Abstract |
Angiogenesis and lymphangiogenesis mediated by vascular endothelial growth factors ( VEGFs) are main features of chronic inflammation and tumors. Secreted phospholipases A(2) ( sPLA(2)s) are overexpressed in inflammatory lung diseases and cancer and they activate inflammatory cells by enzymatic and receptor-mediated mechanisms. We investigated the effect of sPLA(2)s on the production of VEGFs from human macrophages purified from the lung tissue of patients undergoing thoracic surgery. Primary macrophages express VEGF-A, VEGF-B, VEGF-C, and VEGF-D at both mRNA and protein level. Two human sPLA(2)s (group IIA and group X) induced the expression and release of VEGF-A and VEGF-C from macrophages. Enzymatically-inactive sPLA(2)s were as effective as the active enzymes in inducing VEGF production. Me- Indoxam and RO092906A, two compounds that block receptor-mediated effects of sPLA(2)s, inhibited group X-induced release of VEGF-A. Inhibition of the MAPK p38 by SB203580 also reduced sPLA(2)-induced release of VEGF-A. Supernatants of group X-activated macrophages induced an angiogenic response in chorioallantoic membranes that was inhibited by Me- Indoxam. Stimulation of macrophages with group X sPLA(2) in the presence of adenosine analogs induced a synergistic increase of VEGF-A release and inhibited TNF-alpha production through a cooperation between A(2A) and A(3) receptors. These results demonstrate that sPLA(2)s induce production of VEGF-A and VEGF-C in human macrophages by a receptor-mediated mechanism independent from sPLA(2) catalytic activity. Thus, sPLA(2)s may play an important role in inflammatory and/or neoplastic angiogenesis and lymphangiogenesis.
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Authors | Francescopaolo Granata, Annunziata Frattini, Stefania Loffredo, Rosaria I Staiano, Angelica Petraroli, Domenico Ribatti, Rob Oslund, Michael H Gelb, Gerard Lambeau, Gianni Marone, Massimo Triggiani |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 184
Issue 9
Pg. 5232-41
(May 01 2010)
ISSN: 1550-6606 [Electronic] United States |
PMID | 20357262
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Inflammation Mediators
- Protein Isoforms
- Receptor, Adenosine A3
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factor C
- Vascular Endothelial Growth Factors
- Group II Phospholipases A2
- Group X Phospholipases A2
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Topics |
- Animals
- Catalysis
- Chick Embryo
- Chorioallantoic Membrane
(blood supply, enzymology, metabolism)
- Group II Phospholipases A2
(biosynthesis, metabolism, physiology)
- Group X Phospholipases A2
(biosynthesis, metabolism, physiology)
- Humans
- Inflammation Mediators
(physiology)
- Lung
(cytology, enzymology, immunology, pathology)
- Lymphangiogenesis
(immunology)
- Macrophages, Alveolar
(cytology, enzymology, immunology, pathology)
- Neovascularization, Pathologic
(enzymology, immunology, metabolism)
- Neovascularization, Physiologic
(immunology)
- Protein Isoforms
(biosynthesis, metabolism, physiology)
- Receptor, Adenosine A3
(physiology)
- Vascular Endothelial Growth Factor A
(biosynthesis, metabolism, physiology)
- Vascular Endothelial Growth Factor C
(biosynthesis, metabolism, physiology)
- Vascular Endothelial Growth Factors
(biosynthesis)
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