Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) Sequentially Upregulates Nitric Oxide and Prostanoid Production in Primary Human Endothelial Cells

Abstract

Abstract-Endothelial cells express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, but the function of TRAIL in endothelial cells is not completely understood. We explored the role of TRAIL in regulation of key intracellular signal pathways in endothelial cells. Key Words: tumor necrosis factor-related apoptosis-inducing ligand Ⅲ nitric oxide Ⅲ prostanoids T umor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL)/Apo-2L is a member of the TNF family of cytokines, which are structurally related proteins playing important roles in regulating cell death, immune response, and inflammation. 1 TRAIL is a type II membrane protein, which can be proteolytically cleaved to a soluble form, 2 as previously shown also for TNF-␣ and CD95 (Apo-1/Fas)L. The unique feature of TRAIL, compared with other members of the TNF family, is its ability to induce apoptosis in a variety of malignant cells both in vitro and in vivo, displaying minimal toxicity on normal cells and tissues. 3,4 TRAIL interacts with 4 high affinity transmembrane receptors belonging to the apoptosis-inducing TNFreceptor (R) family. TRAIL-R1 (DR4) and TRAIL-R2 (DR5) transduce apoptotic signals on binding of TRAIL, whereas TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) are homologous to DR4 and DR5 in their cysteine-rich extracellular domain, but they lack the intracellular death domain and apoptosis inducing capability. It has been proposed that TRAIL-R3 and TRAIL-R4 function as decoy receptors protecting normal cells, including endothelial cells, from apoptosis. 5,6 It has been shown that endothelial cells express TRAIL receptors, 6 and TRAIL protein is expressed in the medial smooth cell layer of the aorta and pulmonary arteries. 7 Whereas cleavage of Fas ligand from the cell surface requires the action of zinc-dependent metalloproteases, generation of soluble TRAIL involves the action of cysteine proteases. 2 Notably, the vessel wall is a rich source of cysteine proteases. 8 Using human umbilical vein endothelial cells (HUVECs) as a model system, the aim of this study was to investigate the ability of TRAIL to modulate intracellular pathways that play a key role in endothelial cell biology. In particular, we have analyzed whether TRAIL was able to modulate the production of nitric oxide (NO), which regulates vascular tone, promotes endothelial cell survival and migration, and inhibits platelet adhesion and aggregation, leukocyte adherence, and vascular smooth muscle cell proliferation, therefore providing antithrombotic and antiinflammatory activity. 9 -12 Moreover, we have investigated the expression and/or activity of cyclooxygenases (COX) in response to TRAIL, because also these enzymes, by catalyzing the rate-limiting step in the biosynthesis of prostanoids, 13 such as prostaglandin (PGE) 2 , prostacyclin (PGI) 2 , and thromboxane (TXA) 2 , have a profound influence on blood pressure, regional blood flow, vascular remodeling, and angiogenesis.

Prognostic value of TNF-Related Apoptosis Inducing Ligand (TRAIL) in acute coronary syndrome patients

“…However, others have described that soluble TRAIL, in vitro, also induces apoptosis and proinflammatory activity in normal human umbilical vein endothelial cells (HUVEC) [21]. While others have shown that TRAIL, in vitro, on HUVEC exerts anti-inflammatory activity (by increasing nitric oxide and prostanoid production) [22]. TRAIL might play an important role in modulating leukocyte/endothelial cell adhesion.…”

Combination of TRAIL and actinomycin D liposomes enhances antitumor effect in non-small cell lung cancer

“…Recent studies have reported unanticipated side effects of TRAIL, including proangiogenic-enhanced endothelial cell proliferation, migration, and cytoskeletal reorganization. 37,38 In addition, a chief concern with conventional chemotherapies is the inevitable side effects from the nonspecific biodistribution of chemotherapeutic drugs. However, to date a strategy to improve on the challenges posed by combination treatment has not been reported in the published scientific literature.…”

Mesenchymal stem cells-derived vascular smooth muscle cells release abundant levels of osteoprotegerin

“…Therefore one mechanism by which MSC of bone marrow origin may contribute to atherosclerotic progression is through the release of OPG, which could act as a paracrine/autocrine growth factor for vascular SMC. OPG could also contribute to worsen the degree of atherosclerosis by inhibiting the TNF family member TRAIL (Vitovski et al, 2007), which displays anti-inflammatory activity in vitro (Zauli et al, 2003) and anti-atherosclerotic activity in vivo, as documented by studies in the apo-E null mice model (Secchiero et al, 2006b). …”