Gastroenterology (New York, N.Y. 1943), 2011-10, Vol.141 (4), p.1473-1485.e7
2011
Details
- Autor(en) / Beteiligte
- Titel
- Myeloid, but Not Pancreatic, RelA/p65 Is Required for Fibrosis in a Mouse Model of Chronic Pancreatitis
- Ist Teil von
- Gastroenterology (New York, N.Y. 1943), 2011-10, Vol.141 (4), p.1473-1485.e7
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Quelle
- Alma/SFX Local Collection
- Beschreibungen/Notizen
- Background & Aims Little is known about how transcription factors might regulate pathogenesis of chronic pancreatitis (CP). We analyzed the in vivo role of RelA/p65, a component of the transcription factor nuclear factor (NF)-κB, in different cell types during development of CP in mice. Methods RelA/p65 was functionally inactivated in the pancreas ( rela Δpanc), in myeloid cells ( rela Δmye), or both ( rela Δpanc,Δmye) compartments using the Cre- loxP strategy. Experimental CP was induced with repetitive injections of cerulein over 6 weeks. Pancreata were investigated histologically and biochemically. We created an in vitro coculture assay of pancreatic stellate cells (PSC) and macrophages and performed gene arrays from pancreata and macrophages with functionally inactivated RelA/p65. Tissue samples from patients with CP were analyzed for matrix metalloproteinase (MMP) 10 expression. Results In contrast to their rela F/F littermates, rela Δpanc displayed typical signs of CP after long-term stimulation with cerulein. Numerous macrophages and activated α-smooth muscle actin (SMA)-positive PSCs were detected. Additional inactivation of RelA/p65 in myeloid cells ( rela Δpanc,Δmye) attenuated fibrosis. In vitro, RelA/p65-deficient, lipopolysaccharide (LPS)-stimulated macrophages degraded fibronectin in cocultured PSCs. Using gene expression analysis, MMP-10 was identified as a candidate for this process. Recombinant MMP-10 degraded fibronectin in LPS-stimulated PSCs. In tissue samples from patients with CP, MMP-10 was up-regulated in myeloid cells. Conclusions RelA/p65 functions in myeloid cells to promote pathogenesis of CP. In acinar cells, RelA/p65 protects against chronic inflammation, whereas myeloid RelA/p65 promotes fibrogenesis. In macrophage, MMP-10 functions as a RelA/p65-dependent, potentially antifibrogenic factor during progression of CP.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0016-5085eISSN: 1528-0012DOI: 10.1053/j.gastro.2011.06.087Titel-ID: cdi_proquest_miscellaneous_896395691
- Format
- –
- Schlagworte
- Actins - metabolism, Animals, Case-Control Studies, Cells, Cultured, Ceruletide, Coculture Techniques, Disease Models, Animal, Expression Profile, Fibronectins - metabolism, Fibrosis, Gastroenterology and Hepatology, Genetics, Humans, Immune Regulation, Lipopolysaccharides - pharmacology, Macrophages - drug effects, Macrophages - metabolism, Macrophages - pathology, Matrix Metalloproteinase 10 - metabolism, Mice, Mice, Knockout, Microarray Analysis, Myeloid Cells - metabolism, Myeloid Cells - pathology, Pancreas - metabolism, Pancreas - pathology, Pancreatic Stellate Cells - metabolism, Pancreatic Stellate Cells - pathology, Pancreatitis, Chronic - chemically induced, Pancreatitis, Chronic - genetics, Pancreatitis, Chronic - metabolism, Pancreatitis, Chronic - pathology, Time Factors, Transcription Factor RelA - deficiency, Transcription Factor RelA - genetics, Transcription Factor RelA - metabolism