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Inflammation Research

Erschienen in:

01.12.2011 | Review

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

verfasst von: A. D. Mancini, J. A. Di Battista

Erschienen in: Inflammation Research | Ausgabe 12/2011

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Abstract

The process of inflammation is regulated in part by bioactive lipids of which prostaglandins/eicosanoids form an important class. We provide evidence that the phospholipase A₂/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E₂ (PCPP) axis is positioned at the core of a natural regulatory circuit controlling the initiation, magnitude, duration, and resolution of the inflammatory response. During the inflammatory phase, proinflammatory cytokine, chemokine and matrix destructive metalloprotease expression levels are moderated by the PCPP axis through the modulation of signaling pathways that control proinflammatory gene expression at transcriptional, post-transcriptional, and translational levels. The PCPP axis also contributes to the activation of lipid mediator class switching; this highly coordinated process results in the biosynthesis of lipoxins and resolvins that promote inflammatory resolution through a variety of cellular and molecular mechanisms. The PCPP axis activity is autoregulated by way of a positive feedback circuit involving PGE₂-mediated, p38 MAPK-dependent stabilization of COX-2 mRNA and COX-2 catalytic potentiation via its limited proteolytic cleavage (e.g., Ca²⁺-activated calpains). In conclusion, through its fine temporal modulation of multiple signaling cassettes via EP1-EP4 GPCRs, PGE₂ influences the onset, course, magnitude, and duration of the inflammatory response and functions as a key feedback regulator of the cellular and molecular processes controlling inflammation.

Other enzymes also participate in the production of PGE₂. Under basal (i.e., non-inflammatory) conditions, the constitutively and ubiquitously expressed COX-1 isoform catalyzes the rate-limiting step in PGE₂ biosynthesis. Basal PGE₂ production is required for homeostatic purposes (in the kidney and gastrointestinal tract, for example). The ubiquitous and constitutively expressed cytosolic prostaglandin E synthase (cPGES) preferentially couples to COX-1 for basal PGE₂ biosynthesis. Interestingly, a third PGE synthase, namely mPGES-2, has been shown to couple to both COX isoforms with a modest preference for COX-2 [14]. It has been inferred that mPGES-2 may contribute to PGE₂ production during the resolution phase of inflammation [15] and/or to homeostatic PGE₂ biosynthesis.

Fibroblast-like cells of the synovial membrane. These cells are central orchestrators of rheumatoid arthritis (RA) pathophysiology and a principal source of COX-2/PGE₂ axis activity in the RA joint. Synovial fibroblast activation is a defining step in the development of RA as it leads to the formation of the hyperplastic, bone- and cartilage-eroding pannus.

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Titel: The cardinal role of the phospholipase A2/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E2 (PCPP) axis in inflammostasis
verfasst von: A. D. Mancini
J. A. Di Battista
Publikationsdatum: 01.12.2011
Verlag: SP Birkhäuser Verlag Basel
Erschienen in: Inflammation Research / Ausgabe 12/2011
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-011-0385-7

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Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

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