Lysophosphatidylcholine Increases Expression of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Human T Lymphocytes

Abstract

Atherosclerotic lesions contain substantial numbers of activated T lymphocytes in addition to monocytes/macrophages. T cell-derived cytokines and growth factors may play a role in atherogenesis; however, stimuli responsible for T-cell activation in atherogenesis have not been fully elucidated. In this study, we provide evidence that lysophosphatidylcholine (lyso-PC), a polar phospholipid component increased in atherogenic lipoproteins and atherosclerotic lesions, can upregulate gene expression and secretion of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in cultured T lymphocytes isolated from human peripheral blood. Effects of lyso-PC on T lymphocytes appear to be selective and specific, since lyso-PC also increases interleukin (IL)-2 receptor expression but does not affect mRNA levels for IL-2 or IL-4. Lyso-PC-induced upregulation of HB-EGF and IL-2 receptor mRNA in peripheral T cells is mostly dependent on exogenous IL-2 in conditioned medium. The effect of lyso-PC on HB-EGF induction was more potent in CD4+ cells than in CD8+ cells, although lyso-PC increases IL-2 receptor expression dramatically in both CD4+ cells and CD8+ cells. Lyso-PC similarly increased HB-EGF expression in Jurkat cells, a cell line for human CD4+ T lymphocytes. These results in vitro suggest that lyso-PC may be an important stimulus for T cells in atherogenesis in vivo to upregulate HB-EGF and that T cell-derived smooth muscle growth factors may modulate atherosclerotic progression.

Thematic review series: The Immune System and Atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease?

“…LysoPC also can upregulate the expression of adhesion molecules for monocytes (125,126) and stimulate the expression of growth factors, such as heparin binding epidermal growth factor and the platelet-derived growth factor A and B chains (127)(128)(129), all of which may play important roles in atherogenesis. Lysophosphatidic acid, which can be produced by hydrolysis of the polar head group of lysoPC, stimulates platelet aggregation, cell proliferation, and smooth muscle cell contraction (130,131).…”

Lysophosphatidylcholine Induces Early Growth Response Factor-1 Expression and Activates the Core Promoter of PDGF-A Chain in Vascular Endothelial Cells

“…[1][2][3] Lyso-PC is also generated in wounds and inflammatory lesions through the actions of extracellularly secreted phospholipase A 2 . 4 Previous reports have shown that lyso-PC can induce gene expression of platelet-derived growth factor (PDGF)-A and -B chains, heparin-binding epidermal growth factor, [5][6][7] vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM)-1, 8 endothelial cell NO synthase (ecNOS), 9,10 and cyclooxygenase-2 11 in cultured vascular endothelial cells, in addition to the induction of apoptosis 12 as well as the inhibition of endothelium-dependent vasorelaxation 13 and endothelial cell migration. 14 With regard to the signal transduction pathways, lyso-PC has been shown to mobilize intracellular calcium, 15 stimulate the tyrosine phosphorylation of platelet and endothelial cell adhesion molecule-1, 16 disrupt a receptor-G protein coupling, 17 elevate intracellular cAMP, 18 activate mitogen-activated protein (MAP) kinases such as extracellular signalregulated kinase (ERK) 19 and c-Jun N-terminal kinase (JNK), 19,20 protein kinase C, 21 activator protein (AP)-1, 20,22 and nuclear factor (NF)-B 23 in cultured vascular endothelial cells.…”

Immunomodulatory Actions of Lysophosphatidylcholine

“…As the case for T lymphocytes (Nishi et al, 1997), LPC (C18:0, 25 and 37.5 µg/ml) increases the expression of HB-EGF in human monocytes (Nakano et al, 1994). LPC (C16:0, 25, 30 µM) induces the production of IL-1β in human monocytes (Liu-Wu et al, 1998) and in mouse peritoneal macrophages (Yan et al, 2004).…”

“…LPC (C16:0; 37.5, 50 µM) induces gene expression and secretion of heparin-binding epidermal growth factor-like growth factor (HB-EGF), a smooth muscle growth factor (Nishi et al, 1997), and enhances cytokine-induced interferon (IFN)-γ expression in human T (CD4+ and CD8+) lymphocytes. LPC (C16:0, 1, 30 µM) up-regulates CD40 ligand expression in anti-CD3 antibody and CD80-stimulated human CD4+ T cells (SakataKaneko et al, 1998).…”

“…Chemoattractant (McMurray et al, 1993;Ryborg et al, 1994;Radu et al, 2004) IL-2Rα↑/thymidine uptake↑ (Asaoka et al, 1991;Asaoka et al, 1992) HB-EGF↑ (Nishi et al, 1997), IFN-γ↑ CD40 ligand↑ (Sakata-Kaneko et al, 1998), CXCR4↑, IL-2↑ (Han et al, 2004) Antibody formation↑, most notably IgA (Huang et al, 1999) Apoptosis↑/ROS generation↑ (Zurgil et al, 2007) p56 lck and ZAP 70 phosphorylation↑, [Ca2+] i ↑ in Jurkat cells (Legradi et al, 2004) Monocyte/macrophage Chemoattractant (Quinn et al, 1988) Activates p38 and p42/44 MAPKs in THP-1 cells (Jing et al, 2000) Mitogenic effects of acetylated LDL↑ (Sakai et al, 1994) Mature dendritic cell generation↑/CD86↑ (Coutant et al, 2002) Adhesion↑/activation of CD11b (Weber et al, 1995) IFN-γ↑ (Nakano et al, 1994), IL-1 β↑ (Liu-Wu et al, 1998), TNF-α↑ (Huang et al, 1999), MIP2↑ in RAW264.7 cells (Olofsson et al, 2008), arachidonic acid ↑ in THP-1 and Mono Mac6 cells (Oestvang et al, 2003) Phospholipase D (PLD) activity ↑ (Gómez- Muñoz et al, 1999) Extracellular acidification ↑ in RAW264.7 cells (De Vries et al, 1998) EC-SOD ↑ in U937 cells (Yamamoto et al, 2002) Ca 2+ influx ↑ in U937 human monocytes (Yun et al, 2004) De-ramification of murine microglia↑/nonselective cation current↑, calcium-activated potassium current↑/ hyperpolarization↑ (Schilling et al, 2004) …”