title: A pro-fibrotic role for interleukin-4 in cardiac pressure overload.
abstract: OBJECTIVE
  The mechanisms underlying cardiac fibrosis in hypertension are yet to be defined, although inflammatory cells, fibroblasts, and cytokines have been implicated. Here, we investigated the role of interleukin-4 (IL-4) in cardiac fibrosis, which is elevated in the hypertensive heart. IL-4 has been shown to be pro-fibrotic in the liver and the lung, but its role in cardiac fibrosis has not been investigated.
  
  
  RESULTS
  Cardiac fibrosis was induced in mice by constricting the aorta between the two carotid arteries. Fourteen days later marked left ventricular fibrosis developed together with expression of IL-4. Anti-IL-4 neutralizing antibodies attenuated this fibrosis without affecting blood pressure or expression of the transforming growth factor-beta system. The reduction in fibrosis was associated with reductions in interstitial fibroblasts and macrophages together with reductions in proliferating cells and expression of monocyte chemoattractant protein-1 (MCP-1). Since mast cells are a source of IL-4, we also assessed their role in fibrosis. Cromolyn, a mast cell inhibitor attenuated mast cell degranulation as well as IL-4 mRNA expression and cardiac fibrosis without affecting blood pressure. Treatment with Cromolyn also reduced interstitial fibroblasts and macrophages in regions of developing fibrosis as well MCP-1 expression.
  
  
  CONCLUSIONS
  This study demonstrates for the first time that IL-4, most likely produced by mast cells in the heart during pressure overload, is a significant contributor to cardiac fibrosis. Targeting this cytokine may be a useful therapeutic strategy to limit cardiac fibrosis.
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, BakerIDI Heart and Diabetes Institute, St Kilda Road Central, Melbourne, VIC 8008, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kanellakis
authors.forename: Michael
authors.initials: M
authors.lastname: Ditiatkovski
authors.forename: Gina
authors.initials: G
authors.lastname: Kostolias
authors.forename: Alexander
authors.initials: A
authors.lastname: Bobik
mesh_terms: D000818:Animals; D001017:Aortic Coarctation / Q000209:etiology; D049109:Cell Proliferation; D005355:Fibrosis; D006973:Hypertension / Q000473:pathology*; D015847:Interleukin-4 / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D015847:Interleukin-4