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 language | English (US) |
|---|---|
| Pages (from-to) | 499-509 |
| Number of pages | 11 |
| Journal | Immunobiology |
| Volume | 213 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jul 10 2008 |
| Externally published | Yes |
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Keywords
- Airway smooth muscle
- Allergic asthma
- Calcium signaling
- Cytokine
- Hypercontractility
- Inflammation
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
- Hematology
Cite this
Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness. / Jain, Deepika; Keslacy, Stefan; Tliba, Omar; Cao, Yang; Kierstein, Sonja; Amin, Kunjlata; Panettieri, Reynold A.; Haczku, Angela Franciska; Amrani, Yassine.
In: Immunobiology, Vol. 213, No. 6, 10.07.2008, p. 499-509.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness
AU - Jain, Deepika
AU - Keslacy, Stefan
AU - Tliba, Omar
AU - Cao, Yang
AU - Kierstein, Sonja
AU - Amin, Kunjlata
AU - Panettieri, Reynold A.
AU - Haczku, Angela Franciska
AU - Amrani, Yassine
PY - 2008/7/10
Y1 - 2008/7/10
N2 - 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.
AB - 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.
KW - Airway smooth muscle
KW - Allergic asthma
KW - Calcium signaling
KW - Cytokine
KW - Hypercontractility
KW - Inflammation
UR - http://www.scopus.com/inward/record.url?scp=44349172373&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44349172373&partnerID=8YFLogxK
U2 - 10.1016/j.imbio.2007.12.002
DO - 10.1016/j.imbio.2007.12.002
M3 - Article
C2 - 18514752
AN - SCOPUS:44349172373
VL - 213
SP - 499
EP - 509
JO - Immunobiology
JF - Immunobiology
SN - 0171-2985
IS - 6
ER -