Proinflammatory and Th2 Cytokines Regulate the High Affinity IgE Receptor (FcεRI) and IgE-Dependant Activation of Human Airway Smooth Muscle Cells

Background: The high affinity IgE receptor (Fc epsilon RI) is a crucial structure for IgE-mediated allergic reactions. We have previously demonstrated that human airway smooth muscle (ASM) cells express the tetrameric (alpha beta gamma 2) Fc epsilon RI, and its activation leads to marked transient increases in intracellular Ca2+ concentration, release of Th-2 cytokines and eotaxin-1/CCL11. Therefore, it was of utmost importance to delineate the factors regulating the expression of Fc epsilon RI in human (ASM) cells. Methodology/Principal Findings: Incubation of human bronchial and tracheal smooth muscle (B/TSM) cells with TNF-alpha, IL-1 beta or IL-4 resulted in a significant increase in Fc epsilon RI-alpha chain mRNA expression (p<0.05); and TNF-alpha, IL-4 enhanced the Fc epsilon RI-alpha protein expression compared to the unstimulated control at 24, 72 hrs after stimulation. Interestingly, among all other cytokines, only TNF-alpha upregulated the Fc epsilon RI-gamma mRNA expression. Fc epsilon RI-gamma protein expression remained unchanged despite the nature of stimulation. Of note, as a functional consequence of Fc epsilon RI upregulation, TNF-alpha pre-sensitization of B/TSM potentially augmented the CC (eotaxin-1/CCL11 and RANTES/CCL5, but not TARC/CCL17) and CXC (IL-8/CXCL8, IP-10/CXCL10) chemokines release following IgE stimulation (p<0.05, n = 3). Furthermore, IgE sensitization of B/TSM cells significantly enhanced the transcription of selective CC and CXC chemokines at promoter level compared to control, which was abolished by Lentivirus-mediated silencing of Syk expression. Conclusions/Significance: Our data depict a critical role of B/TSM in allergic airway inflammation via potentially novel mechanisms involving proinflammatory, Th2 cytokines and IgE/Fc epsilon RI complex.