title: Interferon-gamma induces chronic active myocarditis and cardiomyopathy in transgenic mice.
abstract: Chronic heart failure is associated with an activation of the immune system characterized among other factors by the cardiac synthesis and serum expression of proinflammatory cytokines. There is unequivocal clinical and experimental evidence that the cytokine tumor necrosis factor-alpha is involved in the development of chronic heart failure, but a putative cardiotoxic potential of the proinflammatory cytokine interferon (IFN)-gamma remains primarily unknown. To investigate this issue we analyzed the cardiac phenotype of SAP-IFN-gamma transgenic mice, which constitutively express IFN-gamma in their livers and hence exhibit high circulating serum levels of this cytokine. SAP-IFN-gamma mice spontaneously developed chronic active myocarditis, characterized by the infiltration of not only CD4(+) and CD8(+) T cells but also Mac2(+) (galectin 3(+)) macrophages and CD11c(+) dendritic cells, eventually culminating in cardiomyopathy. Echocardiographic analyses exhibited a left ventricular dilation and impaired systolic function induced by IFN-gamma overexpression. IFN-gamma-mediated cardiotoxicity was associated with high-level cardiac transcription of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-12 and the macrophage-attracting chemokines MCP1 and MIP1-alpha. Myotoxic IFN-gamma effects could not be detected in smooth or striated muscle tissue, suggesting cardiomyocellular specificity of the toxic IFN-gamma effect. The precise mechanism of IFN-gamma cardiotoxicity remains to be elucidated.
authors.affiliation: Central Laboratory Animal Facility, Johannes Gutenberg-University, Mainz, Germany. reifenbe@uni-mainz.de
authors.forename: Kurt
authors.initials: K
authors.lastname: Reifenberg
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
authors.forename: Gisela
authors.initials: G
authors.lastname: Steige
authors.forename: Elena
authors.initials: E
authors.lastname: Wiese
authors.forename: Ines
authors.initials: I
authors.lastname: Küpper
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Sibylle
authors.initials: S
authors.lastname: Ott
authors.forename: Petra
authors.initials: P
authors.lastname: Nusser
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Gerd
authors.initials: G
authors.lastname: Rechtsteiner
authors.forename: Tobias
authors.initials: T
authors.lastname: Warger
authors.forename: Andrea
authors.initials: A
authors.lastname: Pautz
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kleinert
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schmidt
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Löhler
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002908:Chronic Disease; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D004452:Echocardiography; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics* / Q000502:physiology; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009205:Myocarditis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000683:Serum Amyloid P-Component / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000683:Serum Amyloid P-Component; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma