Key Points
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The resolution of inflammation is a highly controlled and coordinated process that involves the suppression of pro-inflammatory gene expression, and of leukocyte migration and activation, followed by inflammatory-cell clearance by apoptosis and phagocytosis.
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New endogenous anti-inflammatory mediators, such as cyclopentenone prostaglandins (cyPGs) and lipoxins, might regulate the resolution of inflammation.
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Lipoxins are early braking signals for the inflammatory response; they inhibit neutrophil migration and activation, but promote the recruitment of monocytes and the phagocytic clearance of apoptotic cells by monocyte-derived macrophages.
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Cyclopentenone prostaglandins are potent suppressors of macrophage activation and specifically target the pro-inflammatory nuclear factor-κB (NF-κB) signalling pathways.
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NF-κB regulates the expression of pro-inflammatory and anti-apoptotic genes; therefore, cyPGs can mediate the resolution of inflammation through the suppression of pro-inflammatory gene expression and the promotion of leukocyte apoptosis.
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Both lipoxins and cyPGs have shown therapeutic promise in several animal models of inflammatory and autoimmune diseases. Therapeutic agents based on these new anti-inflammatory lipid mediators might offer a new approach to the treatment of chronic inflammatory diseases.
Abstract
The pro-inflammatory signalling pathways and cellular mechanisms that initiate the inflammatory response have become increasingly well characterized. However, little is known about the mediators and mechanisms that switch off inflammation. Recent data indicate that the resolution of inflammation is an active process controlled by endogenous mediators that suppress pro-inflammatory gene expression and cell trafficking, as well as induce inflammatory-cell apoptosis and phagocytosis, which are crucial determinants of successful resolution. This review focuses on this emerging area of inflammation research and describes the mediators and mechanisms that are currently stealing the headlines.
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Acknowledgements
T. L. would like to acknowledge financial support of the Arthritis Research Campaign and The Special Trustees of St Bartholomew's Hospital Joint Research Board. D. W. would like to acknowledge financial support of the William Harvey Research Foundation.
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41577_2002_BFnri915_MOESM1_ESM.gif
Online figure 1| Biochemical pathway for arachidonic-acid release and eicosanoid biosynthesis. Arachidonic acid is liberated through the action of phospholipase enzymes, and converted to prostaglandin G2 (PGG2) and, subsequently, PGH2 by cyclooxygenase. Specific synthase enzymes then generate the different classes of prostaglandin. PLA2, phospholipase A2 (c, cytosolic; i, Ca2+ independent; s, secretory); hPGD2S, prostaglandin D2 synthase; mPGE2S/cPGE2S, prostaglandin E2 synthase; TxA2, thromboxane A2. (GIF 39 kb)
41577_2002_BFnri915_MOESM2_ESM.gif
Online figure 2| Biochemical pathway for lipoxin biosynthesis. The sequential action of 12- or 15-lipoxygenase (LO) and specific lipoxin hydrolase enzymes generates lipoxin A4 (LXA4) and LXB4 from leukotriene A4 (LTA4). (GIF 18 kb)
41577_2002_BFnri915_MOESM3_ESM.gif
Online figure 3| Cyclopentenone-prostaglandin formation. Prostaglandin D2 (PGD2), PGE2 and PGE1 are spontaneously metabolized to the cyclopentenone derivatives PGJ2, PGA2 and PGA1, respectively, by dehydrogenation. These cyclopentenone prostaglandins share the structural feature of a reactive carbonyl group in the cyclopentane ring. (GIF 19 kb)
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DATABASES
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Glossary
- STOP SIGNALS
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This term was coined to introduce the concept of a cellular agonist that acts as an inhibitor of inflammation.
- CYCLOPENTENONE PROSTAGLANDINS
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Prostaglandin metabolites that are characterized by the presence of a highly reactive electrophilic carbon atom in the unsaturated carbonyl group of the cyclopentane ring.
- LIPOXINS
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Leukocyte-derived eicosanoids generated during the inflammatory response that act as downregulatory signals.
- EICOSANOIDS
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A class of lipid mediator that have twenty-carbon fatty-acid derivatives; from the Greek eicosa, meaning 20. Eicosanoids are fatty-acid derivatives, primarily derived from arachidonic-acid precursors, that have a wide variety of biological activities. There are four main classes of eicosanoid — the prostaglandins, prostacyclins, thromboxanes and leukotrienes — derived from the activities of cyclooxygenases and lipoxygenases on membrane-associated fatty-acid precursors.
- LIPOXYGENASE
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A nonheme iron dioxygenase that is the key enzyme in leukotriene production.
- TRANSCELLULAR BIOSYNTHESIS
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A biosynthetic pathway that is dependent on molecules transferred from one cell to another.
- CYCLOOXYGENASE 2
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(COX2). An inducible cyclooxygenase enzyme that is thought to be the main producer of prostaglandins during the inflammatory response.
- TRANSACTIVATION
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The activation of gene transcription by trans-acting factors, such as protein transcription factors, as opposed to cis-acting DNA elements, such as enhancers/promoters.
- CYCLOOXYGENASE PATHWAY
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A biochemical pathway for the intracellular production of prostaglandins from arachidonic acid.
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Lawrence, T., Willoughby, D. & Gilroy, D. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol 2, 787–795 (2002). https://doi.org/10.1038/nri915
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DOI: https://doi.org/10.1038/nri915
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