Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils

Norbert Leitinger, Timothy R. Tyner, Laura Oslund, Cristina Rizza, Ganesamoorthy Subbanagounder, Hans Lee, Peggy T. Shih, Nigel Mackman, Gabor Tigyi, Mary C. Territo, Judith A. Berliner, Devendra K. Vora

Research output: Contribution to journalArticle

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Abstract

We previously have demonstrated that oxidized 1-palmitoyl-2- arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a component of minimally modified low density lipoprotein (MM-LDL), activates endothelial cells to bind monocytes. 1-Palmitoyl-2(5-oxovaleroyl)-sn-glycero-3- phosphorylcholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3- phosphorylcholine (PGPC), which are present in OxPAPC, MM-LDL, and atherosclerotic lesions, were shown to have a major role in the activation of endothelial cells. We now demonstrate that these two highly similar molecules have dramatically different effects on leukocyte endothelial interactions. POVPC is a potent regulator of monocyte-specific endothelial interactions. Treatment of endothelial cells with POVPC increased monocyte binding by inducing the surface expression of the connecting segment 1 domain of fibronectin; no increase in neutrophil binding was observed. In addition, POVPC strongly inhibited lipopolysaccharide-mediated induction of neutrophil binding and expression of E-selectin protein and mRNA. This inhibition was mediated by a protein kinase A-dependent pathway, resulting in down- regulation of NF-κB-dependent transcription. In contrast, PGPC induced both monocyte and neutrophil binding and expression of E-selectin and vascular cell adhesion molecule 1. We present evidence to suggest that the two phospholipids act by different novel receptors present in Xenopus laevis oocytes and that POVPC, but not PGPC, stimulates a cAMP-mediated pathway. At concentrations equal to that present in MM-LDL, the effect of POVPC dominates and inhibits PGPC-induced neutrophil binding and E-selectin expression in endothelial cells. In summary, our data provide evidence that both POVPC and PGPC are important regulators of leukocyte-endothelial interactions and that POVPC may play a dominant role in a number of chronic inflammatory processes where oxidized phospholipids are known to be present.

Original languageEnglish (US)
Pages (from-to)12010-12015
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number21
DOIs
StatePublished - Oct 12 1999

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Phosphorylcholine
Monocytes
Phospholipids
Neutrophils
E-Selectin
Endothelial Cells
LDL Lipoproteins
Leukocytes
Vascular Cell Adhesion Molecule-1
Xenopus laevis
Cyclic AMP-Dependent Protein Kinases
Oocytes
Lipopolysaccharides
Down-Regulation
Messenger RNA
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils. / Leitinger, Norbert; Tyner, Timothy R.; Oslund, Laura; Rizza, Cristina; Subbanagounder, Ganesamoorthy; Lee, Hans; Shih, Peggy T.; Mackman, Nigel; Tigyi, Gabor; Territo, Mary C.; Berliner, Judith A.; Vora, Devendra K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 21, 12.10.1999, p. 12010-12015.

Research output: Contribution to journalArticle

Leitinger, N, Tyner, TR, Oslund, L, Rizza, C, Subbanagounder, G, Lee, H, Shih, PT, Mackman, N, Tigyi, G, Territo, MC, Berliner, JA & Vora, DK 1999, 'Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils', Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 21, pp. 12010-12015. https://doi.org/10.1073/pnas.96.21.12010
Leitinger, Norbert ; Tyner, Timothy R. ; Oslund, Laura ; Rizza, Cristina ; Subbanagounder, Ganesamoorthy ; Lee, Hans ; Shih, Peggy T. ; Mackman, Nigel ; Tigyi, Gabor ; Territo, Mary C. ; Berliner, Judith A. ; Vora, Devendra K. / Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 21. pp. 12010-12015.
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abstract = "We previously have demonstrated that oxidized 1-palmitoyl-2- arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a component of minimally modified low density lipoprotein (MM-LDL), activates endothelial cells to bind monocytes. 1-Palmitoyl-2(5-oxovaleroyl)-sn-glycero-3- phosphorylcholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3- phosphorylcholine (PGPC), which are present in OxPAPC, MM-LDL, and atherosclerotic lesions, were shown to have a major role in the activation of endothelial cells. We now demonstrate that these two highly similar molecules have dramatically different effects on leukocyte endothelial interactions. POVPC is a potent regulator of monocyte-specific endothelial interactions. Treatment of endothelial cells with POVPC increased monocyte binding by inducing the surface expression of the connecting segment 1 domain of fibronectin; no increase in neutrophil binding was observed. In addition, POVPC strongly inhibited lipopolysaccharide-mediated induction of neutrophil binding and expression of E-selectin protein and mRNA. This inhibition was mediated by a protein kinase A-dependent pathway, resulting in down- regulation of NF-κB-dependent transcription. In contrast, PGPC induced both monocyte and neutrophil binding and expression of E-selectin and vascular cell adhesion molecule 1. We present evidence to suggest that the two phospholipids act by different novel receptors present in Xenopus laevis oocytes and that POVPC, but not PGPC, stimulates a cAMP-mediated pathway. At concentrations equal to that present in MM-LDL, the effect of POVPC dominates and inhibits PGPC-induced neutrophil binding and E-selectin expression in endothelial cells. In summary, our data provide evidence that both POVPC and PGPC are important regulators of leukocyte-endothelial interactions and that POVPC may play a dominant role in a number of chronic inflammatory processes where oxidized phospholipids are known to be present.",
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AU - Leitinger, Norbert

AU - Tyner, Timothy R.

AU - Oslund, Laura

AU - Rizza, Cristina

AU - Subbanagounder, Ganesamoorthy

AU - Lee, Hans

AU - Shih, Peggy T.

AU - Mackman, Nigel

AU - Tigyi, Gabor

AU - Territo, Mary C.

AU - Berliner, Judith A.

AU - Vora, Devendra K.

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AB - We previously have demonstrated that oxidized 1-palmitoyl-2- arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a component of minimally modified low density lipoprotein (MM-LDL), activates endothelial cells to bind monocytes. 1-Palmitoyl-2(5-oxovaleroyl)-sn-glycero-3- phosphorylcholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3- phosphorylcholine (PGPC), which are present in OxPAPC, MM-LDL, and atherosclerotic lesions, were shown to have a major role in the activation of endothelial cells. We now demonstrate that these two highly similar molecules have dramatically different effects on leukocyte endothelial interactions. POVPC is a potent regulator of monocyte-specific endothelial interactions. Treatment of endothelial cells with POVPC increased monocyte binding by inducing the surface expression of the connecting segment 1 domain of fibronectin; no increase in neutrophil binding was observed. In addition, POVPC strongly inhibited lipopolysaccharide-mediated induction of neutrophil binding and expression of E-selectin protein and mRNA. This inhibition was mediated by a protein kinase A-dependent pathway, resulting in down- regulation of NF-κB-dependent transcription. In contrast, PGPC induced both monocyte and neutrophil binding and expression of E-selectin and vascular cell adhesion molecule 1. We present evidence to suggest that the two phospholipids act by different novel receptors present in Xenopus laevis oocytes and that POVPC, but not PGPC, stimulates a cAMP-mediated pathway. At concentrations equal to that present in MM-LDL, the effect of POVPC dominates and inhibits PGPC-induced neutrophil binding and E-selectin expression in endothelial cells. In summary, our data provide evidence that both POVPC and PGPC are important regulators of leukocyte-endothelial interactions and that POVPC may play a dominant role in a number of chronic inflammatory processes where oxidized phospholipids are known to be present.

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