title: TWEAK promotes peritoneal inflammation.
abstract: Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing peritonitis. An improved understanding of the molecular contributors to peritoneal injury and defense may increase the therapeutic armamentarium to optimize peritoneal defenses while minimizing peritoneal injury. There is no information on the expression and function of the cytokine TWEAK and its receptor Fn14 during peritoneal injury. Fn14 expression and soluble TWEAK levels were measured in human PD peritoneal effluent cells or fluids with or without peritonitis. Fn14 expression was also analyzed in peritoneal biopsies from PD patients. Actions of intraperitoneal TWEAK were studied in mice in vivo. sTWEAK levels were increased in peritoneal effluent in PD peritonitis. Effluent sTWEAK levels correlated with the number of peritoneal macrophages (r=0.491, p=0.002). Potential TWEAK targets that express the receptor Fn14 include mesothelial cells and macrophages, as demonstrated by flow cytometry of peritoneal effluents and by analysis of peritoneal biopsies. Peritoneal biopsy Fn14 correlated with mesothelial injury, fibrosis and inflammation, suggesting a potential deleterious effect of TWEAK/Fn14. In this regard, intraperitoneal TWEAK administration to mice promoted peritoneal inflammation characterized by increased peritoneal effluent MCP-1, Fn14 and Gr1+ macrophages, increased mesothelial Fn14, MCP-1 and CCL21 expression and submesothelial tissue macrophage recruitment. Taken together these data suggest that the TWEAK/Fn14 system may promote inflammation and tissue injury during peritonitis and PD.
authors.affiliation: Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain; REDinREN, Madrid, Spain.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Sanz
authors.affiliation: Department of Immunology, Instituto de Investigación Biomédica de Vigo (IBIV), Vigo, Pontevedra, Spain.
authors.forename: Luiz Stark
authors.initials: LS
authors.lastname: Aroeira
authors.affiliation: Department of Nephrology, IDIPAZ, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Bellon
authors.affiliation: Department of Nephrology, IDIPAZ, Madrid, Spain; REDinREN, Madrid, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: del Peso
authors.affiliation: Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Jimenez-Heffernan
authors.affiliation: Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Santamaria
authors.affiliation: Department of Nephrology, IDIPAZ, Madrid, Spain; REDinREN, Madrid, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.affiliation: Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.affiliation: REDinREN, Madrid, Spain; Centro Biologia Molecular Severo Ochoa, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Lopez-Cabrera
authors.affiliation: Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain; REDinREN, Madrid, Spain; Universidad Autonoma de Madrid, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain; Universidad Autonoma de Madrid, Madrid, Spain; IRSIN, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Department of Nephrology, IDIPAZ, Madrid, Spain; REDinREN, Madrid, Spain; Universidad Autonoma de Madrid, Madrid, Spain; IRSIN, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Selgas
authors.affiliation: Laboratory of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain; REDinREN, Madrid, Spain; Universidad Autonoma de Madrid, Madrid, Spain; IRSIN, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D000074049:Cytokine TWEAK; D005260:Female; D015870:Gene Expression; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000378:metabolism; D016908:Gram-Positive Bacterial Infections / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000628:therapy; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010530:Peritoneal Dialysis; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000502:physiology*
chemical_list: D018925:Chemokines; D000074049:Cytokine TWEAK; D018836:Inflammation Mediators; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors