Leukotriene C4 induces migration of human monocyte–derived dendritic cells without loss of immunostimulatory function

Abstract

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) (PGE2). Although the inclusion of PGE2 during maturation is imperative for the induction of DC migration, PGE2 has unfavorable effects on the immunostimulatory capacity of these cells. Like PGE2, 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 LTB4, LTC4, LTD4, and PGE2. Here, we demonstrate that DCs matured in the presence of LTC4, but not LTB4 or LTD4, are superior to PGE2-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). LTC4-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 LTD4, LTC4 did not signal through CysLTR1 in DCs. Collectively, our data suggest that LTC4 represents a promising candidate to replace PGE2 in DC maturation protocols for cancer vaccination.

Key Role of Group V Secreted Phospholipase A2 in Th2 Cytokine and Dendritic Cell-Driven Airway Hyperresponsiveness and Remodeling

“…CysLTs augment the antigen-presenting capacity of dendritic cells in the lung [27]. LTC 4 , but not LTD 4 or LTB 4 , matures DCs in a superior fashion than PGE 2 to stimulate DC-driven CD4 + T cell responses and antigen-specific T cell induction [28]. CysLTs also increase the capacity of BMDCs to induce Th2 immune responses in the lungs after adoptive transfer in mice [29].…”

Intravenous anesthetic propofol suppresses leukotriene production in murine dendritic cells

“…Among these roles of leukotrienes, the promotion of DC migration has been well studied (Del Prete et al, 2007;Dannull et al, 2012). LTC 4 induces the migration of human monocyte-derived DC without a loss of immunostimulatory function (Dannull et al, 2012). LTB 4 is required for the migration of DC to regional lymph nodes, as well as for the development of airway hyper-responsiveness and airway inflammation (Del Prete et al, 2007;Miyahara et al, 2008).…”

“…Leukotrienes have been reported to act on DC to modulate their migration, maturation, and activation (Robbiani et al, 2000;Machida et al, 2004;Jozefowski et , 2012). Among these roles of leukotrienes, the promotion of DC migration has been well studied (Del Prete et al, 2007;Dannull et al, 2012). LTC 4 induces the migration of human monocyte-derived DC without a loss of immunostimulatory function (Dannull et al, 2012).…”

“…CysLTs, which consist of LTC 4 , LTD 4 , and LTE 4 , are important mediators of asthmatic responses and induce smooth muscle contraction, increase microvascular permeability, stimulate mucus secretion, and promote inflammatory cell migration, particularly eosinophils and neutrophils, into the airways (Lewis et al, 1990;Henderson, 1994;Byrum et al, 1999). CysLTs also mediate dendritic cell migration and maturation (Alvarez et al, 2011;Dannull et al, 2012). However, LTB 4 is a potent chemotactic and chemokinetic agent for leukocytes (Shin et al, 2006;Del Prete et al, 2007;Miyahara et al, 2008), enhances the phagocytic and antimicrobial activity of neutrophils and macrophages, and stimulates the secretion of immunoglobulins by lymphocytes (Lewis et al, 1990;Henderson, 1994;Byrum et al, 1999).…”

Cysteinyl Leukotriene 2 Receptor on Dendritic Cells Negatively Regulates Ligand-Dependent Allergic Pulmonary Inflammation

“…Thus, the generation of sequential ligands for the classical CysLT 2 R and CysLT 1 R may contribute to regulation of the biologic consequences of pathway activation. As studies of human monocyte-derived DCs suggest comparable cell surface staining for CysLT 1 R and CysLT 2 R (29), it seems possible that LTD 4 /CysLT 1 R conditioning of DCs for their sensitizing function may be critically regulated by the ratio of LTC 4 to LTD 4 present in tissue and the relative affinities of endogenously expressed CysLT 2 R and CysLT 1 R for LTC 4 and LTD 4 in DCs.…”