An Angiogenic Switch in Macrophages Involving Synergy between Toll-Like Receptors 2, 4, 7, and 9 and Adenosine A2A Receptors
| Autor: | Geert-Jan Boons, György Haskó, Madhuri Ramanathan, Grace Pinhal-Enfield, S. Joseph Leibovich, Stefanie N. Vogel, Andrew L. Salzman |
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| Rok vydání: | 2003 |
| Předmět: |
Lipopolysaccharides
Male Vascular Endothelial Growth Factor A Adenosine Vasodilator Agents Adenosine A2A receptor Angiogenesis Inhibitors Adenosine-5'-(N-ethylcarboxamide) Endothelial Growth Factors Pharmacology Mice Enzyme Inhibitors Receptor Cells Cultured Mice Knockout Lymphokines Toll-like receptor Membrane Glycoproteins Vascular Endothelial Growth Factors Toll-Like Receptors NF-kappa B Up-Regulation DNA-Binding Proteins Intercellular Signaling Peptides and Proteins medicine.drug Agonist medicine.medical_specialty Paclitaxel Receptor Adenosine A2A medicine.drug_class Lipoproteins Neovascularization Physiologic Receptors Cell Surface Biology Pathology and Forensic Medicine Internal medicine Purinergic P1 Receptor Agonists medicine Animals Humans Tumor Necrosis Factor-alpha Adenine Receptors Purinergic P1 Toll-Like Receptor 2 Toll-Like Receptor 3 Mice Inbred C57BL Toll-Like Receptor 4 Toll-Like Receptor 5 TLR2 Endocrinology Toll-Like Receptor 7 Toll-Like Receptor 9 Macrophages Peritoneal TLR4 Regular Articles |
| Zdroj: | The American Journal of Pathology. 163:711-721 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/s0002-9440(10)63698-x |
| Popis: | Adenosine A(2A) receptor (A(2A)R) agonists synergize with Escherichia coli (E. coli) LPS [toll-like receptor (TLR)4 agonist] to up-regulate vascular endothelial growth factor (VEGF) expression in murine macrophages. Here, we demonstrate that TLR2, TLR7, and TLR9, but not TLR3 and TLR5 agonists, also synergize with A(2A)R agonists and adenosine to up-regulate VEGF, while simultaneously strongly down-regulating TNFalpha expression. In the absence of adenosine or A(2A)R agonists, Porphyromonas gingivalis (P. gingivalis) LPS and PAM(3)CAG (TLR2 agonists), resiquimod (R848) (TLR7 agonist), and non-methylated CpG DNA (TLR9 agonist) strongly up-regulate TNFalpha expression, with no effect on VEGF. In the presence of adenosine or A(2A)R agonists, but not A(1)R agonists, TLR2, 4, 7, and 9 agonists strongly up-regulate VEGF expression, while simultaneously down-regulating TNFalpha. C57BL/10ScN (TLR4 deletion mutant) macrophages produce TNFalpha in response to TLR2, 3, 7, and 9 agonists, but not the TLR4 agonist E. coli LPS. With adenosine or A(2A)R agonists, TLR2, 7, and 9, but not TLR4 agonists, also synergistically up-regulate VEGF, while down-regulating TNFalpha expression. Polyinosinic-polycytidilic acid (poly(I:C)) (TLR3 agonist) stimulates TNFalpha expression in macrophages from both C57BL/10ScSn and C57BL/10ScN mice, but has little effect on VEGF expression in the presence of adenosine or A(2A)R agonists. R-flagellins from Serratia marcescens (S. marcescens) and Salmonella muenchen (S. muenchen) do not stimulate TNFalpha expression in either C57BL/10ScSn or C57BL10/ScN mice, and have no effect on VEGF production in the presence of adenosine or A(2A)R agonists. While adenosine and A(2A)R agonists strongly down-regulate TNFalpha protein expression induced by TLR2, 3, 4, 7, and 9 agonists, TNFalpha mRNA and NF-kappaB activation are not reduced. We propose a novel signaling pathway in murine macrophages involving synergy between TLRs 2, 4, 7, and 9 and A(2A)Rs, that up-regulates VEGF and down-regulates TNFalpha expression, thus acting as an angiogenic switch. This angiogenic switch may play an important role in ischemia when TLR agonists are present, providing an interface between innate immunity and wound healing. |
| Databáze: | OpenAIRE |
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