title: TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release.
abstract: 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 1beta (IL-1beta; 20-fold). However, pretreatment of endothelial cultures with TRAIL determined a significant reduction of the proadhesive activity induced by both TNF-alpha and IL-1beta. Unexpectedly, the antiadhesive activity of TRAIL was not due to interference with the nuclear factor kappaB (NF-kappaB)-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.
authors.affiliation: Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy. secchier@mail.umbi.umd.edu
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.forename: Federica
authors.initials: F
authors.lastname: Corallini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: di Iasio
authors.forename: Arianna
authors.initials: A
authors.lastname: Gonelli
authors.forename: Elisa
authors.initials: E
authors.lastname: Barbarotto
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D051017:Apoptosis Regulatory Proteins; D002448:Cell Adhesion / Q000187:drug effects; D054412:Chemokine CCL8; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004336:Drug Antagonism; D004730:Endothelium, Vascular / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D051017:Apoptosis Regulatory Proteins; C515453:CCL8 protein, human; D054412:Chemokine CCL8; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D008562:Membrane Glycoproteins; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha