title: Tumor necrosis factor: a mechanistic link between angiotensin-II-induced cardiac inflammation and fibrosis.
abstract: BACKGROUND
  Continuous angiotensin-II infusion induced the uptake of monocytic fibroblast precursors that initiated the development of cardiac fibrosis; these cells and concurrent fibrosis were absent in mice lacking tumor necrosis factor receptor 1 (TNFR1). We now investigated their cellular origin and temporal uptake and the involvement of TNFR1 in monocyte-to-fibroblast differentiation.
  
  
  RESULTS
  Within a day, angiotensin-II induced a proinflammatory environment characterized by production of inflammatory chemokines, cytokines, and TH1-interleukins and uptake of bone marrow-derived M1 cells. After a week, the cardiac environment changed to profibrotic with growth factor and TH2-interleukin synthesis, uptake of bone marrow-derived M2 cells, and the presence of M2-related fibroblasts. TNFR1 signaling was not necessary for early M1 uptake, but its absence diminished the amount of M2 cells. TNFR1-knockout hearts also showed reduced levels of cytokine expression, but not of TH-related lymphokines. Reconstitution of wild-type bone marrow into TNFR1-knockout mice was sufficient to restore M2 uptake, upregulation of proinflammatory and profibrotic genes, and development of fibrosis in response to angiotensin-II. We also developed an in vitro mouse monocyte-to-fibroblast maturation assay that confirmed the essential role of TNFR1 in the sequential progression of monocyte activation and fibroblast formation.
  
  
  CONCLUSIONS
  Development of cardiac fibrosis in response to angiotensin-II was mediated by myeloid precursors and consisted of 2 stages. A primary M1 inflammatory response was followed by a subsequent M2 fibrotic response. Although the first phase seemed to be independent of TNFR1 signaling, the later phase (and development of fibrosis) was abrogated by deletion of TNFR1.
authors.affiliation: From the Division of Cardiovascular Sciences (C.D., J.T., M.L.E., S.B.H.) and Division of Nephrology (Y.W.), Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Clemens
authors.initials: C
authors.lastname: Duerrschmid
authors.affiliation: From the Division of Cardiovascular Sciences (C.D., J.T., M.L.E., S.B.H.) and Division of Nephrology (Y.W.), Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Trial
authors.affiliation: From the Division of Cardiovascular Sciences (C.D., J.T., M.L.E., S.B.H.) and Division of Nephrology (Y.W.), Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Division of Cardiovascular Sciences (C.D., J.T., M.L.E., S.B.H.) and Division of Nephrology (Y.W.), Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.affiliation: From the Division of Cardiovascular Sciences (C.D., J.T., M.L.E., S.B.H.) and Division of Nephrology (Y.W.), Department of Medicine, Baylor College of Medicine, Houston, TX. shaudek@bcm.edu.
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Haudek
mesh_terms: D000804:Angiotensin II / Q000276:immunology*; D000818:Animals; D054443:Cell Migration Assays; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000473:pathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II
keywords: angiotensins; blood cells; collagen; inflammation; ventricular remodeling