Up-regulation of prostaglandin biosynthesis by leukotriene C4 in elicited mice peritoneal macrophages activated with lipopolysaccharide/interferon-{gamma}.
Leukotrienes (LT) and prostaglandins (PG) are proinflammatory mediators generated by the conversion of arachidonic acid via 5-lipoxygenase (5-LO) and cyclooxygenase (COX) pathways. It has long been proposed that the inhibition of the 5-LO could enhance the COX pathway leading to an increased PG generation. We have found that in in vitro models of inflammation, such as mice-elicited peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma), the deletion of the gene encoding for 5-LO or the enzyme activity inhibition corresponded to a negative modulation of the COX pathway. Moreover, exogenously added LTC(4), but not LTD(4), LTE(4), and LTB(4), was able to increase PG production in stimulated cells from 5-LO wild-type and knockout mice. LTC(4) was not able to induce COX-2 expression by itself but rather potentiated the action of LPS/IFN-gamma through the extracellular signal-regulated kinase-1/2 activation, as demonstrated by the use of a specific mitogen-activated protein kinase (MAPK) kinase inhibitor. The LT-induced increase in PG generation, as well as MAPK activation, was dependent by a specific ligand-receptor interaction, as demonstrated by the use of a cys-LT1 receptor antagonist, although also a direct action of the antagonist used, on PG generation, cannot be excluded. Thus, the balance between COX and 5-LO metabolites could be of great importance in controlling macrophage functions and consequently, inflammation and tumor promotion.
Rossi
Antonietta
A
Department of Experimental Pharmacology, 'L. Califano', University of Naples Federico II, Naples, Italy.
Acquaviva
Angela Maria
AM
Iuliano
Francesca
F
Di Paola
Rosanna
R
Cuzzocrea
Salvatore
S
Sautebin
Lidia
L
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D017997:Leukotriene C4 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects*
D008070:Lipopolysaccharides; D011453:Prostaglandins; D017997:Leukotriene C4; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases