IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle

Abstract

In testing the hypothesis that interleukin-4 receptor alpha-subunit (IL-4R alpha)-coupled signaling mediates altered airway smooth muscle (ASM) responsiveness in the atopic sensitized state, isolated rabbit tracheal ASM segments were passively sensitized with immunoglobulin E (IgE) immune complexes, both in the absence and presence of an IL-4R alpha blocking antibody (anti-IL-4R alpha Ab). Relative to control ASM, IgE-sensitized tissues exhibited enhanced isometric constrictor responses to administered ACh and attenuated relaxation responses to isoproterenol. These proasthmatic-like effects were prevented in IgE-sensitized ASM that were pretreated with anti-IL-4R alpha Ab. In complementary experiments, IgE-sensitized cultured human ASM cells exhibited upregulated expression of IL-13 mRNA and protein, whereas IL-4 expression was undetected. Moreover, extended studies demonstrated that 1) exogenous IL-13 administration to naïve ASM elicited augmented contractility to ACh and impaired relaxation to isoproterenol, 2) these effects of IL-13 were prevented by pretreating the tissues with an IL-5 receptor blocking antibody, and 3) IL-13 administration induced upregulated mRNA expression and release of IL-5 protein from cultured ASM cells. Collectively, these findings provide new evidence demonstrating that the altered responsiveness of IgE-sensitized ASM is largely attributed to activation of an intrinsic Th2-type autocrine mechanism involving IL-13/IL-4R alpha-coupled release and action of IL-5 in the sensitized ASM itself.

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

“…Both IL-4 and IL-13 can be detected in intestinal smooth muscle during nematode infection (40) and are required, with STAT-6, to induce muscle contractility, a putative host mechanism for parasite expulsion (40,41). Likewise, airway smooth muscle can produce IL-13 and has been linked to an autocrine pathway inducing smooth muscle hypertrophy, a feature of asthma pathophysiology (42). Moreover, a gene array study by Lee et al (43) has highlighted vast numbers of distinctive genes that are switched on following IL-13 treatment of lung epithelial cells, fibroblasts, and smooth muscle cells.…”

Contribution of Antigen-Primed CD8+ T Cells to the Development of Airway Hyperresponsiveness and Inflammation Is Associated with IL-13

“…Several cell types produce IL-13, including Th2-type cells, mast cells, airway smooth muscle cells, NK cells, and NK T cells; some have been implicated in the development of AHR (41,42,48,49). Although we have shown that CD8 ϩ T cells produce IL-13, it is also possible that CD8 ϩ T cells may not only produce IL-13 but also induce another cell type to release IL-13 for the full development of AHR.…”

Subtypes of Asthma Defined by Epithelial Cell Expression of Messenger RNA and MicroRNA

“…Ultimately, these processes lead to helper T type 2 (Th2) cell differentiation and further production of the Th2 cytokines IL-4, IL-5, and IL-13 (4-6), and memory T and B cells are generated that can lead to chronic inflammation. Much of the remodeling and dysfunction in resident lung cells that are associated with asthma can be reproduced by IL-13 exposure, including goblet cell metaplasia (7), subepithelial fibrosis (8), and airway hyperresponsiveness (9)(10)(11)(12). IL-4 can mimic many of the effects of IL-13 and is thought particularly important in IgE class switching by B cells.…”