A novel role for phospholipase A2 isoforms in the checkpoint control of acute inflammation.
Acute inflammation can be considered in terms of a series of checkpoints where each phase of cellular influx, persistence, and clearance is controlled by endogenous stop and go signals. It is becoming increasingly apparent that in addition to initiating the inflammatory response, eicosanoids may also mediate resolution. This suggests there are two phases of arachidonic acid release: one at onset for the generation of proinflammatory eicosanoids and one at resolution for the synthesis of proresolving eicosanoids. What is unclear is the identity of the phospholipase (PLA2) isoforms involved in this biphasic release of arachidonic acid. We show here that type VI iPLA2 drives the onset of acute pleurisy through the synthesis of PGE2, LTB4, PAF, and IL-1beta. However, during resolution there is a switch to a sequential induction of first sPLA2 (types IIa and V) that mediates the release of PAF and lipoxin A4, which, in turn, are responsible for the subsequent induction of type IV cPLA2 that mediates the release of arachidonic acid for the synthesis of proresolving prostaglandins. This study is the first of its kind to address the respective roles of PLA2 isoforms in acute resolving inflammation and to identify type VI iPLA2 as a potentially selective target for the treatment of inflammatory diseases.
Department of Experimental Pathology, William Harvey Research Institute, St. Bartholomew's & The Royal London School of Medicine and Dentistry, London. d.w.gilroy@qmul.ac.uk
Derek W
DW
Gilroy
Justine
J
Newson
Prescilla
P
Sawmynaden
Derek A
DA
Willoughby
Jamie D
JD
Croxtall
D000208:Acute Disease; D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology; D002351:Carrageenan / Q000633:toxicity; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003289:Convalescence; D003345:Corticosterone / Q000097:blood; D051546:Cyclooxygenase 2; D018450:Disease Progression; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D054501:Group II Phospholipases A2; D054513:Group IV Phospholipases A2; D054505:Group V Phospholipases A2; D054522:Group VI Phospholipases A2; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000502:physiology; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000235:genetics; D044045:Lipoxins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010998:Pleurisy / Q000097:blood / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D007375:Interleukin-1; D007527:Isoenzymes; D044045:Lipoxins; D010972:Platelet Activating Factor; C040527:lipoxin A4; D007975:Leukotriene B4; D016718:Arachidonic Acid; D002351:Carrageenan; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054513:Group IV Phospholipases A2; D054505:Group V Phospholipases A2; D054522:Group VI Phospholipases A2; D054467:Phospholipases A2; C516391:Pla2g4a protein, rat; C101424:phospholipase A2-V, Trimeresurus; D003345:Corticosterone