Arachidonic acid activates phospholipase D in human neutrophils; essential role of endogenous leukotriene B4 and inhibition by adenosine A2A receptor engagement

Abstract

We report in human neutrophils (PMN) that phospholipase D (PLD) was stimulated by micromolar concentrations of arachidonic acid (AA) and nanomolar concentrations of leukotriene B(4) (LTB(4)), and eicosapentaenoic acid was inactive. The stimulatory effect of AA occurred only when adenosine was eliminated from PMN suspensions or when PMN were incubated with adenosine A(2A) receptor antagonists. The mechanism of AA-induced PLD activation was investigated. The results show that AA- and LTB(4)-induced PLD activation were inhibited by the LTB(4) receptor 1 (BLTR1) antagonist CP 105,696, whereas the LTA(4) hydrolase inhibitor SC57461A and the LT biosynthesis inhibitor MK-0591 inhibited AA- but not LTB(4)-mediated PLD activation. The AA-induced ARF1 and RhoA translocation to PMN membranes was inhibited by CP 105,696 and SC57461A. These results provide evidence of a requirement for an autocrine-stimulatory loop involving LTB(4) and BLTR1 in the translocation of small GTPases to membranes and the activation of PMN PLD by AA.

Effects of pyrrophenone, an inhibitor of group IVA phospholipase A2, on eicosanoid and PAF biosynthesis in human neutrophils

“…PLD activity was not inhibited by pyrrophenone in fMLP-activated PMN. In contrast, the data presented herein showed that pyrrophenone inhibited PLD activity in thapsigargin-activated PMN, an effect that could be attributed to inhibition of cPLA 2 a and biosynthesis of LTB 4 , which acts as the direct activator of PLD in these experimental conditions (Grenier et al, 2003). These results demonstrate that pyrrophenone has no direct inhibitory effect on PLD.…”

Phospholipase D as a potential target for the antiproliferative effects of polyunsaturated fatty acids in rat thymocytes

“…These results are in good agreement with those of our previous study showing that 22:6n-3, but not 20:5n-3, stimulated the PLD activity of human mononuclear cells [7]. 20:5n-3 was also found inactive toward the PLD activity of human neutrophils, whereas arachidonate induced a 2-fold increase at micromolar concentrations [10].…”

“…Indeed, we have previously shown that docosahexaenoic acid (22:6n-3) [7,8] or the monohydroxylated derivative of arachidonic acid (20:4n -6), 12-hydroxy eicosatetraenoic acid (12-HETE) [9] stimulated the PLD activity of ConA-stimulated human lymphocytes. Several other groups have reported PLDdependent FA effects in neutrophils [10], smooth muscle cells [11] or macrophages [12]. The functional consequences of PLD activation on mitogenic signaling clearly depends on the cell type considered.…”

The influence of linoleic and linolenic acid on the activity and intracellular localisation of phospholipase D in COS-1 cells

“…Different studies reported an enhancing effect of docosahexaenoic acid (DHA) (Bechoua et al, 1998;Diaz et al, 2002) and the monohydroxylated derivate of arachidonate, hydroxyeicosatetraenoic acid (Meskini et al, 1995) on Con A-stimulated PLD activity in human lymphocytes. Other studies described PLD-dependent effects of fatty acids in neutrophils (Grenier et al, 2003), smooth muscle cells (Askari et al, 2002) or macrophages (Wang and Oram, 2005). Examination of PLD activity in intestinal cells showed that the enzyme activity was stimulated by linolenate (LA) and g-linolenate, with LA being more effective (Awad et al, 1994).…”