Pro-asthmatic cytokines regulate unliganded and ligand-dependent glucocorticoid receptor signaling in airway smooth muscle

To elucidate the regulation of glucocorticoid receptor (GR) signaling under pro-asthmatic conditions, cultured human airway smooth muscle (HASM) cells were treated with proinflammatory cytokines or GR ligands alone and in combination, and then examined for induced changes in ligand-dependent and -independent GR activation and downstream signaling events. Ligand stimulation with either cortisone or dexamethsone (DEX) acutely elicited GR translocation to the nucleus and, comparably, ligand-independent stimulation either with the Th2 cytokine, IL-13, or the pleiotropic cytokine combination, IL-1β/TNFα, also acutely evoked GR translocation. The latter response was potentiated by combined exposure of cells to GR ligand and cytokine. Similarly, treatment with either DEX or IL-13 alone induced GR phosphorylation at its serine-211 residue (GRSer211), denoting its activated state, and combined treatment with DEX+IL-13 elicited heightened and sustained GRSer211phosphorylation. Interestingly, the above ligand-independent GR responses to IL-13 alone were not associated with downstream GR binding to its consensus DNA sequence or GR transactivation, whereas both DEX-induced GR:DNA binding and transcriptional activity were significantly heightened in the presence of IL-13, coupled to increased recruitment of the transcriptional co-factor, MED14. The stimulated GR signaling responses to DEX were prevented in IL-13-exposed cells wherein GRSer211 phosphorylation was suppressed either by transfection with specific serine phosphorylation-deficient mutant GRs or treatment with inhibitors of the MAPKs, ERK1/2 and JNK. Collectively, these novel data highlight a heretofore-unidentified homeostatic mechanism in HASM cells that involves pro-asthmatic cytokine-driven, MAPK-mediated, non-ligand-dependent GR activation that confers heightened glucocorticoid ligand-stimulated GR signaling. These findings raise the consideration that perturbations in this homeostatic cytokine-driven GR signaling mechanism may be responsible, at least in part, for the insensirtivity to glucocorticoid therapy that is commonly seen in individuals with severe asthma

Suppression of LO phonon scattering in Landau quantized quantum dots

Picosecond time-resolved far-infrared measurements are presented of the scattering between conduction-band states in a doped quasi quantum dot. These states are created by the application of a magnetic field along the growth direction of an InAs/AlSb quantum well. A clear suppression of the cooling rate is seen, from 1012 s-1 when the level spacing is equal to the phonon energy, to 1010 s-1 away from this resonance, and thus the results provide unambiguous evidence for the phonon bottleneck. Furthermore, the lifetimes had only weak dependence on temperature between 4 and 80 K.</p

Suppression of LO phonon scattering in Landau quantized quantum dots

Picosecond time-resolved far-infrared measurements are presented of the scattering between conduction-band states in a doped quasi quantum dot. These states are created by the application of a magnetic field along the growth direction of an InAs/AlSb quantum well. A clear suppression of the cooling rate is seen, from 1012 s-1 when the level spacing is equal to the phonon energy, to 1010 s-1 away from this resonance, and thus the results provide unambiguous evidence for the phonon bottleneck. Furthermore, the lifetimes had only weak dependence on temperature between 4 and 80 K.</p