muramidase and angiogenin

Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B-mediated protein sorting in the maintenance of gastrointestinal immune homeostasis.. The role of AP-1B in intestinal immunity was examined in AP-1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice.. Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease.. AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation.

Topics: Acute-Phase Proteins; Adaptor Protein Complex 1; Adaptor Protein Complex beta Subunits; Adaptor Protein Complex mu Subunits; alpha-Defensins; Animals; Antimicrobial Cationic Peptides; beta-Defensins; Cathelicidins; Cell Membrane; Cell Membrane Permeability; Colitis; Colon; Crohn Disease; Down-Regulation; Epithelial Cells; Homeostasis; Humans; Immunoglobulin A; Interleukin-17; Intestinal Mucosa; Lipocalin-2; Lipocalins; Mice; Mice, Knockout; Muramidase; Oncogene Proteins; Proteins; Receptors, Cytokine; Ribonuclease, Pancreatic; Ribonucleases; S100 Proteins; Signal Transduction; Th17 Cells; Tumor Necrosis Factor-alpha

In an earlier study we found that different forms of the v-myb oncogene transform myeloid cells which resemble either monoblasts [when v-myb of avian myeloblastosis virus (AMV) was used] or promyelocytes [when a point mutant in v-myb of AMV was used; Introna, M., Golay, J., Frampton J., Nakano, T., Ness, S.A. & Graf, T. (1990). Cell, 63, 1287-1297]. In the present study we have searched for genes expressed in AMV mutant-transformed promyelocytes that are not expressed in AMV-transformed monoblasts using a differential screening approach. Eight different genes were identified among more than 500 differentially expressed clones. The most abundant of these was the previously identified myb-regulated mim-1 gene. The others were found to encode a small calcium-binding (MRP-like) protein; the p20K protein; goose-type lysozyme; a ribonuclease A/angiogenin-related protein; and three non-identified proteins. Although these genes appear to be rather lineage restricted, their expression varied in different subtypes of transformed myelomonocytic cells, and only two of them (goose lysozyme and ribonuclease) showed a similar expression pattern in normal promyelocytes and macrophages, suggesting an aberrant gene regulation in the transformed cells. Co-transfection experiments of a reporter construct containing the promoter of the ribonuclease A-related gene indicated that this promoter is regulated by the v-Myb oncoprotein without the involvement of Myb-specific binding sequences.

Topics: Amino Acid Sequence; Avian Myeloblastosis Virus; Base Sequence; Bone Marrow; Calcium-Binding Proteins; Cell Transformation, Viral; Cloning, Molecular; DNA; Gene Expression; Macrophages; Molecular Sequence Data; Monocytes; Muramidase; Oncogene Proteins v-myb; Oncogenes; Proteins; Retroviridae Proteins, Oncogenic; Ribonuclease, Pancreatic; Ribonucleases; Sequence Alignment