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.
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.
Del Prete
Annalisa
A
Tumor Immunobiology Program, James Graham Brown Cancer Center, Departmnet of Microbiology and Immunology, University of Louisville Health Sciences Center, KY 40202, USA.
Shao
Wen-Hai
WH
Mitola
Stefania
S
Santoro
Giuseppe
G
Sozzani
Silvano
S
Haribabu
Bodduluri
B
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
C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4