (mPGES-1) 2 (6, 7). After 24 h, TNF␣ levels decrease to base-line levels whereas the activation of glia persists for several days (8). The mechanisms controlling the precise...

Expression of Microsomal Prostaglandin E Synthase-1 in the Spinal Cord in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

“…Lipopolysaccharide-evoked synthesis of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) has been shown to trigger induction of mPGES-1 in neurons and microglia in spinal neuroinflammation (39). It has also been shown that cytokines including IL-1β and TNFα were up-regulated in the degenerating spinal cords in G93A mice (40).…”

The cardinal role of the phospholipase A2/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E2 (PCPP) axis in inflammostasis

“…The following review will serve to highlight and discuss the underrepresented regulatory role of the PCPP axis in each of these processes within the context of rheumatoid (''inflammatory'') arthritis. It should be emphasized, however, that the concepts presented herein are not unique to RA and are generally relevant to other inflammatory disorders (e.g., neuroinflammatory disorders [36], hepatic inflammation [37], airway inflammation [38][39][40]). …”

Characterization of the Micro-Environment of the Testis that Shapes the Phenotype and Function of Testicular Macrophages

“…The residues were reconstituted with 50 ml of acetonitrile:water:formic acid (20:80:0.0025, v/v, pH 4) and injected into the LC-MS/MS. PGs were separated with a Synergi 150 3 2.0 mm Hydro-RP column (Phenomenex, Aschaffenburg, Germany) and determined with a triple quadrupole MS (5500 Q-TRAP; Sciex, Darmstadt, Germany) (27).…”