Essential role of IFNbeta and CD38 in TNFalpha-induced airway smooth muscle hyper-responsiveness.
We recently identified autocrine interferon (IFN)beta as a novel mechanism mediating tumor necrosis factor (TNF)alpha-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 IFNbeta in regulating TNFalpha-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 TNFalpha-induced enhanced contractile responses to carbachol and bradykinin was abrogated by neutralizing anti-IFNbeta antibody or in tracheal rings deficient in CD38. In cultured human ASM cells, where CD38 has been involved in TNFalpha-induced enhanced calcium signals to carbachol and bradykinin, we found that neutralizing anti-IFNbeta prevented TNFalpha 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 IFNbeta 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 IFNbeta and CD38 may play a significant role in the development of TNFalpha-associated AHR.
Pulmonary and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Deepika
D
Jain
Stefan
S
Keslacy
Omar
O
Tliba
Yang
Y
Cao
Sonja
S
Kierstein
Kunjlata
K
Amin
Reynold A
RA
Panettieri
Angela
A
Haczku
Yassine
Y
Amrani
D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000276:immunology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000276:immunology / Q000378:metabolism*; D014132:Trachea; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D002217:Carbachol; D051997:ADP-ribosyl Cyclase 1; D001920:Bradykinin; D002118:Calcium