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

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journal contribution
posted on 16.09.2008, 14:51 by Deepika Jain, Stefan Keslacy, Omar Tliba, Yang Cao, Sonja Kierstein, Kunjalata Amin, Reynold A. Jr. Panettieri, Angela Haczku, Yassine Amrani
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.

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Citation

Immunobiology, 2008, 213 (6), pp. 499-509.

Published in

Immunobiology

Publisher

Elsevier

issn

0171-2985

Copyright date

2008

Available date

16/09/2008

Publisher version

http://www.sciencedirect.com/science/article/pii/S0171298507001714

Language

en

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