Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse model of chronic pancreatitis.

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)-?B, in different cell types during development of CP in mice.RelA/p65 was functionally inactivated in the pancreas (rela?panc), in myeloid cells (rela?mye), or both (rela?panc,?mye) 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.In contrast to their relaF/F littermates, rela?panc displayed typical signs of CP after long-term stimulation with cerulein. Numerous macrophages and activated ?-smooth muscle actin (SMA)-positive PSCs were detected. Additional inactivation of RelA/p65 in myeloid cells (rela?panc,?mye) 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.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.     «

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)-?B, in different cell types during development of CP in mice.RelA/p65 was functionally inactivated in the pancreas (rela?panc), in myeloid cells (rela?mye), or both (rela?panc,?mye) compartments using the Cre-loxP strategy. Experimental CP was induced with repetitive injections of cerulein o...     »