Lymphocytes stimulate expression of 5-lipoxygenase and its activating protein in monocytes in vitro via granulocyte macrophage colony-stimulating factor and interleukin 3.

Abstract

The aim of this study was to examine the role of lymphocytes in regulating expression of the 5-lipoxygenase pathway in monocytes. When monocytes were cultured over a period of days with lymphocytes, calcium ionophore-stimulated 5-lipoxygenase activity was enhanced. If lymphocytes alone were activated with lectins and their supernatants added to monocytes, stimulated 5-lipoxygenase activity was increased, whereas supernatants from lymphocytes cultured without lectins had no effect. Increased immunoreactive protein and mRNA for 5-lipoxygenase and 5-lipoxygenase activating protein were present in cells conditioned with lectin-activated lymphocyte supernatants. The effect of activated-lymphocyte supernatants could be mimicked by either GM-CSF or IL-3, but there was no additive effect with both cytokines. Both GM-CSF and IL-3 were present in the supernatant from lectin-activated lymphocytes at concentrations above their ED 50 , but were undetectable in the supernatant from nonactivated lymphocytes. The effect of lectin-activated lymphocyte supernatant could be inhibited by neutralizing antibodies to both cytokines, but not to either cytokine alone. We conclude that lymphocytes can regulate the expression of 5-lipoxygenase in monocytes, over a period of days, via the release of soluble factors, primarily GM-CSF and IL-3. ( J. Clin. Invest. 1996. 97:1293-1301.)

Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.

“…This led us to speculate that direct HIV infection of AM resulted in reduced 5-LO expression, while reduced numbers of CD4 cells resulted in reduced FLAP expression. This hypothesis is further supported by the evidence that AM from a CD4 T cell-depleted murine model demonstrate reduced 5-LO metabolism and FLAP expression (Coffey, M., S. Phare, M. Peters-Golden, and G. Huffnagle, manuscript submitted for publication) and that mediators released by activated blood lymphocytes upregulate 5-LO metabolism in peripheral blood monocytes (27). PMN, which are not susceptible to direct HIV infection, also demonstrate reduced FLAP expression with reduced LT synthetic capacity, consistent with the liklehood that reduced elaboration of mediators by CD4 T cells may be responsible for their reduced 5-LO metabolism as well.…”

International Union of Pharmacology XLIV. Nomenclature for the Oxoeicosanoid Receptor

“…There is a marked increase in the quantities of 5-oxo-ETE only when neutrophils are pretreated with phorbol myristate acetate (PMA), which elevates NADP ϩ (Powell et al, 1994). Zhang and coworkers (1996) end products identified (Ring et al, 1996(Ring et al, , 1997Werz and Steinhilber, 1996;Bonizzi et al, 1997;Larsson et al, 1998;Werz et al, 2000). In the murine-elicited peritoneal macrophage, 5-oxo-ETE was also detected (Hevko et al, 2001;Heveko and Murphy, 2002).…”

Leukotriene pathway genetics and pharmacogenetics in allergy

“…The transcription initiation site is located 65 bp upstream of the ATG and there are no TATA or CAAT sequences in the promoter (67). The gene is regulated at the transcriptional level (68) with basal mRNA levels remaining constant, but which rise rapidly during cell activation (69,70). Another level of regulation is the calcium-dependent translocation of 5-LO to the membrane from the cytosol to arrange the protein closer to its substrate (which is derived from the membrane) (8).…”