Essential role of IFN β and CD38 in TNF α-induced airway smooth muscle hyper-responsiveness

Abstract

We recently identified autocrine interferon (IFN) β as a novel mechanism mediating tumor necrosis factor (TNF) α-induced expression of inflammatory genes in airway smooth muscle (ASM) cells, including CD38, known to regulate calcium signaling. Here, we investigated the putative involvement of IFN β in regulating TNF α-induced airway hyper-responsiveness (AHR), a defining feature of asthma. Using our pharmacodynamic model to assess ex vivo AHR isolated murine tracheal rings, we found that TNF α-induced enhanced contractile responses to carbachol and bradykinin was abrogated by neutralizing anti-IFN β antibody or in tracheal rings deficient in CD38. In cultured human ASM cells, where CD38 has been involved in TNF α-induced enhanced calcium signals to carbachol and bradykinin, we found that neutralizing anti-IFN β prevented TNF α enhancing action only on carbachol responses but not to that induced by bradykinin. In a well-characterized model of allergic asthma (mice sensitized and challenged with Aspergillus fumigatus ( Af)), we found heightened expression of both IFN β and CD38 in the airways. Furthermore, allergen-associated AHR to methacholine, assessed by lung resistance and dynamic compliance, was completely suppressed in CD38-deficient mice, despite the preservation of airway inflammation. These data provide the first evidence that ASM-derived IFN β and CD38 may play a significant role in the development of TNF α-associated AHR.