Browsing by Subject "Matrix Metalloproteinases"

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    Airway fibroblasts in asthma manifest an invasive phenotype.
    (American journal of respiratory and critical care medicine, 2011-06) Ingram, Jennifer L; Huggins, Molly J; Church, Tony D; Li, Yuejuan; Francisco, Dave C; Degan, Simone; Firszt, Rafael; Beaver, Denise M; Lugogo, Njira L; Wang, Ying; Sunday, Mary E; Noble, Paul W; Kraft, Monica

    Rationale

    Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor (TGF)-β1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-β1 and MMPs.

    Objectives

    We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-β1 and MMPs in asthma compared with normal controls.

    Methods

    Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV(1): 90 ± 3.6% pred) and 17 normal control subjects (FEV(1): 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-β1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels.

    Measurements and main results

    IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-β1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared with normal control subjects.

    Conclusions

    IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-β1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.
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    MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction.
    (Virology, 2010-10) Nolting, Anne; Dugast, Anne-Sophie; Rihn, Suzannah; Luteijn, Rutger; Carrington, Mary F; Kane, Katherine; Jost, Stephanie; Toth, Ildiko; Nagami, Ellen; Faetkenheuer, Gerd; Hartmann, Pia; Altfeld, Marcus; Alter, Galit
    Natural killer (NK) cells play a critical role in host defense against viral infections. However chronic HIV-1 infection is associated with an accumulation of dysfunctional NK cells, that poorly control viral replication. The underlying mechanisms for this NK cell mediated dysfunction are not understood. Certain tumors evade NK cell mediated detection by dampening NK cell activity through the downregulation of NKG2D, via the release of soluble NKG2D-ligands, resulting in a potent suppression of NK cell function. Here we show that chronic HIV-1 infection is associated with a specific defect in NKG2D-mediated NK cell activation, due to reduced expression and transcription of NKG2D. Reduced NKG2D expression was associated with elevated levels of the soluble form of the NKG2D-ligand, MICA, in patient sera, likely released by HIV+CD4+ T cells. Thus, like tumors, HIV-1 may indirectly suppress NK cell recognition of HIV-1-infected CD4+ T cells by enhancing NKG2D-ligand secretion into the serum resulting in a profound impairment of NK cell function.