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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3413-3419.
Prepublished online as a Blood First Edition Paper on January 11, 2005; DOI 10.1182/blood-2004-10-4111.


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CHEMOKINES

TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release

Paola Secchiero, Federica Corallini, Maria Grazia di Iasio, Arianna Gonelli, Elisa Barbarotto, and Giorgio Zauli

From the Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Ferrara, Italy; and the Department of Normal Human Morphology, University of Trieste, Trieste, Italy.

Exposure of endothelial cells to recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced a modest (2-fold) increase of HL-60 cell adhesion as compared to TNF-{alpha} (40-fold) or interleukin 1{beta} (IL-1{beta}; 20-fold). However, pretreatment of endothelial cultures with TRAIL determined a significant reduction of the proadhesive activity induced by both TNF-{alpha} and IL-1{beta}. Unexpectedly, the antiadhesive activity of TRAIL was not due to interference with the nuclear factor {kappa}B (NF-{kappa}B)-mediated up-regulation of surface intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin adhesion molecules in response to inflammatory cytokines. In searching for the molecular mechanism underlying this biologic activity of TRAIL, a cDNA microarray analysis was performed. TRAIL pretreatment variably down-modulated the mRNA steady-state levels of several TNF-{alpha}-induced chemokines, and, in particular, it abrogated the TNF-{alpha}-mediated up-regulation of CCL8 and CXCL10. Of note, the addition of optimal concentrations of recombinant CCL8 plus CXCL10 to endothelial cultures completely restored the proadhesive activity of TNF-{alpha}. Moreover, experiments performed with agonistic anti-TRAIL receptor antibodies demonstrated that both TRAIL-R1 and TRAIL-R2 contributed, although at different levels, to TRAIL-induced chemokine modulation. Taken together, our data suggest that TRAIL might play an important role in modulating leukocyte/endothelial cell adhesion by selectively down-regulating CCL8 and CXCL10 chemokines.


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