Unique Effect of Arachidonic Acid on Human Neutrophil TNF Receptor Expression: Up-Regulation Involving Protein Kinase C, Extracellular Signal-Regulated Kinase, and Phospholipase A2

Abstract

Arachidonic acid (AA) regulates the function of many cell types, including neutrophils. Although much emphasis has been placed on agonist-induced down-regulation of TNFR, our data show that AA caused a rapid (10–20 min) and dose-dependent (0.5–30 μM) increase in the surface expression of both classes of TNFR (TNFR1 and TNFR2) on human neutrophils. This increased TNFR expression correlated with an increase in TNF-induced superoxide production. In contrast, the ω3 fatty acids eicosapentaenoic acid, docosahexaenoic acid, and linolenic acid failed to stimulate TNFR expression. Although fMLP and LPS reduced the neutrophil expression of TNFR, when pretreated with AA, fMLP caused an increase in TNFR expression. Consistent with this result was the finding that AA prevented the fMLP-induced receptor release in neutrophil cultures. AA also caused an increase in TNFR expression in matured HL-60 cells (neutrophil-like cells), but a decrease in nonmatured cells and HUVEC. The AA effects were independent of the lipoxygenase and cyclooxygenase pathways, but dependent on protein kinase C, the extracellular signal-regulated kinases 1 and 2, and cytosolic phospholipase A2. The data demonstrate a unique effect of AA in the inflammatory reaction, through its action on neutrophil TNFR expression, and suggest that AA may regulate the response of neutrophils to TNF by altering its receptor number.

Regulation of the NADPH oxidase activity and anti-microbial function of neutrophils by arachidonic acid

“…Consistent with this, we reported that AA can upregulate the expressions of both the p55 and p75 TNF receptors on neutrophils, but suppress the expressions of these receptors in other cell--types [74]. This neutrophil-specific effect is restricted to the mature cells, since this upregulation in TNF receptor expression could only be reproduced in differentiated, but not in undifferentiated HL60 cells [74].…”

“…The increase in surface TNF receptors is likely to be the result of recruitment from neutrophil granules, which are known to contain "spare" TNF receptors, following AA-stimulated degranulation. Consistent with the increased expression of TNF receptors, AA-pretreated cells exhibit enhanced capacity to produce superoxide in response to a subsequent challenge with TNF [74]. These data suggest that AA may promote the inflammatory response by up-regulating the expression of TNF receptors, which makes these cells more responsive to the cytokine.…”

“…The effect of AA was not dependent on the formation of metabolites, since inhibitors of lipoxygenases and cyclooxygenases did not block this effect of AA. Indomethacin, a non-selective cyclooxygenase inhibitor, actually increased the expression of TNF receptors [74], whereas expression was down-regulated by LTB 4 [88]. The increase in surface TNF receptors is likely to be the result of recruitment from neutrophil granules, which are known to contain "spare" TNF receptors, following AA-stimulated degranulation.…”

Effect of pulmonary surfactant on TNF-α-activated endothelial cells and neutrophil adhesion in vitro

“…arachidonic acid is able to serve as an intracellular second messenger and to induce adhesion processes by influencing different signal transduction cascades resulting in a modulation of the potency of the TNF-a signal pathway with the consequence of changeable expression levels of adhesion molecules. Recently, Moghaddami et al (2003) showed that arachidonic acid stimulates the expression of receptors for TNF in different cell lines. Thus, an increase in TNF-receptor expression could result in a more pronounced effect of TNF-a with the consequence of activating signal transduction pathways and upregulating the expression of adhesion molecules as we have observed.…”

Dietary Intake, Neutrophil Fatty Acid Profile, Serum Antioxidant Vitamins and Oxygen Radical Absorbance Capacity in Patients with Ulcerative Colitis

“…Arachidonic acid up-regulated phospholipase A2 and caused rapid increase in the surface expression of TNF receptors on human neutrophils (22). An increase in the arachidonic acid concentration of phospholipids may be accompanied by a rise in phospholipase A2 activity within the intestinal mucosa (23).…”