title: Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse model of chronic pancreatitis.
abstract: OBJECTIVE
  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 (relaΔpanc), in myeloid cells (relaΔmye), or both (relaΔpanc,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 relaF/F littermates, relaΔpanc 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 (relaΔpanc,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.
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Treiber
authors.forename: Patrick
authors.initials: P
authors.lastname: Neuhöfer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Anetsberger
authors.forename: Henrik
authors.initials: H
authors.lastname: Einwächter
authors.forename: Marina
authors.initials: M
authors.lastname: Lesina
authors.forename: Mariana
authors.initials: M
authors.lastname: Rickmann
authors.forename: Song
authors.initials: S
authors.lastname: Liang
authors.forename: Timo
authors.initials: T
authors.lastname: Kehl
authors.forename: Hassan
authors.initials: H
authors.lastname: Nakhai
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D002108:Ceruletide; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D005353:Fibronectins; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C544013:alpha-smooth muscle actin, mouse; D002108:Ceruletide; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10