Production of Vascular Endothelial Growth Factors from Human Lung Macrophages Induced by Group IIA and Group X Secreted Phospholipases A2

Abstract

Angiogenesis and lymphangiogenesis mediated by vascular endothelial growth factors (VEGFs) are main features of chronic inflammation and tumors. Secreted phospholipases A2 (sPLA2s) are overexpressed in inflammatory lung diseases and cancer and they activate inflammatory cells by enzymatic and receptor-mediated mechanisms. We investigated the effect of sPLA2s 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 sPLA2s (group IIA and group X) induced the expression and release of VEGF-A and VEGF-C from macrophages. Enzymatically-inactive sPLA2s were as effective as the active enzymes in inducing VEGF production. Me-Indoxam and RO092906A, two compounds that block receptor-mediated effects of sPLA2s, inhibited group X-induced release of VEGF-A. Inhibition of the MAPK p38 by SB203580 also reduced sPLA2-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 sPLA2 in the presence of adenosine analogs induced a synergistic increase of VEGF-A release and inhibited TNF-α production through a cooperation between A2A and A3 receptors. These results demonstrate that sPLA2s induce production of VEGF-A and VEGF-C in human macrophages by a receptor-mediated mechanism independent from sPLA2 catalytic activity. Thus, sPLA2s may play an important role in inflammatory and/or neoplastic angiogenesis and lymphangiogenesis.

The immune network in thyroid cancer

“…A normal tissue microenvironment can suppress malignancy, while certain pathogenetic tissue features are critical for tumor development. 63,54 A myriad of immune cells are present in the TC microenvironment and in some cases are associated with patient outcome. 66,68 However, only studies assessing the functional role of TAMs and TAMCs in the TC microenvironment have provided evidence for their protumorigenic role.…”

“…TC cells, TAMs, TAMCs and other immune cells are a major source of proangiogenic and lymphangiogenic molecules. 53,54 Interestingly, immune cells and tumors can produce pro-and anti-angiogenic isoforms of VEGFs. 62 A deeper knowledge of the balance between these isoforms could lead to the discovery of novel targets that can be manipulated to block TC growth.…”

“…53 In addition, thyroid MCs modulated angiogenesis through the release of CXCL8/IL-8. 25 Human macrophages are also a major source of both angiogenic and lymphangiogenic factors 54 as well as of several proangiogenic enzymes such as MMP-9, Cox-2 and iNOS. 13 Tumor-associated NK cells produce VEGF-A and CXCL8/IL-8.…”

Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8

“…Many studies have demonstrated that myeloid cells produce various angiogenic factors including vascular endothelial growth factor (VEGF) (2), interleukin 8 (IL-8) (3), basic fibroblast growth factor (bFGF) (4), and Bv8 (5).…”

Anti-inflammatory and antioxidant properties of Eriobotrya japonica leaves extracts

“…The sPLA2 group IIA was initially detected in synovial fluid of patients with rheumatoid arthritis 15,16 . Several studies demonstrated that the sPLA2 group IIA was involved in inflammatory process [17][18][19] and many phospholipases A2 inhibitors have been discovered and their effectiveness have been proved as a treatment of inflammatory diseases [20][21][22] . Because overproduction of these inflammatory mediators might cause inflammatory damage, we focused in the present study on the evaluation of the anti-inflammatory effect of LEJ extracts by measuring the inhibition of the pro-inflammatory sPLA2 group IIA as well as their antioxidant activity.…”