title: Epstein-Barr virus-induced gene 3 (EBI3) can mediate IL-6trans-signaling.
abstract: Epstein-Barr virus-induced gene 3 (EBI3) is a subunit of the composite cytokines IL-27 and IL-35. Both have beneficial functions or effects in models of infectious and autoimmune diseases. This suggests that administration of EBI3 could be therapeutically useful by binding free p28 and p35 to generate IL-27 and IL-35. IL-27- and IL-35-independent functions of EBI3 could compromise its therapeutic uses. We therefore assessed the effects of EBI3 on cytokine receptor-expressing cells. We observed that EBI3 activates STAT3 and induces the proliferation of the IL-6-dependent B9 mouse plasmacytoma cell line. Analyses using blocking mAbs and Ba/F3 transfectants expressing gp130 indicate that EBI3 activity was linked to its capacity to mediate IL-6trans-signaling, albeit less efficiently than soluble IL-6Rα. In line with this interpretation, co-immunoprecipitation and SPR experiments indicated that EBI3 binds IL-6. An important pro-inflammatory function of IL-6trans-signaling is to activate blood vessel endothelial cells. We observed that EBI3 in combination with IL-6 could induce the expression of chemokines by human venal endothelial cells. Our results indicate that EBI3 can promote pro-inflammatory IL-6 functions by mediatingtrans-signaling. These unexpected observations suggest that use of EBI3 as a therapeutic biologic for autoimmune diseases will likely require co-administration of soluble gp130 to prevent the side effects associated with IL-6trans-signaling. Together with previous studies that demonstrated activation of IL-6R by p28 (IL-30), new findings further suggest a complex interrelation between IL-27 and IL-6.
authors.affiliation: From the Départements de Pharmacologie and.
authors.forename: Salma
authors.initials: S
authors.lastname: Chehboun
authors.affiliation: Chimie, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Labrecque-Carbonneau
authors.affiliation: From the Départements de Pharmacologie and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pasquin
authors.affiliation: From the Départements de Pharmacologie and.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Meliani
authors.affiliation: the Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco.
authors.forename: Bouchra
authors.initials: B
authors.lastname: Meddah
authors.affiliation: NovImmune, 1228-Plan-les-Ouates, Switzerland, and.
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
authors.affiliation: the Research Service, Kansas City Veterans Affairs Medical Center and Midwest Biomedical Research Foundation, Kansas City, Missouri 64128-2226.
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
authors.affiliation: From the Départements de Pharmacologie and.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Tormo
authors.affiliation: Chimie, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Masson
authors.affiliation: From the Départements de Pharmacologie and jf.gauchat@umontreal.ca.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gauchat
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D010766:Phosphorylation; D010954:Plasmacytoma / Q000378:metabolism; D011485:Protein Binding; D018121:Receptors, Cytokine / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D018925:Chemokines; C499601:Ebi3 protein, mouse; C486767:Il27 protein, mouse; C494200:Il6st protein, mouse; D015850:Interleukin-6; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; C577686:interleukin-6, mouse; D050822:Cytokine Receptor gp130
keywords: cytokine; endothelial cell; inflammation; interleukin 6 (IL-6); interleukin 6 receptor (IL6R)