A Novel Role of Cysteinyl Leukotrienes to Promote Dendritic Cell Activation in the Antigen-Induced Immune Responses in the Lung

Abstract

Although the critical role of cysteinyl leukotrienes (cysLTs) in the inflammation, especially eosinophilic lung inflammation, in asthma has been well documented, their role in the early stage of Ag-specific immune response has not been completely clarified. In the present study, with a mouse model of asthma and in vitro studies we demonstrated that cysLTs potentiated dendritic cell (DC) functions such as Ag-presenting capacity and cytokine production. The cysLT-1 receptor antagonist (LTRA) strongly suppressed the activation of these DC functions and led to inhibition of subsequent not only Th2, but also Th1, responses in the early stage of immune response. Moreover, treatment with LTRA during the early stage of the immune response potently suppressed the development of Ag inhalation-induced eosinophilic airway inflammation, mucus production, and airway hyper-reactivity in vivo. Treatment with LTRA significantly increased PGE2 production in the lung, and treatment with the cyclooxygenase inhibitor indomethacin abolished LTRA’s suppressive effect on DCs and deteriorated the Th2 and Th1 responses and airway inflammation. With in vitro studies, we also confirmed that cysLTs production by DCs increased with LPS stimulation, and that LTRA directly suppressed the alloantigen-presenting capacity of DCs. These results suggested that cysLTs potentiate DC functions both in vivo and in vitro, and that LTRA could be beneficial to suppress the initial immune response in many immune-mediated disorders beyond asthma.

Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation

“…The concentration of IFN-␥ in BAL fluid was increased in mice injected with DCs pulsed with Ag plus a CysLT 1 R antagonist (54). In another pharmacologic study, the treatment of BALB/c mice with CysLT 1 R antagonists during OVA sensitization reduced the production of IL-4, IL-5, and IFN-␥ in BAL fluid without affecting the levels of OVA-specific IgE and IgG in serum (55). Lung DCs harvested from OVA-sensitized and aerosol-challenged mice treated with a CysLT 1 R antagonist during sensitization supported less OVA-specific CD4 ϩ T cell proliferation.…”

“…Lung DCs harvested from OVA-sensitized and aerosol-challenged mice treated with a CysLT 1 R antagonist during sensitization supported less OVA-specific CD4 ϩ T cell proliferation. Similarly, splenic DCs harvested from OVA-sensitized mice treated with a CysLT 1 R antagonist during sensitization supported less OVA-specific CD4 ϩ T cell proliferation and produced less IL-10 and IL-12 in response to LPS as compared with DCs from OVA-sensitized mice not treated with a CysLT 1 R antagonist (55). Finally, in a Th1 cell-biased immunization protocol, splenic DCs from mice sensitized with OVA plus CFA and treated with a CysLT 1 R antagonist also produced less IL-10 and IL-12 in response to LPS (55).…”

“…Similarly, splenic DCs harvested from OVA-sensitized mice treated with a CysLT 1 R antagonist during sensitization supported less OVA-specific CD4 ϩ T cell proliferation and produced less IL-10 and IL-12 in response to LPS as compared with DCs from OVA-sensitized mice not treated with a CysLT 1 R antagonist (55). Finally, in a Th1 cell-biased immunization protocol, splenic DCs from mice sensitized with OVA plus CFA and treated with a CysLT 1 R antagonist also produced less IL-10 and IL-12 in response to LPS (55). Thus, cys-LTs may augment DC function in a Th2-dominant manner or in both Th2-and Th1-biased immune responses in some conditions.…”

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

“…On the other hand, in allergen-pulsed DCs from spleen there was strong inhibition of both IL-10 and IL-12p70 in the presence of CysLTR1 antagonists. 62 These differences can be explained by the origin of the DCs used in each study; however, the main difference would be the nature of the stimuli used, we evaluated the effect of LTC 4 in DCs activated with LPS, a classic Toll-like receptor 4 agonist, which triggers a Th1 profile compared with the allergens that trigger Th2 responses.…”

Leukotriene pathway genetics and pharmacogenetics in allergy

“…In addition to their inflammatory effects similar to those seen in asthma, they modulate nasal allergic inflammation and clinical symptoms (especially sneezing and rhinorrhea) via activation of CYSLTR1 in nasal mucosa, in particular in vascular endothelial cells and interstitial cells (eosinophils, mast cells, macrophages and neutrophils) (39). In addition, CysLTs have been shown to participate in the process of allergic sensitisation by enhancing dendritic cell-stimulated antigen presentation (40). There is also evidence of enhanced CysLT production in the pathogenesis of atopic dermatitis (AD).…”