Acylation of lysophosphatidylcholine plays a key role in the response of monocytes to lipopolysaccharide

Abstract

Mononuclear phagocytes play a pivotal role in the progression of septic shock by producing tumor necrosis factor‐α (TNF‐α) and other inflammatory mediators in response to lipopolysaccharide (LPS) from Gram‐negative bacteria. Our previous studies have shown monocyte and macrophage activation correlate with changes in membrane phospholipid composition, mediated by acyltransferases. Interferon‐γ (IFN‐γ), which activates and primes these cells for enhanced inflammatory responses to LPS, was found to selectively activate lysophosphatidylcholine acyltransferase (LPCAT) (P < 0.05) but not lysophosphatidic acid acyltransferase (LPAAT) activity. When used to prime the human monocytic cell line MonoMac 6, the production of TNF‐α and interleukin‐6 (IL‐6) was approximately five times greater in cells primed with IFN‐γ than unprimed cells. Two LPCAT inhibitors SK&F 98625 (diethyl 7‐(3,4,5‐triphenyl‐2‐oxo2,3‐dihydro‐imidazole‐1‐yl)heptane phosphonate) and YM 50201 (3‐hydroxyethyl 5,3′‐thiophenyl pyridine) strongly inhibited (up to 90%) TNF‐α and IL‐6 production in response to LPS in both unprimed MonoMac‐6 cells and in cells primed with IFN‐γ. In similar experiments, these inhibitors also substantially decreased the response of both primed and unprimed peripheral blood mononuclear cells to LPS. Sequence‐based amplification methods showed that SK&F 98625 inhibited TNF‐α production by decreasing TNF‐α mRNA levels in MonoMac‐6 cells. Taken together, the data from these studies suggest that LPCAT is a key enzyme in both the pathways of activation (priming) and the inflammatory response to LPS in monocytes.

Loss of G2A promotes macrophage accumulation in atherosclerotic lesions of low density lipoprotein receptor-deficient mice

“…Additionally, the amphipathic nature of LPC results in its rapid nonspecific internalization through plasma membranes (47,48), raising the possibility that some of its effects may be mediated intracellularly. For example, internalized LPC can induce macrophage apoptosis by inhibiting the ratelimiting enzyme of the de novo phosphatidylcholine biosynthetic pathway, CTP:phosphocholine cytidylyltransferase (47), and its reacylation by cytosolic acyltransferases promotes monocyte inflammatory responses to lipopolysaccharide (49)(50)(51). Our data nevertheless suggest that specific modulation of G2A activity in macrophages could provide a therapeutic approach to attenuate atherosclerotic lesion destabilization.…”

Lysophospholipid acyltransferases in monocyte inflammatory responses and sepsis

“…Thus, we suggested that IFN-g might increase responsiveness to LPS in macrophages by up-regulating the activity of these enzymes. While the activity of phospholipases was not influenced by IFN-g; the activity of certain acyltransferases was significantly increased by this priming agent (Schmid et al, 2003).…”

“…Studies from our laboratory recently demonstrated that TNF can modify phospholipid compositions in monocytes via activation of CoA-independent transacylases (Neville et al, manuscript submission). Furthermore, we showed that IFN-g and concanavalin A, another priming agent, could selectively activate lysophosphatidyl choline acyltransferase (LPCAT) but not the lysophosphatidic acid acyltransferase (LPAAT) (Schmid et al, 2003) (Fig. 2).…”

Synergistic Activation of Macrophages via CD40 and TLR9 Results in T Cell Independent Antitumor Effects

“…First, M have to be "primed" by IFN-␥. IFN-␥ activates signal transducing molecules (e.g., MyD88 and NF-B) (5,6,7), induces expression of certain TLRs (TLR2, TLR4, and TLR9) (5,6,8), and activates selected enzymes (9) facilitating the responsiveness to a second signal. The second signal, typically provided by bacterial derivatives or TNF-␣ (5, 10, 11), then activates the spectrum of biological responses attributable to effector M. These include secretion of NO, IL-12, IL-1␤, TNF-␣, M tumor cytotoxin-170 kDa, chemokines (e.g., CCL2), as well as expression of costimulatory molecules (CD40, CD80, and CD86) and cell death-inducing ligands (Fas ligand, TRAIL, and membrane-bound TNF-␣) (5,(12)(13)(14)(15)(16)(17).…”