Published online before print July 26, 2005

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(Journal of Leukocyte Biology. 2005;78:985-991.)
© 2005 by Society for Leukocyte Biology

Up-regulation of prostaglandin biosynthesis by leukotriene C₄ in elicited mice peritoneal macrophages activated with lipopolysaccharide/interferon-

Antonietta Rossi^*, Angela Maria Acquaviva, Francesca Iuliano, Rosanna Di Paola, Salvatore Cuzzocrea and Lidia Sautebin^*,1

^* Departments of Experimental Pharmacology and
Biology and Cellular and Molecular Pathology "L. Califano," University of Naples Federico II, Italy; and
Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Italy

¹Correspondence: Department of Experimental Pharmacology, University of Naples Federico II, Via D. Montesano, 80131 Naples, Italy. E-mail: sautebin{at}unina.it

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- (IFN-), 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 LTC₄, but not LTD₄, LTE₄, and LTB₄, was able to increase PG production in stimulated cells from 5-LO wild-type and knockout mice. LTC₄ was not able to induce COX-2 expression by itself but rather potentiated the action of LPS/IFN- 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.

Key Words: eicosanoids • cyclooxygenase 2 • 5-lipoxygenase • mitogen-activated protein kinase

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