Leukotrienes modulate cytokine release from dendritic cells

Summary Leukotriene B4 (LTB4) and cysteinyl leukotrienes (CysLTs) are known as potent mediators of inflammation, whereas their role in the regulation of adaptive immunity remains poorly characterized. Dendritic cells (DCs) are specialized antigen‐presenting cells, uniquely capable to initiate primary immune responses. We have found that zymosan, but not lipopolysaccharide (LPS) stimulates murine bone marrow‐derived dendritic cells (BM‐DCs) to produce large amounts of CysLTs and LTB4 from endogenous substrates. A selective inhibitor of leukotriene synthesis MK886 as well as an antagonist of the high affinity LTB4 receptor (BLT1) U‐75302 slightly inhibited zymosan‐, but not LPS‐stimulated interleukin (IL)‐10 release from BM‐DCs. In contrast, U‐75302 increased zymosan‐stimulated release of IL‐12 p40 by ∼23%. Pre‐treatment with transforming growth factor‐β1 enhanced both stimulated leukotriene synthesis and the inhibitory effect of U‐75302 and MK886 on IL‐10 release from DCs. Consistent with the effects of leukotriene antagonists, exogenous LTB4 enhanced LPS‐stimulated IL‐10 release by ∼39% and inhibited IL‐12 p40 release by ∼22%. Both effects were mediated by the BLT1 receptor. Ligands of the high affinity CysLTs receptor (CysLT1), MK‐571 and LTD4 had little or no effect on cytokine release. Agonists of the nuclear LTB4 receptor peroxisome proliferator‐activated receptor‐α, 8(S)‐hydroxyeicosatetraenoic acid and 5,8,11,14‐eicosatetraynoic acid, inhibited release of both IL‐12 p40 and IL‐10. Our results indicate that both autocrine and paracrine leukotrienes may modulate cytokine release from DCs, in a manner that is consistent with previously reported T helper 2‐polarizing effects of leukotrienes.