Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness

Deepika Jain, Stefan Keslacy, Omar Tliba, Yang Cao, Sonja Kierstein, Kunjlata Amin, Reynold A. Panettieri, Angela Franciska Haczku, Yassine Amrani

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)499-509
Number of pages11
JournalImmunobiology
Volume213
Issue number6
DOIs
StatePublished - Jul 10 2008
Externally publishedYes

Keywords

  • Airway smooth muscle
  • Allergic asthma
  • Calcium signaling
  • Cytokine
  • Hypercontractility
  • Inflammation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Hematology

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  • Cite this

    Jain, D., Keslacy, S., Tliba, O., Cao, Y., Kierstein, S., Amin, K., Panettieri, R. A., Haczku, A. F., & Amrani, Y. (2008). Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness. Immunobiology, 213(6), 499-509. https://doi.org/10.1016/j.imbio.2007.12.002