Assessment of signal transducer and activator of transcription 6 as a target of glucocorticoid action in human airway epithelial cells

Abstract

We conclude that airway epithelial STAT6 is not the central target of GC in allergic inflammation and that the inhibitory effect of GC on STAT6-mediated IL-4- and IL-13-induced responses is exerted by targeting pathways distinct from STAT6.

A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

“…As a novel piece of the molecular mechanism in A549 human lung epithelial cells, we found that CpdA, as well as DEX, interfered with the IL-4-induced nuclear accumulation of STAT6. These results are in contrast to a previous report that GCs do not target STAT6 nuclear translocation in BEAS-2B cells (36), but are in line with another report that STAT6 activity, in particular the binding to its response element, can be targeted as part of the anti-inflammatory mechanism of activated protein C (37). As such, the result we obtained may represent part of the underlying mechanism to explain the lower levels of IgE and general therapeutic antiasthmatic response of both CpdA and DEX in the animal model and emphasizes that cytokinesignaling pathways can be targeted by different GR modulators at the level of nuclear accumulation of transcription factors.…”

Glucocorticoid actions on airway epithelial responses in immunity: Functional outcomes and molecular targets

“…55 Importantly, IL-13-dependent hypersecretory changes were found to be STAT-6-dependent 58 ; in airway epithelial cells, both the expression and the activation of STAT-6 induced by IL-4 are not sensitive to glucocorticoid action. 59 In human asthma, Groneberg et al 48 found no difference in the expression and distribution of MUC5AC and MUC5B in bronchial biopsies from patients with mild asthma after a 1-month period of daily treatment with 1600 mg of the ICS budesonide.…”

“…37,38 Given the potential relevance of the EGFR signaling pathway in regulating mucin expression in innate immune responses, 68 this lack of direct glucocorticoid effect may be consistent with the hypothesis of a sparing effect of glucocorticoids on innate immunity 8 ; on the other hand, it constitutes one of the most important glucocorticoid-insensitive epithelial pathways in severe asthma. 3,38 Given the insensitivity to glucocorticoids of IL-13-induced GCH and of STAT-6 expression and activation in airway epithelium, 55,59 it can be hypothesized that glucocorticoids would not affect the IL-13-dependent and STAT-6-dependent expression of the SAM pointed domain-containing ETS transcription factor, recently identified in mouse airway epithelium in association with GCH. 69 …”

Screening for soluble expression constructs using cell-free protein synthesis

“…Both cytokines play a crucial role in the pathophysiology of asthma and allergic diseases [14,15]. Inhibition of STAT6 should reduce the common IL-4/IL-13 associated features of asthma.…”