doi: 10.1161/ATVBAHA.107.158451
© 2008 American Heart Association, Inc.
Letters to the Editor |
The Puzzling Role of TRAIL in Endothelial Cell Biology
Department of Morphology and Embryology, University of Ferrara, Italy
To the Editor:
In their study published online in Arteriosclerosis, Thrombosis, and Vascular Biology, O’Brien et al demonstrate that activated protein C (APC) decreases tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression in endothelial cells.1 Although the molecular mechanism by which APC decreases the expression of TRAIL mRNA and protein via an Egr-1/Erk-1/2 pathway appears convincing, much less clear is whether the downregulation of TRAIL reflects a physiological relevant decrease of surface TRAIL or TRAIL release by endothelial cells. In fact, we have never detected surface TRAIL by flow cytometry in human umbilical vein endothelial cells (HUVECs), cultured with or without TNF-
(Figure). On the other hand, surface TRAIL was easily detectable in other cell model systems, such as peripheral blood-derived adherent macrophages (Figure). Moreover, we were also unable to document in ELISA (R&D System) detectable release of soluble TRAIL by HUVECs treated or not with TNF- (data not shown).
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Because in their study O Brien et al used an ELISA approach to detect the TRAIL protein in endothelial cell lysates, the reported modulation of TRAIL by TNF- and APC likely involves an intracellular pool of TRAIL protein. Although this represents an interesting observation, the mechanisms involved in membrane expression/release of TRAIL in endothelial cells have not been defined yet, making unclear the physiopathological implications of this study. However, what raises some concern in the study of O’Brien et al is their interpretation on the putative role of TRAIL in endothelial cell biology in the context of the available scientific literature. In fact, although O’Brien and colleagues postulate a detrimental effect of TRAIL in vascular biology, in our opinion this hypothesis is not adequately supported.
In spite of the observation that human endothelial cells obtained from different vascular districts express detectable levels of all transmembrane TRAIL receptors (TRAIL-R1–R4),2–4 most of the published studies have reported lack of toxicity in vitro when endothelial cells were exposed to recombinant TRAIL.2–6 Notwithstanding, different authors, including us, have shown that particular culture conditions, such as serum and extracellular matrix deprivation coupled to pharmacological inhibition of the PI-3 kinase/Akt prosurvival pathway were required to efficiently sensitize endothelial cells to TRAIL-mediated cytotoxicity.4–8 How these culture conditions reflect a physiopathological condition remains to be determined.
Contrary to the hypothesis of a detrimental effect of TRAIL in vascular biology, in a series of in vitro studies we have documented that soluble recombinant TRAIL exhibits protective and antiinflammatory effects on endothelial cells.4,9,10 Moreover, we have recently reported that soluble TRAIL shows antiatherogenic effects in an in vivo model of Apo-E knockout mouse.11 Thus, the overall scenario emerging from these published studies is that the role of TRAIL in vascular biology deserves further investigation before any conclusion on the usefulness of drug decreasing its expression/release by endothelial cells can be drawn.
Acknowledgments
Disclosures
None.
References
1. O’Brien LA, Richardson MA, Mehrbod SF, Berg DT, Gerlitz B, Gupta A, Grinnell BW. Activated protein C decreases tumor necrosis factor-related apoptosis-inducing ligand by an EPCR independent mechanism involving Egr-1/Erk-1/2 activation. Arterioscler Thromb Vasc Biol. 2007; 27: 2634–2641.
2. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997; 277: 815–818.
3. Zhang XD, Nguyen T, Thomas WD, Sanders JE, Hersey P. Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types. FEBS Lett. 2000; 483: 193–199.
4. Secchiero P, Gonelli A, Carnevale E, Milani D, Pandolfi A, Zella D, Zauli G. TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways. Circulation. 2003; 107: 2250–2256.
5. Alladina SJ, Song JH, Davidge ST, Hao C, Easton AS. TRAIL-induced apoptosis in human vascular endothelium is regulated by phosphatidylinositol 3-kinase/Akt through the short form of cellular FLIP and Bcl-2. J Vasc Res. 2005; 42: 337–347.[CrossRef][Medline] [Order article via Infotrieve]
6. Chen PL, Easton AS. Apoptotic phenotype alters the capacity of tumor necrosis factor-related apoptosis-inducing ligand to induce human vascular endothelial activation. J Vasc Res. 2008; 45: 111–122.[CrossRef][Medline] [Order article via Infotrieve]
7. Li JH, Kirkiles-Smith NC, McNiff JM, Pober JS. TRAIL induces apoptosis and inflammatory gene expression in human endothelial cells. J Immunol. 2003; 171: 1526–1533.
8. Malyankar U, Scatena M, Suchland K, Yun T, Clark E, Giachelli C. Osteoprotegerin is an vβ3-induced, NF-kB-dependent survival factor for endothelial cells. J Biol Chem. 2000; 275: 20959–20962.
9. Zauli G, Pandolfi A, Gonelli A, Di Pietro R, Guarnieri S, Ciabattoni G, Rana R, Vitale M, Secchiero P. TNF-related apoptosis-inducing ligand (TRAIL) sequentially up-regulates nitric oxide and prostanoid production in primary human endothelial cells. Circ Res. 2003; 92: 732–740.
10. Secchiero P, Corallini F, di Iasio MG, Gonelli A, Barbarotto E, Zauli G. TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release. Blood. 2005; 105: 3413–3419.
11. Secchiero P, Candido R, Corallini F, Zacchigna S, Toffoli B, Rimondi E, Fabris B, Giacca M, Zauli G. Systemic TRAIL delivery shows anti-atherosclerotic activity in apoE-null diabetic mice. Circulation. 2006; 114: 1522–1530.
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