| First Author | Buck M | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 10 | Pages | e25497 |
| PubMed ID | 21998664 | Mgi Jnum | J:178116 |
| Mgi Id | MGI:5297309 | Doi | 10.1371/journal.pone.0025497 |
| Citation | Buck M, et al. (2011) C/EBPbeta-Thr217 phosphorylation signaling contributes to the development of lung injury and fibrosis in mice. PLoS One 6(10):e25497 |
| abstractText | BACKGROUND: Although C/EBPbeta(ko) mice are refractory to Bleomycin-induced lung fibrosis the molecular mechanisms remain unknown. Here we show that blocking the ribosomal S-6 kinase (RSK) phosphorylation of the CCAAT/Enhancer Binding Protein (C/EBP)-beta on Thr217 (a RSK phosphoacceptor) with either a single point mutation (Ala217), dominant negative transgene or a blocking peptide containing the mutated phosphoacceptor ameliorates the progression of lung injury and fibrosis induced by Bleomycin in mice. METHODOLOGY/PRINCIPAL FINDINGS: Mice expressing the non-phosphorylatable C/EBPbeta-Ala217 transgene had a marked reduction in lung injury on day-13 after Bleomycin exposure, compared to C/EBPbeta(wt) mice, judging by the decrease of CD68(+) activated monocytes/macrophages, bone marrow-derived CD45(+) cells and lung cytokines as well as by the normal surfactant protein-C expression by lung pneumocytes. On day-21 after Bleomycin treatment, C/EBPbeta(wt) mice but not mice expressing the dominant negative C/EBPbeta-Ala217 transgene developed severe lung fibrosis as determined by quantitative collagen assays. All mice were of identical genetic background and back-crossed to the parental wild-type inbreed FVB mice for at least ten generations. Treatment of C/EBPbeta(wt) mice with a cell permeant, C/EBPbeta peptide that inhibits phosphorylation of C/EBPbeta on Thr217 (40 microg instilled intracheally on day-2 and day-6 after the single Bleomycin dose) also blocked the progression of lung injury and fibrosis induced by Bleomycin. Phosphorylation of human C/EBPbeta on Thr266 (human homologue phosphoacceptor) was induced in collagen-activated human lung fibroblasts in culture as well as in activated lung fibroblasts in situ in lungs of patients with severe lung fibrosis but not in control lungs, suggesting that this signaling pathway may be also relevant in human lung injury and fibrosis. CONCLUSIONS/SIGNIFICANCE: These data suggest that the RSK-C/EBPbeta phosphorylation pathway may contribute to the development of lung injury and fibrosis. |
