Regulation of the microsomal prostaglandin E synthase-1 in polarized mononuclear phagocytes and its constitutive expression in neutrophils.
PGs are potent mediators of pain and inflammation. PGE synthases (PGES) catalyze the isomerization of PGH(2) into PGE(2). The microsomal (m)PGES-1 isoform serves as an inducible PGES and is responsible for the production of PGE(2), which mediates acute pain in inflammation and fever. The present study was designed to investigate the regulation of expression of mPGES-1 in polarized phagocytes, which represent central, cellular orchestrators of inflammatory reactions. Here, we report that human peripheral blood monocytes did not express mPGES-1. Exposure to LPS strongly induced mPGES-1 expression. Alternatively activated M2 monocytes-macrophages exposed to IL-4, IL-13, or IL-10 did not express mPGES-1, whereas in these cells, IL-4, IL-13, and to a lesser extent, IL-10 or IFN-gamma inhibited LPS-induced, mPGES-1 expression. It is unexpected that polymorphonuclear leukocytes expressed high basal levels of mPGES-1, which was up-regulated by LPS and down-regulated by IL-4 and IL-13. Induction of mPGES-1 and its modulation by cytokines were confirmed at the protein level and correlated with PGE(2) production. Cyclooxygenase 2 expression tested in the same experimental conditions was modulated in monocytes and granulocytes similarly to mPGES-1. Thus, activated M1, unlike alternatively activated M2, mononuclear phagocytes express mPGES-1, and IL-4, IL-13, and IL-10 tune expression of this key enzyme in prostanoid metabolism. Neutrophils, the first cells to enter sites of inflammation, represent a ready-made, cellular source of mPGES-1.
Mosca
Michela
M
Department of Immunology and Cell Biology, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy.
Polentarutti
Nadia
N
Mangano
Giorgina
G
Apicella
Claudia
C
Doni
Andrea
A
Mancini
Francesca
F
De Bortoli
Maida
M
Coletta
Isabella
I
Polenzani
Lorenzo
L
Santoni
Giorgio
G
Sironi
Marina
M
Vecchi
Annunciata
A
Mantovani
Alberto
A
D000818:Animals; D045744:Cell Line, Tumor; D016764:Cell Polarity; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000235:genetics / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000201:enzymology*; D009504:Neutrophils / Q000201:enzymology* / Q000378:metabolism*; D010586:Phagocytes / Q000502:physiology*; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism
D007527:Isoenzymes; D012333:RNA, Messenger; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse