Leukotriene C4 induces migration of human monocyte-derived dendritic cells without loss of immunostimulatory function.
Generation of human monocyte-derived dendritic cells (DCs) for cancer vaccination involves ex vivo maturation in the presence of proinflammatory cytokines and prostaglandin E(2) (PGE(2)). Although the inclusion of PGE(2) during maturation is imperative for the induction of DC migration, PGE(2) has unfavorable effects on the immunostimulatory capacity of these cells. Like PGE(2), leukotrienes (LTs) are potent mediators of DC migration. We therefore sought to characterize the migratory and immunologic properties of DCs that matured in the presence of LTB(4), LTC(4), LTD(4), and PGE(2). Here, we demonstrate that DCs matured in the presence of LTC(4), but not LTB(4) or LTD(4), are superior to PGE(2)-matured DCs in stimulating CD4(+) T-cell responses and in inducing antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without concomitant induction or recruitment of regulatory T cells (Tregs). LTC(4)-matured DCs migrate efficiently through layers of extracellular matrix and secrete higher levels of immunostimulatory IL-12p70 while producing reduced levels of immune-inhibitory IL-10, IL12p40, indoleamine-2,3-dioxidase, and TIMP-1 (tissue inhibitor of matrix metalloproteinases). Intracellular calcium mobilization and receptor antagonist studies reveal that, in contrast to LTD(4), LTC(4) did not signal through CysLTR(1) in DCs. Collectively, our data suggest that LTC(4) represents a promising candidate to replace PGE(2) in DC maturation protocols for cancer vaccination.
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Jens
J
Dannull
Tristan
T
Schneider
Walter T
WT
Lee
Nicole
N
de Rosa
Douglas S
DS
Tyler
Scott K
SK
Pruitt
D000951:Antigens, Neoplasm / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D018077:Receptors, Leukotriene / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
D000951:Antigens, Neoplasm; D018077:Receptors, Leukotriene; D017997:Leukotriene C4; D017998:Leukotriene D4