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Blood, 15 January 2007, Vol. 109, No. 2, pp. 626-631.
Prepublished online as a Blood First Edition Paper on September 19, 2006September 22, 2006; DOI 10.1182/blood-2006-02-003665.
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Submitted February 13, 2006
Accepted September 5, 2006
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
Annalisa Del Prete, Wen-Hai Shao, Stefania Mitola, Giuseppe Santoro, Silvano Sozzani, and Bodduluri Haribabu*
James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY
Dept. of Microbiology & Immunology, University of Louisville Health Sciences Center, Louisville, KY
Section of General Pathology & Immunology, University of Brescia, Rozzano, Italy
Section of Clinical Biochemistry, Dept. of Medical Biochemistry, University of Bari, Bari, Italy
* Corresponding author; email: h0bodd01{at}gwise.louisville.edu.
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 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 that was associated with a rapid (30 min) increase of CCR7 expression at the membrane level. At longer incubation times (6 hrs) 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 inhibition of migration to the draining lymph nodes relative to WT DCs. Consistent with these observations, BLT1/2-/- mice showed a reduced response in a model of DNFB-induced contact hypersensitivity. Adoptive transfer of DNBS-pulsed DC 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.
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