title: Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function.
abstract: Trafficking of dendritic cells (DCs) to peripheral tissues and to secondary lymphoid organs depends on chemokines and lipid mediators. Here, we show that bone marrow-derived DCs (BM-DCs) express functional leukotriene B4 (LTB4) receptors as observed in dose-dependent chemotaxis and calcium mobilization responses. LTB4, at low concentrations, promoted the migration of immature and mature DCs to CCL19 and CCL21, which was associated with a rapid (30-minute) increase of CCR7 expression at the membrane level. At longer incubation times (6 hours), gene array analysis revealed a promoting role of LTB4, showing a significant increase of CCR7 and CCL19 mRNA levels. BM-DCs cultured from BLT1-/- or BLT1/2-/- mice showed a normal phenotype, but in vivo BLT1/2-/-DCs showed dramatic decrease in migration to the draining lymph nodes relative to wild-type (WT) DCs. Consistent with these observations, BLT1/2-/- mice showed a reduced response in a model of 2,4-dinitro-fluorobenzene (DNFB)-induced contact hypersensitivity. Adoptive transfer of 2,4-dinitrobenzene sulfonic acid (DNBS)-pulsed DCs directly implicated the defect in DC migration to lymph node with the defect in contact hypersensitivity. These results provide strong evidence for a role of LTB4 in regulating DC migration and the induction of adaptive immune responses.
authors.affiliation: Tumor Immunobiology Program, James Graham Brown Cancer Center, Departmnet of Microbiology and Immunology, University of Louisville Health Sciences Center, KY 40202, USA.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Del Prete
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Shao
authors.forename: Stefania
authors.initials: S
authors.lastname: Mitola
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Santoro
authors.forename: Silvano
authors.initials: S
authors.lastname: Sozzani
authors.forename: Bodduluri
authors.initials: B
authors.lastname: Haribabu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007109:Immunity; D007975:Leukotriene B4 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4