Leukotrienes modulate cytokine release from dendritic cells

Abstract

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.

Cutting Edge: Regulatory T Cells Prevent Efficient Clearance of Mycobacterium tuberculosis

“…More precisely, we observed a correlation between IL-10 and the presence of T cells, although not specifically with T reg . A possible explanation for this observation could be that other cells, like M. tuberculosis-infected dendritic cells and macrophages, express IL-10, particularly in the presence of effector T cells (20,21). Despite significant differences in protection and T cell responses, histological analyses revealed similar granuloma shape, size, and numbers between infected C57BL/6 wt and T cellreconstituted Rag1…”

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

“…23 Zymosan, a Toll-like receptor 2 agonist, but not lipopolysaccharide (LPS), a classic Toll-like receptor 4 agonist, stimulates the production of CysLT by DCs. 24,25 Despite these observations, their impact on cytokine production by DCs is unclear. In spite of the close relationship between mast cells and DCs in mucosal epithelium and skin, little progress has been made regarding the impact of CysLT on the genesis of DCs.…”

Cysteinyl-Leukotriene Receptor Type 1 Expression and Function Is Down-Regulated during Monocyte-Derived Dendritic Cell Maturation with Zymosan: Involvement of IL-10 and Prostaglandins

“…In addition, pretreatment of patients with mild asthma using a CysLT1 antagonist decreased the number of circulating myeloid DCs, demonstrating a significant role of cysLTs in DC trafficking in vivo (29). Finally, a recent study showed that LTs can modulate cytokine release from DCs (30). Despite these observations, LT receptor expression in DC has not been extensively examined.…”