Essential role of IFNβ and CD38 in TNFα-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 IFNβ in regulating TNFα-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 TNFα-induced enhanced contractile responses to carbachol and bradykinin was abrogated by neutralizing anti-IFNβ antibody or in tracheal rings deficient in CD38. In cultured human ASM cells, where CD38 has been involved in TNFα-induced enhanced calcium signals to carbachol and bradykinin, we found that neutralizing anti-IFNβ prevented TNFα 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 IFNβ 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 IFNβ and CD38 may play a significant role in the development of TNFα-associated AHR.

Dissociation of FK506-Binding Protein 12.6 kD from Ryanodine Receptor in Bronchial Smooth Muscle Cells in Airway Hyperresponsiveness in Asthma

“…KBP12.6 overexpression prevented the decrease in the association of FKBP12.6 with RyR2 induced by asthmatic serum (Figures 4C and 4D) and by IL-5, IL-13, and TNF-a ( Figures 4E and 4F), indicating that the decrease in the association of FKBP12.6 with RyR2 induced by asthmatic serum, IL-5, IL-13, and TNF-a is caused by a decrease in FKBP12. 6 5A and 5B) and with IL-5, IL-13, and TNF-a ( Figures 5C and 5D). These results indicate that asthmatic serum-, IL-5-, IL-13-, and TNF-a-induced decrease in the association of FKBP12.6 with RyR2 is responsible for the increase in calcium response of BSMCs to bradykinin.…”

Group 2 innate lymphoid cells mediate ozone-induced airway inflammation and hyperresponsiveness in mice

“…Airway hyperresponsiveness to aerosolized acetyl-β-methylcholine chloride methacholine (MCh) inhalation was assessed using the FlexiVent system (SCIREQ, Montreal, Canada) as described before 23 . Briefly, lung mechanics were studied in tracheostomized mice under anesthesia by intra-peritoneal injection of ketamine and xylazine.…”

Asthmatic airway hyperresponsiveness: the ants in the tree

“…A classic example is tumor necrosis factor (TNF) a, which has been shown to increase ASM contractility to the spasmogens histamine, leukotriene D 4 , bradykinin, des-Arg 9 -bradykinin, serotonin, neurokinin A, the tromboxane A 2 analog U46619, and the muscarinic agonists acetylcholine, methacholine, and carbachol. TNFa is actually used by a few groups as an ex vivo model of AHR [24,25]. IL-1b is another classic example of a molecule shown to increase ASM contractility to several spasmogens, such as bradykinin, des-Arg 9 -bradykinin, substance P, serotonin, neurokinin A, and the muscarinic agonists acetylcholine and methacholine.…”