title: CD154 is released from T-cells by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and ADAM17 in a CD40 protein-dependent manner.
abstract: CD154 (CD40 ligand) is a type II transmembrane protein that belongs to the tumor necrosis factor superfamily. The soluble form of CD154 (sCD154), which results from the shedding of membrane-bound CD154, plays a key role in the production of proinflammatory cytokines and has been linked to various autoimmune and vascular disorders. Therefore, elucidating the mechanisms by which CD154 is released from the cell surface following its interaction with its various receptors is of primordial importance. Using co-culture experiments, we show that CD154 is shed predominantly upon its engagement with CD40. Indeed, only CD40 (both membrane-bound and soluble) and not α5β1 or αMβ2 is involved in the cleavage and release of CD154 from Jurkat E6.1 T-cells. Interestingly, CD154 is cleaved independently of the formation of cell surface CD40 homodimers and independently of its association into lipid rafts. In contrast, we found that the protein kinase C (PKC) signaling family and the matrix metalloproteinases ADAM10 and ADAM17 are intimately involved in this process. In conclusion, our data indicate that CD154 is released from T-cells by ADAM10 and ADAM17 upon CD40 ligation. These findings add significant insights into the mechanisms by which CD154 is down-regulated and may lead to the generation of novel therapeutic targets for the treatment of CD154-associated disorders.
authors.affiliation: From the Laboratoire d'Immunologie Cellulaire et Moléculaire, Centre Hospitalier de l'Université de Montréal, Hôpital St-Luc, Montréal, Quebec H2X 1P1, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Yacoub
authors.forename: Nadir
authors.initials: N
authors.lastname: Benslimane
authors.forename: Loubna
authors.initials: L
authors.lastname: Al-Zoobi
authors.forename: Ghada
authors.initials: G
authors.lastname: Hassan
authors.forename: Amal
authors.initials: A
authors.lastname: Nadiri
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D019013:CD40 Antigens / Q000737:chemistry / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D008565:Membrane Proteins; D023201:CD40 Ligand; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: CD154; CD40; Cell Signaling; Inflammation; Integrins; Molecular Biology; Receptors; T-cells