Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation

Abstract

The Th2 cell-dependent inflammatory response is a central component of asthma, and the ways in which it is regulated is a critical question. The cysteinyl leukotrienes (cys-LTs) are 5-lipoxygenase pathway products implicated in asthma, in particular, by their function as smooth muscle constrictors of airways and microvasculature. To elucidate additional roles for cys-LTs in the pathobiology of pulmonary inflammation, we used an OVA sensitization and challenge protocol with mice lacking leukotriene C4 synthase (LTC4S), the terminal enzyme for cys-LT generation. Ag-induced pulmonary inflammation, characterized by eosinophil infiltration, goblet cell hyperplasia with mucus hypersecretion, and accumulation and activation of intraepithelial mast cells was markedly reduced in LTC4Snull mice. Furthermore, Ag-specific IgE and IgG1 in serum, Th2 cell cytokine mRNA expression in the lung, and airway hyperresponsiveness to methacholine were significantly reduced in LTC4Snull mice compared with wild-type controls. Finally, the number of parabronchial lymph node cells from sensitized LTC4Snull mice and their capacity to generate Th2 cell cytokines ex vivo after restimulation with Ag were also significantly reduced. In contrast, delayed-type cutaneous hypersensitivity, a prototypic Th1 cell-dependent response, was intact in LTC4Snull mice. These findings provide direct evidence of a role for cys-LTs in regulating the initiation and/or amplification of Th2 cell-dependent pulmonary inflammation.

Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis

“…immunization with OVA without alum and aerosol challenge (7). In the lung model, the function of the cys-LT pathway is directed to the antigen-presenting dendritic cells (20), whereas in the EC-initiated allergic skin model, its role is downstream.…”

Cutting Edge: Interleukin 4-Dependent Mast Cell Proliferation Requires Autocrine/Intracrine Cysteinyl Leukotriene-Induced Signaling

“…In a MC-dependent model of allergic airway disease, mice lacking LTC 4 S showed diminished Th2 cytokine generation and airway inflammation as compared with identically treated wild-type controls (18). The numbers of MCs in the tracheal epithelia of allergen-challenged Ltc4s Ϫ/Ϫ mice were decreased by ϳ90% compared with wild-type control mice but were normal in the adjacent submucosa.…”

Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor

“…12 It has been shown in a murine model of pulmonary inflammation that CysLTs were required not only for antigen-induced eosinophil infiltration, goblet cell hyperplasia, and mucus hypersecretion but also for an initiation and amplification of antigen-specific T H 2-dependent inflammatory responses. 13 These effects suggest an important role for CysLTs in the regulation of adaptive immune responses, probably through dendritic cells. Interestingly, it has been shown that monocytederived dendritic cells require for differentiation multidrug resistance protein 1 (ABCC1) transporter activity, which actively transports LTC 4 out of the cell.…”