title: HMGB1 expression and secretion are increased via TWEAK-Fn14 interaction in atherosclerotic plaques and cultured monocytes.
abstract: OBJECTIVE
  High-mobility group box 1 (HMGB1), a DNA-binding cytokine expressed mainly by macrophages, contributes to lesion progression and chronic inflammation within atherosclerotic plaque. It has been suggested that different cytokines could regulate HMGB1 expression in monocytes. We have analyzed the effect of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) on HMGB1 expression both in vivo and in vitro.
  
  
  RESULTS
  Expression of TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) was positively correlated with HMGB1 in human carotid atherosclerotic plaques. TWEAK increased HMGB1 mRNA expression and protein secretion in human acute monocytic leukemia cell line cultured monocytes. TWEAK-mediated HMGB1 increase was only observed in M1 macrophages but not in M2 ones. These effects were reversed using blocking anti-Fn14 antibody or nuclear factor-kappa B and phosphotidylinositol-3 kinase inhibitors. TWEAK also increased monocyte chemoattractant protein-1 secretion in human acute monocytic leukemia cell line cells, an effect blocked with an HMGB1 small interfering RNA. Systemic TWEAK injection in ApoE(-/-) mice increased HMGB1 protein expression in the aortic root and mRNA expression in total aorta of ApoE(-/-) mice. Conversely, TWEAK-blocking antibodies diminished HMGB1 protein and mRNA expression compared with IgG-treated mice.
  
  
  CONCLUSIONS
  Our results indicate that TWEAK can regulate expression and secretion of HMGB1 in monocytes/macrophages, participating in the inflammatory response associated with atherosclerotic plaque development.
authors.affiliation: Vascular Reseach Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Moreno
authors.forename: Cristina
authors.initials: C
authors.lastname: Sastre
authors.forename: Julio
authors.initials: J
authors.lastname: Madrigal-Matute
authors.forename: Begoña
authors.initials: B
authors.lastname: Muñoz-García
authors.forename: Luis
authors.initials: L
authors.lastname: Ortega
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Jose L
authors.initials: JL
authors.lastname: Martín-Ventura
authors.forename: Luis M
authors.initials: LM
authors.lastname: Blanco-Colio
mesh_terms: D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058226:Plaque, Atherosclerotic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D000074050:TWEAK Receptor; D014162:Transfection; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D057134:Antibodies, Neutralizing; D001057:Apolipoproteins E; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D000074049:Cytokine TWEAK; D024243:HMGB1 Protein; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D058539:Phosphatidylinositol 3-Kinase