Sipra Saha

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

Prostaglandin (PG)E2 is a potent mediator of pain and inflammation, and high levels of this lipid mediator are observed in numerous disease states. The inhibition of PGE2 production to control pain and to treat diseases such as rheumatoid arthritis to date has depended on nonsteroidal antiinflammatory agents such as aspirin. However, these agents inhibit the synthesis of all prostanoids. To produce biologically active PGE2, PGE synthases catalyze the isomerization of PGH2 into PGE2. Recently, several PGE synthases have been identified and cloned, but their role in inflammation is not clear. To study the physiological role of the individual PGE synthases, we have generated by targeted homologous recombination a mouse line deficient in microsomal PGE synthase 1 (mPGES1) on the inbred DBA/1lacJ background. mPGES1-deficient (mPGES1-/-) mice are viable and fertile and develop normally compared with wild-type controls. However, mPGES1-/- mice displayed a marked reduction in inflammatory responses compared with mPGES1+/+ mice in multiple assays. Here, we identify mPGES1 as the PGE synthase that contributes to the pathogenesis of collagen-induced arthritis, a disease model of human rheumatoid arthritis. We also show that mPGES1 is responsible for the production of PGE2 that mediates acute pain during an inflammatory response. These findings suggest that mPGES1 provides a target for the treatment of inflammatory diseases and pain associated with inflammatory states.

Inflammatory response : pathway across the blood–brain barrier

Inflammatory reactions against invaders in the body call upon cytokine molecules that elicit systemic responses, such as fever, fatigue, increased pain sensitivity and appetite loss, mediated by the central nervous system. But how cytokines can induce these effects has been a mystery as they are unlikely to cross the blood–brain barrier. Here we show that cerebral vascular cells express components enabling a blood-borne cytokine to stimulate the production of prostaglandin E2, an inflammatory mediator whose small size and lipophilic properties allow it to diffuse into the brain parenchyma. As receptors for this prostaglandin are found on responsive deep neural structures, we propose that the activated immune system controls central reactions to peripheral inflammation through a prostaglandin-dependent, cytokine-mediated pathway.

Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis

We studied the febrile response in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells. These animals showed no fever and no central prostaglandin (PG) E2 synthesis after peripheral injection of bacterial-wall lipopolysaccharide, but their pyretic capacity in response to centrally administered PGE2 was intact. Our findings identify mPGES-1 as the central switch during immune-induced pyresis and as a target for the treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain.

Prostaglandins as inflammatory messengers across the blood-brain barrier

Abstract. Upon immune challenge the brain launches a wide range of responses, such as fever, anorexia, and hyperalgesia that serve to maintain homeostasis. While these responses are adaptive during acute infections, they may be destructive during chronic inflammatory conditions. Research performed during the last decade has given us insight into how the brain monitors the presence of a peripheral inflammation and the mechanisms underlying the brain-mediated acute-phase reactions. Here we give a brief review on this subject, with focus on the role of prostaglandin E2 produced in cells associated with the blood-brain barrier in immune-to-brain signaling. The recent advances in this field have not only elucidated the mechanisms behind the anti-pyretic and anti-hyperalgesic effects of cyclooxygenase inhibitors, but have also identified novel and more-selective potential drug targets.

The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

Infection during the neonatal period commonly induces apnea episodes, and the proinflammatory cytokine IL-1β may serve as a critical mediator between these events. To determine the mechanism by which IL-1β depresses respiration, we examined a prostaglandin E2 (PGE2)-dependent pathway in newborn mice and human neonates. IL-1β and transient anoxia rapidly induced brainstem-specific microsomal prostaglandin E synthase-1 (mPGES-1) activity in neonatal mice. Furthermore, IL-1β reduced respiratory frequency during hyperoxia and depressed hypoxic gasping and autoresuscitation in mPGES-1 wild-type mice, but not in mPGES-1 knockout mice. In wild-type mice, PGE2 induced apnea and irregular breathing patterns in vivo and inhibited brainstem respiratory rhythm generation in vitro. Mice lacking the EP3 receptor (EP3R) for PGE2 exhibited fewer apneas and sustained brainstem respiratory activity, demonstrating that PGE2 exerts its respiratory effects via EP3R. In human neonates, the infectious marker C-reactive protein was correlated with elevated PGE2 in the cerebrospinal fluid, and elevated central PGE2 was associated with an increased apnea frequency. We conclude that IL-1β adversely affects breathing and its control by mPGES-1 activation and PGE2 binding to brainstem EP3 receptors, resulting in increased apnea frequency and hypoxia-induced mortality.

Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis

Although central nervous symptoms such as hyperalgesia, fatigue, malaise, and anorexia constitute major problems in the treatment of patients suffering from chronic inflammatory disease, little has been known about the signaling mechanisms by which the brain is activated during such conditions. Here, in an animal model of rheumatoid arthritis, we show that microsomal prostaglandin E‐synthase, the inducible terminal isomerase in the prostaglandin E2‐synthesizing pathway, is expressed in endothelial cells along the blood‐brain barrier and in the parenchyma of the paraventricular hypothalamic nucleus. The endothelial cells but not the paraventricular hypothalamic cells displayed a concomitant induction of cyclooxygenase‐2 and expressed interleukin‐1 type 1 receptors, which indicates that the induction is due to peripherally released cytokines. In contrast to cyclooxygenase‐2, microsomal prostaglandin E synthase had very sparse constitutive expression, suggesting that it could be a target for developing drugs that will carry fewer side effects than the presently available cyclooxygenase inhibitors. These findings, thus, suggest that immune‐to‐brain communication during chronic inflammatory conditions involves prostaglandin E2‐synthesis both along the blood‐brain barrier and in the parenchyma of the hypothalamic paraventricular nucleus and point to novel avenues for the treatment of the brain‐elicited disease symptoms during these conditions. J. Comp. Neurol. 452:205–214, 2002.

c-Jun N-terminal kinase-mediated stabilization of microsomal prostaglandin E2 synthase-1 mRNA regulates delayed microsomal prostaglandin E2 synthase-1 expression and prostaglandin E2 biosynthesis by cardiomyocytes.

Microsomal prostaglandin (PG) E2 synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE2, a key proinflammatory mediator. The purpose of this study was to elucidate the regulation of mPGES-1 mRNA expression in cardiomyocytes, define the role of JNK enzymes in this process, and characterize the role of mPGES-1 in cardiomyocyte PGE2 biosynthesis. In neonatal cardiomyocytes, interleukin-1β and lipopolysaccharide (LPS) both stimulated mPGES-1 mRNA expression and increased mPGES-1 mRNA stability and protein synthesis but failed to increase mPGES-1 mRNA transcription. Treatment with the JNK1/2 inhibitor, SP600125, abrogated the increases in mPGES-1 mRNA stability, mPGES-1 protein synthesis, and PGE2 release induced by interleukin-1β or LPS. mPGES-1 protein synthesis was observed in LPS-stimulated neonatal cardiomyocytes from jnk1–/– or jnk2–/– mice. In contrast, infection of jnk1–/– cardiomyocytes with an adenovirus encoding phosphorylation-resistant JNK2 (ad-JNK2-DN), or of jnk2–/– cardiomyocytes with ad-JNK1-DN, significantly decreased LPS-stimulated mPGES-1 protein synthesis. Similarly, co-infection with ad-JNK1-DN and ad-JNK2-DN attenuated LPS-stimulated mPGES-1 protein synthesis in cardiomyocytes from wild type mice. Targeted deletion of the gene encoding mPGES-1 led to a 3.2-fold decrease in LPS-stimulated PGE2 release by cardiomyocytes in comparison with wild type cells but had no effect on COX-1, COX-2, mPGES-2, or cytosolic PGES mRNA levels. These studies provide direct evidence that mPGES-1 mRNA levels in cardiomyocytes are augmented by stabilization of mPGES-1 mRNA, that JNK1 or JNK2 can participate in the regulation of mPGES-1 protein synthesis in these cells, and that mPGES-1 catalyzes the majority of LPS-induced PGE2 biosynthesis by cardiomyocytes.

PGE2 – metabolite levels in CSF correlate to HIE score and outcome after perinatal asphyxia

Acute anoxic exposure rapidly increases prostaglandin E2 (PGE2) production and release in neonatal mice brains. We hypothesize that PGE2 is released in human cerebrospinal fluid (CSF) during perinatal asphyxia and that it might be used as a biomarker for perinatal asphyxia.