@Article{ecn.2009.0156,
AUTHOR = {Yaping Zhang, Cang-Bao Xu, Lars-Olaf Cardell},
TITLE = {Long-term exposure to IL-1β enhances Toll-IL-1 receptor-mediated inflammatory signaling in murine airway hyperresponsiveness},
JOURNAL = {European Cytokine Network},
VOLUME = {20},
YEAR = {2009},
NUMBER = {3},
PAGES = {148--156},
URL = {http://www.techscience.com/ECN/v20n3/65901},
ISSN = {1952-4005},
ABSTRACT = {Toll-interleukin-1 (Toll-IL-1) receptor signaling may play a key role in the development of airway
hyperreactivity (AHR) and chronic airway inflammatory diseases such as asthma. Previously, we have demon-strated
that pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), induce
AHR. However, the underlying intracellular signaling mechanisms that lead to AHR remain elusive. In order
to see if the Toll-IL-1 receptor-mediated inflammatory signal pathways are involved in the development of
AHR, the present study was designed to use a real-time PCR array, a sensitive and powerful tool, consisting of
84 genes related to Toll-IL-1 receptor signal pathways. Murine tracheal segments were organ cultured for four
days in the presence and absence of IL-1β. The Toll-IL-1 receptor-mediated inflammatory signal gene profile
was studied using the real-time PCR-based cDNA array. The key gene expressions that were altered were veri-fied
by immunohistochemistry using confocal microscopy. Tracheal ring segment contractile responsiveness to
the inflammatory mediator bradykinin was monitored using a sensitive myograph system. The results showed
that after exposed to IL-1β for four days, the tracheal segments exhibited increased mRNA expression of 67
genes (out of the 84 genes in the array), although expression reached statistical significance for only 16 of these
genes. There were 14 genes that showed only a tendency towards a decrease in mRNA expression following
IL-1β treatment. Immunohistochemistry confirmed that protein expression for CD14, RP105, MCP-1 and phos-phorylated
IκB-α were increased in both the airway epithelial and smooth muscle cells. In order to link the acti-vation
of Toll-IL-1 receptor-mediated inflammatory signal mechanisms to the AHR, the anti-inflammatory drug
dexamethasone, was used. Dexamethasone not only completely abolished the IL-1β-induced AHR to bradykinin,
but also abrogated the increased mRNA expression for inflammatory mediators, IL-6, IFN-γ and Cox-2. In con-clusion,
long-term exposure of murine airway to IL-1β induces up- and down-regulation of mRNA expression
for Toll-IL-1 receptor signal molecules, with a significant increase in the expression of 16 genes that contribute
to the development of airway inflammation and AHR. Understanding cytokine-induced activation of the Toll-IL-1
receptor-mediated inflammatory signaling mechanisms may provide new options for the treatment of air-way
inflammation and AHR.},
DOI = {10.1684/ecn.2009.0156}
}