title: A novel role of the scaffolding protein JLP in tuning CD40-induced activation of dendritic cells.
abstract: Receptor internalization is a common mechanism underlying surface receptor down-regulation (and thus receptor signaling) upon its engagement with the cognate ligand. Tight regulation of surface CD40 expression is critical in regulating different functional properties of dendritic cell (DC). Engagement of CD40 on mature DC and the cognate CD40 ligand on T cell activates c-Jun N-terminal MAPK, p38 and ERK1/2 MAPK pathways in mature DC. JNK-associated leucine zipper protein (JLP) is a scaffolding protein that interacted with p38 and JNK. The molecular mechanism underlying CD40 internalization and its physiological impact on DC functions remained unclear. Here we reported that the engagement of CD40 on the LPS-activated DC down-regulated the surface expression of CD40. We examined the role of the JLP protein in DC differentiation, and in the regulation of DC function(s) in vitro. In contrast to the abundant JLP expression observed in immortal cell lines, primary immature DC expressed low levels of the JLP proteins. The induction of the JLP protein expression was observed in the LPS-mature DC that were activated by CD40 ligation, and also in the poly I:C stimulated DC. JLP-silenced DC was impaired in regulating CD40 surface expression upon LPS stimulation and CD40 induced receptor internalization. Such aberrant change in the regulation of surface CD40 expression was associated with an augmented capacity of the JLP-silenced DC in IL-12 production. Collectively, our data identified a novel role of a scaffolding protein JLP in the regulation of surface CD40 expression and fine-tuning of DC function.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Manitoba, Canada.
authors.forename: Huiming
authors.initials: H
authors.lastname: Wang
authors.forename: Chongbo
authors.initials: C
authors.lastname: Zhao
authors.forename: Manli
authors.initials: M
authors.lastname: Zhang
authors.forename: Clement M
authors.initials: CM
authors.lastname: Lee
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: Sam K P
authors.initials: SK
authors.lastname: Kung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D005434:Flow Cytometry; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D034622:RNA Interference
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; D008070:Lipopolysaccharides; C468928:Spag9 protein, mouse; D018664:Interleukin-12; D011070:Poly I-C