A non-BRICHOS surfactant protein c mutation disrupts epithelial cell function and intercellular signaling
| Autor: | Beers Michael F, Mulugeta Surafel, Liebisch Gerhard, Hartl Dominik, Hector Andreas, Thurm Tobias, Kern Sunčana, Sparr Christiane, Woischnik Markus, Schmitz Gerd, Griese Matthias |
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| Jazyk: | angličtina |
| Předmět: |
CD4-Positive T-Lymphocytes
Calnexin Receptors CCR2 610 Medizin Pulmonary Surfactant-Associated Protein C/metabolism Methylprednisolone Calreticulin/metabolism Receptors Interleukin-8A Cell Line Mice Azathioprine Animals Humans Lung Diseases Interstitial/drug therapy HSP70 Heat-Shock Proteins HSP90 Heat-Shock Proteins lcsh:QH573-671 Methylprednisolone/therapeutic use Cyclophosphamide ddc:610 lcsh:Cytology Calnexin/metabolism Epithelial Cells HSP70 Heat-Shock Proteins/metabolism Receptors CCR2/metabolism Cell Biology respiratory system Pulmonary Surfactant-Associated Protein C Epithelial Cells/metabolism Receptors Interleukin-8A/metabolism Amino Acid Substitution Cyclophosphamide/therapeutic use Hydroxychloroquine/therapeutic use Mutation Phosphatidylcholines CD4-Positive T-Lymphocytes/immunology Phosphatidylcholines/metabolism HSP90 Heat-Shock Proteins/metabolism Calreticulin Lung Diseases Interstitial Azathioprine/therapeutic use Bronchoalveolar Lavage Fluid Research Article Hydroxychloroquine Signal Transduction |
| Zdroj: | BMC Cell Biology BMC Cell Biology, Vol 11, Iss 1, p 88 (2010) |
| ISSN: | 1471-2121 |
| DOI: | 10.1186/1471-2121-11-88 |
| Popis: | Background Heterozygous mutations of SFTPC, the gene encoding surfactant protein C (SP-C), cause sporadic and familial interstitial lung disease (ILD) in children and adults. The most frequent SFTPC mutation in ILD patients leads to a threonine for isoleucine substitution at position 73 (I73T) of the SP-C preprotein (proSP-C), however little is known about the cellular consequences of SP-CI73T expression. Results To address this, we stably expressed SP-CI73T in cultured MLE-12 alveolar epithelial cells. This resulted in increased intracellular accumulation of proSP-C processing intermediates, which matched proSP-C species recovered in bronchial lavage fluid from patients with this mutation. Exposure of SP-CI73T cells to drugs currently used empirically in ILD therapy, cyclophosphamide, azathioprine, hydroxychloroquine or methylprednisolone, enhanced expression of the chaperones HSP90, HSP70, calreticulin and calnexin. SP-CI73T mutants had decreased intracellular phosphatidylcholine level (PC) and increased lyso-PC level without appreciable changes of other phospholipids. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-CI73T cells secreted into the medium soluble factors that modulated surface expression of CCR2 or CXCR1 receptors on CD4+ lymphocytes and neutrophils, suggesting a direct paracrine influence of SP-CI73T on neighboring cells in the alveolar space. Conclusion We show that I73T mutation leads to impaired processing of proSP-C in alveolar type II cells, alters their stress tolerance and surfactant lipid composition, and activates cells of the immune system. In addition, we show that some of the mentioned cellular aspects behind the disease can be modulated by application of pharmaceutical drugs commonly applied in the ILD therapy. |
| Databáze: | OpenAIRE |
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