Prostaglandin E Receptor Subtypes in Cultured Rat Microglia and Their Role in Reducing Lipopolysaccharide‐Induced Interleukin‐1 β Production

Caggiano, Anthony O.; Kraig, Richard P.

doi:10.1046/j.1471-4159.1999.0720565.x

Cited by 159 publications

(119 citation statements)

References 46 publications

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“…Previously, PGE 2 was shown to block innate immune responses from microglia in vitro via EP2 and EP4 (16,17,35). Here, we found that EP2-and EP4-expressing spinal microglia had an amoeboid morphology that is characteristic for activated microglia.…”

Section: Discussionsupporting

confidence: 50%

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

Brenneis

Coste

Altenrath

et al. 2011

Journal of Biological Chemistry

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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...

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Section: Discussionsupporting

confidence: 50%

“…However, PGE 2 also has anti-inflammatory properties. It mediates bradykinininduced neuroprotection and blocks LPS-and ATP-induced cytokine synthesis in cultured microglia or in neuron-glia cocultures (16,17). The anti-inflammatory and neuroprotective effects of PGE 2 are suggested to be mediated via microglial EP2 and EP4 receptors.…”

mentioning

confidence: 99%

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

Brenneis

Coste

Altenrath

et al. 2011

Journal of Biological Chemistry

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“…Immunocytochemical studies of EP2 receptor distribution confirm at the protein level a robust and widespread expression of EP2 receptor in forebrain, with high expression in neurons and astrocytes in cerebral cortex, striatum, and hippocampus (Caggiano, 1999;Zhang and Rivest, 1999). Using the selective EP2 receptor agonist butaprost, we observed a marked protective effect in pure neuronal cultures and organotypic hippocampal cultures subjected to glutamate or OGD toxicity.…”

Section: Discussionmentioning

confidence: 60%

“…In addition, our reperfusion paradigm lasted 24 hr, and in these experiments, we cannot address the function of EP2 receptor at later times, specifically its role in the recruitment and activation of immune cells in the postischemic inflammatory phase of stroke. This is of relevance, given that PGE 2 has been shown to inhibit lymphocytic and microglial activation and the expression of neurotoxic cytokines and inflammatory mediators (Fedyk, 1996;Caggiano, 1999;Montine, 2002).…”

Section: Discussionmentioning

confidence: 94%

Neuroprotective Function of the PGE₂EP2 Receptor in Cerebral Ischemia

McCullough¹,

Wu²,

Haughey³

et al. 2004

J. Neurosci.

338

375

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The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE 2 , a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE 2 exerts its downstream effects by signaling through a class of four distinct G-proteincoupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE 2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMPdependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE 2 receptor subtype in brain that may provide a target for therapeutic intervention.

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“…How the cAMP pathway regulates IL-1β expression is an active area of investigation. Several studies have shown that raising cAMP levels with either neurotransmitters or phosphodiesterase inhibitors reduce IL-1β levels, but the exact mechanism is still unclear (Cogswell et al, 1994, Verghese et al, 1995, Si et al, 1998, Caggiano and Kraig, 1999, Cho et al, 2001, Dello Russo et al, 2004.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

133

151

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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Prostaglandin E Receptor Subtypes in Cultured Rat Microglia and Their Role in Reducing Lipopolysaccharide‐Induced Interleukin‐1 β Production

Cited by 159 publications

References 46 publications

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

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

Neuroprotective Function of the PGE₂EP2 Receptor in Cerebral Ischemia

Modulation of the cAMP signaling pathway after traumatic brain injury

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Prostaglandin E Receptor Subtypes in Cultured Rat Microglia and Their Role in Reducing Lipopolysaccharide‐Induced Interleukin‐1 β Production

Cited by 159 publications

References 46 publications

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

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

Neuroprotective Function of the PGE2EP2 Receptor in Cerebral Ischemia

Modulation of the cAMP signaling pathway after traumatic brain injury

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Neuroprotective Function of the PGE₂EP2 Receptor in Cerebral Ischemia